BK virus infection in renal transplant recipients: an overview
Please summarise this article.
*This article to discuss the most recent evidence addressing the virology, pathogenesis, clinical features, diagnostic tools, screening protocols, treatment strategy, and short-term and long-term renal allograft survival concerning BKV infection.
*Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
*Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people.
*BKV infection, an early complication of renal transplant, often presents within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection and poses a diagnostic and therapeutic dilemma
*Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss.
*A routine screening protocol for early recognition of asymptomatic BKV infection has been reported to result in better allograft outcomes.
*BKV-DNA genome can be divided into three parts
-The early viral gene region
-The late viral gene region (LVGR)
-The capsid protein VP1 in the LVGR is the main capsid protein present on the surface and is responsible for receptor binding to the host cells.
*BK viral replication follows a state of immune suppression; it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period.
*BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as aconsequence of intense immunosuppression
*CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
*Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies.
*There is a relationship between BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis.
*The common screening methods for BK virus: Decoy cells, Haufen, Urinary BK-PCR, Urinary BK-mRNA and Plasma BK-PCR.
*Allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction.
*Treatment of presumptive BK virus nephropathy:
-The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
-Leflunomide, Cidofovirm, TOR inhibitors, Intravenous immunoglobulin
-Other therapeutic options for treating BK virus nephropathy
Quinolones, statins, Rituximab
#Conclusion
*Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology.
*There is a bigger ‘known unknown’ that just proves the elusive nature of BKV.
*An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
What is the level of evidence provided by this article?
BK virus (BKV) often presents within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection and poses a diagnostic and therapeutic dilemma. Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss. A routine screening protocol for early recognition of asymptomatic BKV infection has been reported to result in better allograft outcomes. In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Routes of transmission of primary BK virus
(1) Respiratory route
(2) Gastrointestinal transmission
(3) Vertical transmission
(4) Sexual transmission
(5) Donor-derived infection
(6) Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK polyomavirus-associated nephropathy (BKVN)/ (PyVAN) .BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia. The estimated incidence of BKVN in different literature ranges between 2 and 15% of kidney allograft recipients.
Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years. The prevalence of ureteric stenosis is 2–6%. BKV-associated Hemorrhagic cystitis or non- Hemorrhagic cystitis is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients. Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy
BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients.
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically, whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BK viral inclusions within tubular epithelium can be identified via the conventional hematoxylin and eosin (H&E) and PAS staining . An alternative histological detection approach is through the identification of BKV via in-situ hybridization.
Treatment is with antiviral drugs which include :
Leflunomide
Cidofovir
brincidofovir
mTOR inhibitors
Intravenous immunoglobulin
Quinolones
artesunate
statins (pravastatin)
Rituximab
BKV post transplantation:
one of the major complications post transplanation is infection with BKV which portend a higher morbidity and mortality.BKV is a DNA virus that is commonly repoted in the first year post transplantation.
its causing tubulo-interstitial allograft nephropathy featuring progressive deterioration of allograft function. Its commonly encountered in the first year post transplantation.
Cell mediated immunity is keeping BKV under scrutiny and CD8 T lymphocytes are dstroying the infected cells. When cell -mediated immunity faltered by immune suppressants, BKV proliferate and produce intra neuclear and paraneuclear inclusion bodies. The explanation for increasing risk for BKV infection is absence of natural surveillance by cell-mediated immune system and lack of targeted humoral immunity against the viral infection.
BKV most portal of entry is respiratory system where it can get into circulation and stay dormant in uroepithelium. However, GIT , vertical and donor related trasfer of BKV is another reported routs.
Clinincal presentation:
1]viruria
2] BK viremia
3]BKVN
4]ureteric stenosis
5] hemorrhagic cystits
Please summarise this article.BKV, one of two human polyomaviruses discovered in 1971, was shown to induce interstitial nephritis and allograft failure in renal transplant patients three decades later. In the first year following kidney transplantation, BKV infection is one of several possible reasons of renal failure. Asymptomatic creatinine increases with tubulointerstitial nephritis may resemble acute rejection, creating a diagnostic and management conundrum. BK epidemics:
BKV—polyomavirus hominins-1—infects most persons worldwide. In immune-competent humans, the virus remains latent after early childhood infection. 60–85% of the general population is BKV-positive. The only study on BKV prevalence in the Middle East and Africa came from Iran, with a seroprevalence of 41.8%. The age of the studied population, sample size, and antibody threshold explain such percentage variations. BK virus immunity:
BK virus replication occurs after immune suppression in pregnancy, diabetes, HIV infection, cancer, and post-transplantation. As a result of strong immunosuppression, BKV replication usually starts early post-transplant. BKV replication and BKVN resolution depend on the immune system [48]. BKVN may be caused by (a) inadequate immunological surveillance by host T lymphocytes, (b) lack of humoral immunity to BKV, (c) alloimmune activation, and (d) viral variation in molecular sequences. BK pathogenesis:
BKV primary infection seldom causes respiratory symptoms in children. BKV enters the circulatory system by infected tonsils and infects peripheral blood mononuclear cells, which spread to secondary sites, including the kidneys. The virus remains latent in the uroepithelium and renal tubular cells for life, sometimes reactivating as asymptomatic viruria.
BKV may also hide in leukocytes, brain tissues, and lymph nodes. In immunosuppressive treatment, the virus activates and proliferates in the interstitium and enters the peritubular capillaries, causing tubular cell lysis and viruria. Damage, inflammation, and fibrosis determine outcomes. Viral cytolysis and subsequent inflammatory responses harm tissue.
Different BKV illness symptoms originate from complex immune system-BKV interactions. BK virus renal disease:
This virus proliferates in uroepithelial cells, causing viruria, viremia, and BK polyomavirus-associated nephropathy (BKVN) or PyVAN. 30–40% of renal transplant patients develop BK viruria, whereas 10–15% develop viremia.
BKVN is reported in 2–15% of kidney transplant patients. Different immunosuppressive regimens and screening strategies—including biopsy surveillance in certain centers—can explain these differences. BK-related nephropathy:
BKV-associated nephropathy starts with viruria or asymptomatic hematuria and progresses to permanent damage and allograft failure. Nephritis might start 6 days or 5 years after a kidney transplant.
Ureteric stenosis the prevalence of ureteric stenosis is 2–6%.
Hemorrhagic cystitis: HSCT patients often develop BKV-associated HC or non-HC, although renal allograft recipients seldom do.
Other rare manifestations: neurological manifestations; pulmonary diseases, Ophthalmologic manifestations, BK virus, urothelial cancers
BKV-DNA was found in urothelial malignancies such as bladder carcinoma, and many believe BKV plays a major role in their development. Risk factors:
There are many risk factors for BKVN. Immunosuppression is the most consistent risk factor in the research. Male sex, older recipient age, past rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, specific ethnic groups, a lower total lymphocyte percentage, and ureteral stent insertion are further risk factors for BKVN, however, not all investigations have found them. Screening tests: 1 — Decoy cells: sensitivity: 25, specificity: 84 . Widely available, it is a useful marker in the identification of BKV infection but a poor diagnostic tool in predicting BKVN. Not useful for monitoring the decline in viral load 2-Haufen: sensitivity 100, specificity 99. Highly predictive for BKVN, but not practical for routine practice as it requires electron microscopy with interpretation from a pathologist 3-Urinary BK-PCR sensitivity: 100; specificity: 78. Measurement variations between laboratories limit its use. 4-Plasma BK-PCR Sen: 100 Spe: 88 Broadly available but costly. Has good sensitivity and specificity but a low PPV for BKVN. Kidney biopsy: allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/mL. Histology reveals streaky fibrosis of the medulla with circumscribed cortical scars macroscopically, and sclerosed glomeruli, necrotic, atrophic tubules with interstitial fibrosis microscopically.
BK virus inclusions within tubular epithelium can be seen via hematoxylin and eosin and PAS staining. Differential diagnosis
Includes allograft rejection, and any disease associated with early and late allograft dysfunction. Early period would be within 2 weeks post transplant. Late period would be more than 3 months posttransplant.
Treatment
Reducing immunosuppression and switching drugs may be the initial therapeutic approach. Consider steroid withdrawal.
If MMF dosages stay the same, switching to cyclosporine may lower MMF levels, but if BK viremia persists, MMF must be stopped. MMF reduces proinflammatory and profibrotic cytokines.
Oral leflunomide inhibits viral replication in vitro and is administered at 100 mg/day for 3–5 days, followed by 20–40 mg/day. Nevertheless, MMF and azathioprine cannot be used with leflunomide.
Cidofovir, generally used for CMV, may induce BKV-induced cell death by reactivating p53 and pRB. but has a nephrotoxicity side effect.
Quinolone, statins, and Rituximab are other treatments. Therefore, regular monitoring of BKV PCR and renal function is crucial to a successful transplant, graft protection, and BKV clearance.
Discussion
BK virus is a Polyomavirus, a small non enveloped DNA virus with an isohedral capsid. The virus has different regions – early viral gene region that encodes regulatory nonstructural proteins, and late viral gene region that encodes capsid proteins within the nucleus.
BKV comes under 4 major categories or subtypes :
-Genotype I – predominant and most common subtype
-Genotype II and III – rare and infect a small minority of patients
-Genotype IV – second most frequent subtype
There are other subtypes reflecting different geographical and migration patterns.
BKV viral replication occurs in a state of immune suppression in the host, such as pregnancy, HIV infection, diabetes, cancer, or following transplant. Replication begins in the early posttransplant period. Risk factors
Intensive immunosuppression
Male gender
Older recipient
Previous rejection episodes
Degree of HLA mismatch
Prolonged cold ischemia
BK sero status
Lower percentage of lymphocytes
Ureteral stent insertion Pathogenesis :
Defective immune surveillance by host T lymphocytes
Absent humoral immunity to BKV
Patients with prior immunity to BKV may not show manifestation of disease, irrespective of viral copies.
Alloimmune activation
Viral variation in molecular sequences
CD4+ and CD8+ T cells are the main factors in cell mediated immunity that play a role in clearing BKV.
Recipients who receive graft from a BKV seropositive donor have a higher chance of developing the infection in comparison with those how have a seronegative donor.
BKV goes into the circulatory system through the tonsils, and then infects the mononuclear cells in the peripheral blood. This then gets disseminated into different secondary places in the body, including the kidneys.
BKV can also remain latent in the brain, lymph nodes, and leukocytes.
BKV does not cause infection in people who are immunocompetent. Clinical manifestations
Virus sheds in the urine. Urine examination can be done to check for infection.
Ureteric stenosis
Late onset hemorrhagic cystitis
Multi Organ involvement
Neurological manifestations include encephalitis, meningoencephalitis, Guillan Barre syndrome, and basculopathy. Signs include headache, dizziness, confusion, paraplegia, ataxia, and seizures.
Bilateral atypical retinitis may occur, although this is rare. Conclusion
BK virus, a diagnostic and therapeutic dilemma, is the focus of the given article. The main issue with this kind of infection is that it can mimic acute rejection, and thus treatment becomes difficult. This infection can be caused by intensive immunosuppression regimen aimed at preventing graft rejection.
Early diagnosis through molecular techniques and tissue analysis can achieve a good outcome in terms of the virus clearance as well as good allograft outcome.
What is the level of evidence provided by this article?Level V
Introduction;
BK virus was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipient. Epidemiology;
It affects around >80% of population in childhood, and becomes dormant until immunocompromised. BK virus varients;
There are four genotypes. Type I is 80%, II is around 15%, class II and IV are relatively rare. Routes of transmission;
It can be transmitted in every fluid. BKV associated nephropathy;
Usually asymptomatic until immunocompetant, on immunosuppression nephritis can occur as early as six days post-transplantation.
Can present with uretric stenosis,
BKV nephropathy,
Heamurrhagic cystitis,
Very rarly can cause malignancy. Treatment;
There is no definite treatment yet, main stay of treatment is reduction of dose of immunosuppression. Level of evidence V
BK virus (BKV) and JC virus (JCV), 2 human polyomaviruses, were discovered in 1971. Their negative effect was poorly understood untill 3 decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
History of BK virus: In 1971, Gardner et al. first detected BK polyomavirus (BKV) in urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. They named the virus ‘BK’ after the initials of the patient. Epidemiology of BK virus BKV, is ubiquitous that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent ghosts. Studies showed as much as 60–85% of the general population is seropositive for BKV. Immunological response to BK virus BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and post-transplant patients. BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression. BK virus variants categorized into 4 genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1. Genotype I is the predominant subtype (80%) of all circulating viruses; genotype IV is second most frequent (15%). Genotypes II and III are relatively rare and infect only a minority of patients. Routes of transmission of primary BK virus Several routes for the primary BKV virus transmission – might be respiratory, feco-oral, transplacental, or from donor tissues. BK virus and renal disease Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN). BK virus and renal disease Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN). BK virus-associated nephropathy BKV-Nephropathy begins with viruria or asymptomatic haematuria; progresses through extensive irreversible injury and allograft failure. Onset of nephritis might occur as early as 6 days after renal transplant, or as late as 5 years Ureteric stenosis The prevalence of ureteric stenosis is 2–6%. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppression. Haemorrhagic cystitis BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients BK virus and malignancy: thoughts on viral oncogenesis The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors BK virus and urothelial tumors BKV is thought to have fundamental role in pathogenesis of urothelial malignancy, particularly bladder carcinoma as BKV-DNA was isolated in these tumors. Geetha et al. reported a bladder carcinoma with widespread metastases in a simultaneous pancreatic and kidney transplant recipient with concomitant BK interstitial nephritis. Screening tests and timeline Viral replication starts early after transplantation and progresses through noticeable phases: viruria then viremia followed by nephropathy. Viral replication in the urine precedes BK viremia by ∼4 weeks, and although there have been confined cases of patients developing viremia without viruria, this is uncommon. Histological changes of BKVN are observed 12 weeks after BK viruria Kidney biopsy The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract, and (b) persistent viremia of > 104 copies/ml for more than 3 weeks. Although plasma BK-PCR has high sensitivity and specificity in anticipating BKVN, different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN Treatment of BK virus nephropathy in the setting of allograft dysfunction Favourable renal allograft outcomes in patients with acute BKV infection were reported after immunosuppression reduction, started early upon detection of BK viremia. When BKVN is identified at advanced stage, then IS reduction is probably going to be less effective. Advanced disease, with severe histological changes leads to progressive, irreversible renal damage. Whether reducing or discontinuing one or more of the immunosuppressive regimen can alter the prognosis is not yet clear. However, allograft function may stabilize with modifying immunosuppressants. Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises BKV-specific IgG-antibodies titre and increases BKV- specific cellular immunity Level of evidence: level V
Introduction
Although the two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
BK virus and renal transplantation: historical perception
In 1971, Gardner et al.were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. They named the virus ‘BK’ after the initials of this patient.
Epidemiology of BK virus
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people . Studies showed as much as 60–85% of the general population is seropositive for BKV.
Immunological response to BK virus
BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period .BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
BK virus variants
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1 . Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population. Alternatively, genotypes II and III are relatively rare and infect only a minority of patients
Routes of transmission of primary BK virus
Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN).
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN).
BK virus-associated nephropathy
Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% [2]. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications Hemorrhagic cystitis
BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients
BK virus and malignancy: thoughts on viral oncogenesis
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors
BK virus and urothelial tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors. Geetha et al. reported a bladder carcinoma with widespread metastases in a simultaneous pancreatic and kidney transplant recipient with concomitant BK interstitial nephritis.
Screening tests
Viral replication starts early after transplantation and progresses through noticeable phases: viruria then viremia followed by nephropathy. Viral replication in the urine precedes BK viremia by ∼4 weeks, and although there have been confined cases of patients developing viremia without viruria, this is uncommon. Histological changes of BKVN are observed 12 weeks after BK viruria
Kidney biopsy
The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks . Although plasma BK-PCR has high sensitivity and specificity in anticipating BKVN , different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN
Treatment of BK virus nephropathy in the setting of allograft dysfunction
Favorable renal allograft outcomes in the context of acute BKV infection were reported when immunosuppression reduction had started early upon detection of BK viremia, permitting early and appropriate therapeutic interference
Nevertheless, if the identification of BKVN is made at an advanced stage when nephropathy ensues, then reducing immunosuppression is probably going to be less effective, owing to the advanced disease, with severe histological changes leading to progressive, irreversible renal damage
Whether reducing or discontinuing one or more of the immunosuppressive regimen can alter the prognosis is not yet clear. However, allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy
Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises BKV-specific IgG-antibodies titer and increases BKV- specific cellular immunity
Polyomaviridae variants the human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40). It is a family of small, nonenveloped DNA viruses
12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017. These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery.
Epidemiology of BK virus:
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent.
60–85% of the general population is seropositive for BKV. BK virus structure: Noncoding control region (NCCR):
It regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell. BK virus variants:
4types, type one more common 80percent of cases type 4, 15percent of cases.
Phylogenetic analysis there’s:
Four more subgroups, subcloned of subtype and six subgroups of subtype IV. Immunological response to BK virus:
BKV replication characteristically begins early in the post transplant period and can follow antirejection therapy as a consequence of intense immunosuppression. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN). The role of cell-mediated immunity:
Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA.
The lysis of an infected cell can lead to viral leakage into the tubular lumen.
Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation. The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis.
The role of humoral immunity:
May have a role.
Role of alloimmune activation:
(HLA)-reactivity and heterologous immunity. The latter concerns with T cells, which cross-react to both BKV and allo-antigens. Moreover, one can propose that the host BKV-specific effector memory T cells cannot identify the allo-HLA molecules representing BKV-peptides; thus, it allows BKV to escape the immunological surveillance.
The role of other factors:
In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role. Pathogenesis of BK infection:
Primary infection:
Usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
The virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
Immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitial and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria. Tissue damage is by direct viral cytolytic effects and secondary inflammatory responses. Routes of transmission of primary BK virus:
Respiratory, fecal-oral, Trans placental, or from donor tissue. Urine and were present in peripheral blood leukocyte Clinical manifestations: BK virus and renal disease:
BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia.
BKVN in ranges between 2 and 15%. BK virus-associated nephropathy:
Begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years. Ureteric stenosis:
The prevalence of ureteric stenosis is 2–6%.
Treatment percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications. Hemorrhagic cystitis:
BKV-associated HC or non-HC. More common with HSCT recipients. RARE in renal transplant.
Presents with bladder cramps, painful voiding, hematuria, and/or flank pain.
Four degrees of disease severity:
Grade me: microscopic hematuria.
Grade II: macroscopic hematuria.
Grade III: hematuria with clots.
Grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy.
Management:
Vigorous intravenous hydration. Severe cases of BKV-HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation.
Cidofovir, through bladder installation (hence reducing the cumulative drug nephrotoxicity) was suggested as a therapeutic option for HC.
BK nephropathy in the native kidney BKVN:
Has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients. Presented with acute kidney injury without significant proteinuria and had characteristic histological findings on kidney biopsy.
Other less apparent clinical manifestations Neurological manifestations:
Picture of meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy,
Headache, dizziness, confusion, paraplegia, ataxia, and seizures. Pulmonary diseases:
Reactivated acute respiratory infection leading to severe interstitial pneumonitis in association with BKV has been reported! Ophthalmologic manifestations:
To date, there is only a single case report with bilateral atypical retinitis, reported.
BK virus and hepatic disease:
Similarly, a single report in the literature regarding the association between BKV and hepatitis was r BK virus and autoimmune diseases:
A relationship between BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immunocompromised individuals. BK virus and malignancy:
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors . BK virus and urothelial tumors:
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma. Risk factors:
Degree of immunosuppression.
male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion. Screening and diagnostic tools: Most cases arise in the first post-transplant year. Early Peak early 3 month decline by nine month and raise again after 12months.
KDIGO guidelines had recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years. Screening test: Monitoring of the urine: Urine cytology Decoy cells:
In 13–30%.
A sensitivity of 100%, and a specificity of 71% [positive predictive value (PPV) of 29% and negative predictive value (NPV) of 100%]. In contrast, reported a 25% sensitivity and 84% specificity (5% PPV and 97% NPV) to diagnose BKVN. Urine electron microscopy (EM Haufen):
A higher sensitivity and specificity for biopsy-proven BKVN (100 and 99% correspondingly).
PPV 97, 100 NPP. Quantitative measurements of urinary BK virus-viral loads:
Compared with urine cytology, molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity.NPP 40 PPV 100
BK virus mRNA levels in urine:
Has highly specific and sensitive (sensitivity of 100% and specificity 97%) in predicting patients who might develop BKVN, using 6.5×105 BKV-VP1 mRNAs/ng RNA in urinary cells as a cutoff value . Serology Serum BK-PCR:
BK viremia is noticed only among immunocompromised patients, with an estimated prevalence of 7–30% in the initial 6 months and 5–10% after that among kidney recipients.
Preferred screening technique at most transplant institution.
BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively, for the development of BKVN than BK viruria.
A definite viral load cutoff associated with nephropathy has not yet been defined. Nonetheless, retrospective analyses had proposed a quantitative BKV-PCR of more than 4 logs (1×104) copies/ml to correlate strongly with findings of BKVN on allograft biopsy. Treatment strategy of BK virus nephropathy:
The aim is to eradicate the virus while saving the kidney function.
BKVN has limited treatment option.
Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response. Treatment of presumptive BK virus nephropathy:
Manipulation or reduction of IS:
Reducing the dose of immunosuppressant or withdrawal
Switching a drug within the same class or to a different class and steroid avoidance.
withdrawal of antimetabolite drugs or change MMF to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI .
Withdrawal of the antimetabolite such as MMF is the most usual method.
Switching tacrolimus to cyclosporine might reduce MMF levels if doses of MMF remain the same.
If there’s allograft Dysfunction:
Reducing immunosuppression remained a rational option even in the presence of allograft dysfunction. Drugs with antiviral activities: Leflunomide:
Immunomodulatory, prodrug, and ant rheumatic disease-modifying drug.
Inhibit pyrimidine synthesis, resulting in ant proliferative and anti-inflammatory effects. Dose:
Loading dose of 100 mg daily for 3–5 days followed with a maintenance dose of 20–40 mg/day and recommended target level of 40–100 μg/ml.
Simultaneous withdrawal of ant proliferative medication and reduced CNI dosages. Limited use of this medication:
(a) Higher dosage of the drug (≥40 mg/day) is necessary to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity;
(b) Monitoring of the trough A77 1726 level is not accessible in all laboratories; and
(c) The immunosuppressive effectiveness of leflunomide is weak. Adverse effects:
Hemolysis, aplastic anemia, thrombocytopenia, and probably thrombotic microangiopathy, hepatitis, and worsening of hypertension. Cidofovir:
Cidofovir is a cytosine analog and viral DNA polymerase inhibitor.
When used for treating BKVN, cidofovir has been given as slow intravenous infusion (over 2 h) at an initial dose of 0.25 mg/kg/dose every 2–3 weeks for a period of 10–15 weeks.
Dosage can be increased if the BKV-PCR load does not reduce by one-log fold to a maximum dose of 1 mg/kg/dose.
Its nephrotoxic. Acute kidney injury, renal tubular acidosis, and proteinuria
Vigorous intravenous prehydration.
Dose adjustment if renal dysfunction.
Severe anterior uveitis was reported with cidofovir, which may lead to permanent visual impairment
Used carefully in kidney recipients, with frequent monitoring and informed consent for its potential complication.
Promising antiviral drug brincidofovir is a prodrug of cidofovir, and the oral form of the medicine gets converted to cidofovir when it goes intracellular.
The benefit of CMX001 is its effectiveness against all DNA viruses with no documented nephrotoxicity and ease of oral administration. MTor inhibitors:
MTor inhibitors have shown effectiveness in in-vitro analysis in inhibiting BK replication and early gene expression. Intravenous immunoglobulin:
Treatment with IVIG has been used for BKVN for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection.
Other therapeutic options for treating BK virus nephropathy:
(1) Quinolones have been described, no effect.
(2) Artesunate (an antimalarial drug) on BK viral proliferation in a primary human renal cell culture. The investigators found a decrease in BKV proliferation in a dose-dependent way with artesunate.
(3) Similarly, statins (pravastatin) were found experimentally to reduce the percentage of BKV-infected cells and LTAg expression in human renal proximal tubular epithelial cells, possibly owing to inhibiting the formation of caveolin-1, resulting in blocking viral entry into the cells
(4) Rituximab:
As an adjuvant therapy with cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN. In both groups, the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine.
Triple therapy was switched to cyclosporine and azathioprine. The viral load had normalized in most within 18.3±6.8 weeks.
Short-term and long-term allograft survival
There’s improve prognosis now for BKVN.
IS reduction associated with 6-12 % risk of rejection rate graft loss?
Reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified.
27% had experienced permanent allograft dysfunction, 18% ultimately lost their allograft secondary to BKVN.
Reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis. BK nephropathy with concurrent acute rejection
Combination of antirejection therapy with a subsequent reduction in immunosuppression is suggested. Postinfection monitoring:
Observation of BKV-PCR and renal function.
Serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
Subsequently, it should be done on a monthly bases until clearance of BK viremia and stabilization of renal function.
BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression. I
Viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide. Conclusion:
BKV. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
Introduction BKV, JCV, and SV40 are Polyomaviridae, a subfamily discovered in 1971. BKV was discovered to cause interstitial nephritis and allograft failure in renal transplant recipients three decades later. BKV infection is one of many possible causes of renal failure in kidney transplant recipients, generally within the first year. Asymptomatic creatinine increases with tubulointerstitial nephritis may mimic acute rejection, creating a diagnostic and management conundrum. The most common BKV genotype is 1, followed by 4. Pathogenesis BKV infection in children typically presents as a mild respiratory symptom and is subclinical in nature. In the renal tubular cells and urothelium, the virus is still inactive. Moreover, it may remain latent in leukocytes, brain tissue, and lymph nodes. Immunosuppressive medication causes tubular cell lysis and viruria when the virus replicates and spreads to the peritubular capillaries. BK illness manifests itself in a variety of ways depending on how the immune system and the BKV interact. Primary BK virus transmission routes The main modes of transmission for the BKV virus have been identified. The infection may spread through the airways, orally through feces, transplacentally, or from donor tissues. Clinical symptoms 7% of immunocompetent adults shed BKV in their urine, but it does not cause disease. BKV nephropathy, ureteric stenosis, and late-onset hemorrhagic cystitis are diseases. BKV and renal disease: Uroepithelial cell replication leads to viruria, viremia, and BK-associated nephropathy. BKV-associated nephropathy starts with viruria or asymptomatic hematuria and concludes with significant, irreparable harm and allograft failure. Uretric stenosis: 2-6% prevalence; rarely causes hydronephrosis or allograft dysfunction. Percutaneous ureteral dilatation, stent insertion, and immunosuppression reduction treat ureteric stenosis. Hemorrhagic cystitis: painful urination, hematuria, bladder spasms, and flank pains Neurological manifestations: BKV rarely causes original or reactivated CNS illness. BKV and cancer: Several neoplasms have BKV DNA. LTAG and STAG proteins may make BKV carcinogenic. Tests for screening Viruria comes about 4 weeks before viremia, and BKVN happens 12 weeks after viruria. 1) Urine cytology: Decoy cells are basophilic intranuclear inclusions that are larger tubular cells that are infected. Decoy cells are thought to be a sign of BKV reactivation and are highly predictive of polyomavirus infection. It can diagnose BKVN with a sensitivity of 25–100% and a specificity of 71–84. 2) Urine viral loads: PCR has 100% sensitivity and 78% specificity. Patients at risk for BKVN can be predicted by their persistently elevated viral loads. 3) Serum BK PCR is the screening method of choice in the majority of transplant hospitals due to its 100% sensitivity and 88% specificity. 4) Kidney biopsy: the gold standard for BKVN diagnosis. Treatment The only proven therapy to cure BKVN and restore the immune system’s response to viruses is to reduce immunosuppression; however, any reduction in immunosuppression must always be weighed against the danger of inducing acute or chronic rejection. The most common approach is the withdrawal of the antimetabolite, such as MMF. Medications with antiviral properties Leflunomide: This immune modulator is taken by mouth at loading doses of 100 mg per day for 3–5 days, then 20–40 mg per day for maintenance. Cidofovir is an analog of cytosine and an inhibitor of viral DNA polymerase. As BKV lacks the viral polymerase gene, which is cidofovir’s known target, the mechanism of action is uncertain. Due to the fact that urine is the only method of excretion, renal tubular cell concentrations are high. Inhibitors of mTOR improves the immunological response after BKV infection by controlling memory CD8 T cell development and preventing the growth of BKV-specific T cells. Strong neutralizing antibodies that can neutralize all main BK virus genotypes are seen in intravenous immunoglobulin. Treatment of BKVN with concomitant acute rejection using IVIG in a dosage of 2-3.5 g/kg spread over 2–5 days with a contemporaneous reduction in immunosuppressive drugs has been successful. Post-infection surveillance serum creatinine every one to two weeks. Plasma BK PCR: 2–4 weeks for an 8/52 sample, then every month until BK viremia disappeared. Leflunomide addition or sirolimus switch should be explored if viremia continues despite RIS. Level of evidence: V
Introduction
BKV, JCV, and SV40 are Polyomaviridae, a subfamily discovered in 1971.
BKV was discovered to cause interstitial nephritis and allograft failure in renal transplant recipients three decades later.
BKV infection is one of many possible causes of renal failure in kidney transplant recipients, generally within the first year. Asymptomatic creatinine increases with tubulointerstitial nephritis may mimic acute rejection, creating a diagnostic and management conundrum.
The most common BKV genotype is 1, followed by 4. Pathogenesis
BKV infection in children typically presents as a mild respiratory symptom and is subclinical in nature.
In the renal tubular cells and urothelium, the virus is still inactive. Moreover, it may remain latent in leukocytes, brain tissue, and lymph nodes.
Immunosuppressive medication causes tubular cell lysis and viruria when the virus replicates and spreads to the peritubular capillaries. BK illness manifests itself in a variety of ways depending on how the immune system and the BKV interact. Primary BK virus transmission routes
The main modes of transmission for the BKV virus have been identified.
The infection may spread through the airways, orally through feces, transplacentally, or from donor tissues. Clinical symptoms
7% of immunocompetent adults shed BKV in their urine, but it does not cause disease.
BKV nephropathy, ureteric stenosis, and late-onset hemorrhagic cystitis are diseases.
BKV and renal disease: Uroepithelial cell replication leads to viruria, viremia, and BK-associated nephropathy. BKV-associated nephropathy starts with viruria or asymptomatic hematuria and concludes with significant, irreparable harm and allograft failure.
Uretric stenosis: 2-6% prevalence; rarely causes hydronephrosis or allograft dysfunction. Percutaneous ureteral dilatation, stent insertion, and immunosuppression reduction treat ureteric stenosis.
Hemorrhagic cystitis: painful urination, hematuria, bladder spasms, and flank pains
Neurological manifestations: BKV rarely causes original or reactivated CNS illness.
BKV and cancer: Several neoplasms have BKV DNA. LTAG and STAG proteins may make BKV carcinogenic. Tests for screening
Viruria comes about 4 weeks before viremia, and BKVN happens 12 weeks after viruria.
1) Urine cytology: Decoy cells are basophilic intranuclear inclusions that are larger tubular cells that are infected.
Decoy cells are thought to be a sign of BKV reactivation and are highly predictive of polyomavirus infection.
It can diagnose BKVN with a sensitivity of 25–100% and a specificity of 71–84.
2) Urine viral loads: PCR has 100% sensitivity and 78% specificity.
Patients at risk for BKVN can be predicted by their persistently elevated viral loads.
3) Serum BK PCR is the screening method of choice in the majority of transplant hospitals due to its 100% sensitivity and 88% specificity.
4) Kidney biopsy: the gold standard for BKVN diagnosis. Treatment
The only proven therapy to cure BKVN and restore the immune system’s response to viruses is to reduce immunosuppression; however, any reduction in immunosuppression must always be weighed against the danger of inducing acute or chronic rejection. The most common approach is the withdrawal of the antimetabolite, such as MMF. Medications with antiviral properties
Leflunomide: This immune modulator is taken by mouth at loading doses of 100 mg per day for 3–5 days, then 20–40 mg per day for maintenance.
Cidofovir is an analog of cytosine and an inhibitor of viral DNA polymerase. As BKV lacks the viral polymerase gene, which is cidofovir’s known target, the mechanism of action is uncertain. Due to the fact that urine is the only method of excretion, renal tubular cell concentrations are high.
Inhibitors of mTOR improves the immunological response after BKV infection by controlling memory CD8 T cell development and preventing the growth of BKV-specific T cells.
Strong neutralizing antibodies that can neutralize all main BK virus genotypes are seen in intravenous immunoglobulin. Treatment of BKVN with concomitant acute rejection using IVIG in a dosage of 2-3.5 g/kg spread over 2–5 days with a contemporaneous reduction in immunosuppressive drugs has been successful. Post-infection surveillance
serum creatinine every one to two weeks.
Plasma BK PCR: 2–4 weeks for an 8/52 sample, then every month until BK viremia disappeared.
Leflunomide addition or sirolimus switch should be explored if viremia continues despite RIS. Level of evidence: V
BKV infection is among many other causes responsible for renal dysfunction in kidney transplant recipients occurring within the first year after transplantation. Negative impacts involve interstitial nephritis and allograft failure in renal transplant recipients resembling acute rejection causing a conflict in the diagnostic as well as the therapeutic approach. BK virus and renal transplantation: historical perception
1971, Gardner et al. were the first who detected BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. The presence of abundant large cells with intranuclear inclusions were present in the urine known as ‘decoy cells’ as they resemble malignant cells.
Furthermore, Mackenzie et al. in 1978 had established the histological changes consistent with polyomavirus nephritis in renal biopsy.
JCV is the culprit of progressive multifocal leukoencephalopathy. Polyomaviridae variants
It is a subgroup of papovaviruses BKV, JCV, and simian virus 40 (SV40). They are small, nonenveloped DNA viruses.
Epidemiology of BK virus
Polyomavirus hominis-1 is a ubiquitous virus, causes worldwide infection during early childhood after that the virus remains dormant lifelong in immune-competent population. This can be confirmed according to many studies reporting 60–85% of the general population is seropositive for BKV.
BK virus structure
BKV-DNA genome
The noncoding control region (NCCR) which is responsible for regulation of the expression of viral genes for further differentiation and activation within the host cell.
The early viral gene region encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg). Their role is to bind to cellular target proteins (tumor suppressor proteins Rb, p107, p130, and p53) for efficient viral replication.
The late viral gene region (LVGR) which is responsible for encoding the capsid proteins VP-1, VP-2, and VP-3 within the nucleus.
The capsid protein VP1 in the LVGR present on the surface facilitates the viral entry into the cell.
Among BK virus variants, Genotype I is considered the predominant subtype exceeding 80% worldwide infections while the second common is genotype IV accounts for 15% of the healthy human population.
Immunological response to BK virus
BK viral replication usually occurs in immunocompromised population as clinical states of pregnancy, diabetes, HIV infection, cancer, and post-transplantation.
Regarding the post-transplant early period, it is to be more expected after antirejection therapy administration derived by more intense immunosuppression leading to BK virus nephropathy (BKVN).
Proposed factors explaining to the pathogenesis of BKVN are combination of defective immune surveillance by the host T-lymphocytes, absence of humoral immunity to BKV, alloimmune activation, and viral variation in molecular sequences.
The role of cell-mediated immunity
CD4+ and CD8+ T cells play a role in cellular-mediated immunity to control the BKV and BK clearance. Cytotoxic T cells (CTL) are responsible for killing the BK-infected cells.
Lack of proper immunological regulation in addition to progressive lytic infection results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
Collateral destruction with necrosis and apoptosis of non-infected tubular cells, consequences include continuous intragraft inflammation, tubular injury, up-regulation of profibrotic mediators ending by allograft dysfunction and loss.
Bohl and his colleagues discovered that renal transplant recipients from seropositive donors were more prone to develop BK viremia compared to those from seronegative donors. The role of antibody mediated immunity is significant as patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
Role of alloimmune activation
Allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity are believed to be other contributing factors. As thehost BKV-specific effector memory T cells become unable to identify the allo-HLA molecules representing BKV-peptides allowing them to escape the immunological surveillance. Moreover, CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans.
Awadalla et al. also had linked the higher degree of HLA mismatches with an increase in the incidences of BKVN, suggesting the validated role of alloimmune activation.
In contrast, Drachenberg et al. proposed a reverse association between allograft survival and the level of HLA matches in patients with BKVN, suggesting a lack of HLA matches might predict better outcomes in recipients with BKVN.
Another contributing factor is BKV tropism to the renal tubular epithelial cells.
Pathogenesis of BK infection
During primary infection in childhood, BKV affects the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell then get disseminated to secondary places mainly kidneys.
Resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation, manifesting as asymptomatic viruria. It is known BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
Routes of transmission of primary BK virus
Route of infection could be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations
Different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis in renal transplant recipients.
In HIV infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement up to death.
BK virus and renal disease
The virus proliferates within the uroepithelial cells resulting in viruria followed by viremia and finally to BK polyomavirus-associated nephropathy (BKVN). Viruria could be detected in 30–40% of renal transplant recipients, while viremia accounts for 10–15% of recipients. Overall, the estimated incidence of BKVN is variable between 2 and 15% of kidney allograft recipients due to worldwide difference in immunosuppressive regimens, screening strategies and early performance of surveillance biopsies.
BK virus-associated nephropathy onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
Ureteric stenosis occurs in 2–6% while hemorrhagic cystitis is even rarer.
It has been proposed also that BKV has an oncogenic sequel owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA. Agnoprotein and LTAg will make infected cells incapable of arresting the cell cycle and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
However, it was discovered that BKV-DNA by PCR existed in only 5.5% of urothelial tumors.
Risk factors are mainly degree of immunosuppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus.
Screening and diagnostic tools
Most cases arise in the first posttransplant year, Last American Society of Transplantation Infectious Diseases Guidelines and KDIGO guidelines recommended BKV screening to start at first month after transplant, then monthly for the first 6 months and then every 3 months for up to 2 years.
Screening tests
Viral replication in the urine precedes BK viremia by ∼4 weeks, histological changes of BKVN are observed 12 weeks after BK viruria. Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
Monitoring of the urine include detection of BKV-infected epithelial cells ‘decoy cells,’ or aggregates of BKV virions ‘Haufen’ or by quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
BK viremia is prevalent in immunocompromised patients by of 7–30% in the initial 6 months and 5–10% after that among kidney recipients
Retrospective analyses had proposed a quantitative BKV-PCR of more than 4 logs (1×104) copies/ml to correlate strongly with findings of BKVN on allograft biopsy.
Serial determinations of viremia are required to follow-up patients who lost their allograft due to BKVN and considered for retransplantation.
BKV grows slowly in tissue culture, which might extend from weeks to months.
Kidney biopsy
Allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction.
Fluorescence in-situ hybridization (FISH) analysis allows BKV identification in renal transplant tissues through bright nuclear fluorescence technique with a specificity of 100% and sensitivity of 94.7%.
Positive IHC using specific antibodies against BKV or the cross-reacting SV40 LTAg has a specificity of nearly 100% for polyomavirus nephropathy.
Histologically includes viral cytopathic changes of near-normal renal parenchyma, with no or minimal tubular atrophy, interstitial fibrosis, or inflammation, diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation. BK-PCR of allograft biopsy tissue is inapplicable investigation to diagnose BKVN, as it can identify a latent virus, even in asymptomatic recipients.
Suggested algorithm for screening
Recommended a step-wise methodology for BKV screening in renal transplant recipients.
Start by screening patients for BKV, first with urine cytology for decoy cells every 3 months, if positive proceed for quantification of viral level in the plasma with the possibility of performing allograft biopsy only when deterioration of renal functions occur.
Another option is to rely on routine surveillance biopsies to detect patients with silent BKVN. Allograft biopsies were performed at third/fourth month and at 12 months post transplantation, accordingly many patients were detected with a silent disease. Thus, surveillance biopsies had resulted in improved allograft outcomes compared to patients with renal allograft impairment at the time of diagnosis.
Currently, many transplant centres recommend BK surveillance with plasma BK-PCR. It is better to be performed on periodic intervals, starting after 1 month, monthly for 3–6 months and then every 3 months for the initial 1–2 years post renal transplantation.
Annual screening till the fifth year after transplant is suggested by American Society of Transplantation guidelines.
Differential diagnosis
Allograft rejection
Analysis of blood or urine PCR also as BKVN may coexist concurrently with acute rejection. Presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells. Absence of definitive features of acute cellular rejection, such as endotheliitis, extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful in excluding rejection.
Other differential diagnosis includes any disease common in the early (1–12 weeks post renal transplantation) late (≥3 months post renal transplantation) renal allograft dysfunction.
Treatment strategy of BK virus nephropathy
Decreasing immunosuppression is the only validated therapy to treat BKVN. Withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less). Switching tacrolimus to cyclosporine might reduce MMF levels if doses of MMF remain the same. The total withdrawal of MMF in some situations might be essential if BK viremia persists as MMF may limit the proinflammatory and profibrotic cytokines.
Drugs with antiviral activities
Leflunomide is a known immunomodulatory, prodrug, and antirheumatic disease-modifying drug as it acts by inhibiting pyrimidine synthesis having an antiproliferative and anti-inflammatory role.
Leflunomide dosage is orally with a loading dose of 100 mg daily for 3–5 days, then a maintenance dose of 20–40 mg/day with recommended target level of 40–100 μg/ml. highlighting the necessity of frequent liver function monitoring to avoid hepatotoxicity.
Adverse effects are variable as hemolysis, aplastic anemia, thrombocytopenia, thrombotic microangiopathy, hepatitis, and worsening of hypertension.
Cidofovir is acytosine analog and viral DNA polymerase inhibitor used to manage other viral infections such as CMV. The mechanism of action is thought to be by re-establishing p53 and pRB function (targets of the LTAg) inducing apoptosis of the BKV infected cells.
Recommended dosage is via slow intravenous infusion (over 2 h) at an initial dose of 0.25 mg/kg/dose every 2–3 weeks for 10–15 weeks duration. Dose adjustment is required in cases of renal dysfunction as it is exclusively excreted through urine resulting in high renal tubular cell concentrations.
Side effects are deleterious as acute kidney injury, renal tubular acidosis, proteinuria, severe anterior uveitis up to permanent visual impairment.
New promising antiviral agent is a prodrug of cidofovir is discovered known as brincidofovir (CMX001) which has an advantage of being effective against all DNA viruses without nephrotoxicity and availability of oral administration.
mTOR inhibitors have antiviral effect by inhibiting BK replication and early gene expression. They are thought to produce their inhibitory impact by restoring the down regulation of translation that occurs under cellular stress delaying viral replication.
Moreover, it inhibits the proliferation of BKV specific T cells as well as controlling the differentiation of memory CD8 T cells resulting in improving the immune reaction sequel of BKV infection.
Intravenous immunoglobulin
The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications. It has been effective in cases with BKVN and concurrent acute rejection.
Other therapeutic options are Quinolones, statins (inhibiting the formation of caveolin-1, resulting in blocking viral entry into the cells), Rituximab (an adjuvant therapy with cidofovir)
Finally, close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression is crucial to improve allograft outcome.
The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV. BK viremia clears in 7–20 weeks.
If viremia persists even after reducing the maintenance therapy then further reduction should be considered or trial to shift to sirolimus, or add leflunomide.
Inability to clear BKV can lead to worse allograft outcomes.
Retransplantation is possible and can be done successfully. According to studies the 1- and 3-year graft survival among the retransplanted individuals was excellent at 98.5 and 93.6%, respectively. Provided that pretransplant clearance of BK viremia is crucial after minimizing immunosuppression. Allograft nephrectomy is not necessary prior to retransplantation.
However, Recurrence of BKV after retransplantation suggests another BK variant or even a new infection (de-novo BKV) acquired owing to the long post-transplantation stage duration.
Conclusion
Early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has led to substantial improvement in allograft outcomes.
BKV
named after initials of first patient
1971
DNA virus
like JCV , it is polyoma virus
most adults are infected
genotype 1 – 80% common
type 4 -15%
T cell immunity has major role to play on BKV infection
screening
during 1 yr post transplant
urine test is easy and simple , high negative predictive value
Decoy cell
Haufen BKV VIRION
BKV DNA
VIRUS CULTURE
SEROLOGY
KIDNEY BIOPSY are other options
diff diagnosis
allograft rejection
The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
Withdrawal of the antimetabolite such as MMF is the most usual method;
lefunomide
cidofovir
IV Ig
statin
fluroquinolone
antimalarial artesan
BKV infection, an early complication of renal transplant, often presents within the first year after transplantation.
It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection and poses a diagnostic and therapeutic dilemma.
Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss.
Increased awareness among nephrologists to recognize BKV disease at an earlier stage and the development of better diagnostic laboratory techniques contributed to the ever-increasing incidence of BKV infection
Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population. Alternatively, genotypes II and III are relatively rare and infect only a minority of patients
BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period .BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN) .Possible factors that add to the pathogenesis of BKVN might be a combination of (a) defective immune surveillance by the host Tlymphocytes, (b) absence of humoral immunity to BKV, (c) alloimmune activation, and (d) viral variation in molecular sequences.
Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
In immunocompromised patients, particularly in renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis
BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia.
BK virus-associated nephropathy
Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% [2]. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen ,and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Hemorrhagic cystitis
BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients .
The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain .
Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy .
BKV-HC is extremely rare in renal transplant.
BK virus and malignancy: thoughts on viral oncogenesis
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
BK virus and urothelial tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors.
Risk factors
The most consistent risk factor identified in the literature is the overall degree of immunosuppression. Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; however, these risk factors have not been uniformly observed in all studies.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood. However, no single diagnostic pathway has appeared as predominant.
Monitoring of the urine
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Presence of decoy cells is strongly suggestive of polyomavirus infection and considered a useful marker of BKV reactivation, though it is not a real diagnostic tool for BKVN.
Quantitative measurements of urinary BK virus-viral loads
Compared with urine cytology, molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity .
Persistent DNA-PCR more than 107 /ml instead of episodic identification can recognize patients at risk for BKVN .However, variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis.
Pros and cons of urinary tests in identifying BKVN:
Urinary tests are highly sensitive for detecting active BKV infections. However, they lack specificity for BKVN as the detected viral particles could originate anywhere along the urinary tract.
Different laboratory assays have created difficulty in standardizing the cutoff values for a definite diagnosis. Although decoy cells are suggestive but not definitive in diagnosing BKVN, their absence does not exclude the disease. Additionally, it can be confused with other viruses, such as cytomegalovirus (CMV) and adenovirus infection, though CMV can cause cytoplasmic besides the intranuclear inclusions.
BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively, for the development of BKVN than BK viruria ,hence, it is the preferred screening technique at most transplant institutions.
Nephritis, however, can be seen with plasma BKVDNA of less than 7000 copies/ml
Serum antibodies
Serum antibodies against BKV are commonly present among the general public. The significance of assessing BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain. Additionally, it has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients .
Nevertheless, the positive donor BKV serostatus and negative recipient serostatus (BK D+/R−) have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients.
Although plasma BK-PCR has high sensitivity and specificity in anticipating BKVN ,different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN .
Thus, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction .
Immunosuppression reduction…. May rebuild the immune responses against BKV
Can induce acute rejection
Leflunomide ….Pyrimidine depletion and tyrosine kinase inhibition
Hemolytic anemia thrombocytopenia, and thrombotic microangiopathy
Cidofovir… Inhibits viral replication; mechanism unknown
Potentially nephrotoxic and severe anterior uveitis
IVIG …. Contain neutralizing antibodies against BKV and are immunomodulatory
May lead to paradoxical increase in viral load
mTOR inhibitors ….Inhibits the proliferation of BKV-specific T-cell and controls the differentiation of memory CD8 T cells
Hyperlipidemia, bone marrow toxicity, mucositis and oral ulcerations, and lymphedema
Fluoroquinolones …Inhibit BKV replication in vitro and inhibit the large T antigen helicase activity
Rarely occurs, such as gastritis, C difficile, hepatoxicity, neurological adverse effects, and altered mental status
Artesunate (an antimalarial drug) …Inhibit BK viral proliferation in a primary human renal cell culture
Anorexia, dizziness, nausea, and diarrhea
Rituximab
Although therapy with anti-CD20mAb rituximab used for the treatment of antibody-mediated rejection was associated with several adverse effects including BKVN, CMV viremia, herpes zoster, and septic shock.
Conclusion
Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology. There is a bigger ‘known unknown’ that just proves the elusive nature of BKV. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
Introduction:
There are two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971.
BKV cause of interstitial nephritis and allograft failure in renal transplant recipients.it causes renal dysfunction in kidney transplant recipients within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma.
causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma Epidemiology of BK virus:
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people. BK virus structure:
It is DNA genome the NCCR regulate the expression of the virus and divided into 3 parts:
1) The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen).
2) The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus.
3) The capsid protein VP1 in the LVGR is the main capsid protein present on the surface and is responsible for receptor binding to the host cells, facilitating virus entry into the cell. BK virus variants:
Divided into 4 subtypes the most common is subtype 1 account for 80% and subtype 4 15%.subtype 2 and 3 are rare. Immunological response to BK virus:
viral replication follows a state of immune suppression as in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period. Pathogenesis of BK infection:
Primary infection is subclinical, manifests as a mild respiratory symptom in childhood. After resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria and remain latent in leukocytes, brain tissues, and lymph nodes, and reactivate after immunosuppression. Routes of transmission of primary BK virus:
1) Respiratory route: it’s the primary route
2) Gastrointestinal transmission: salivary gland
3) Vertical transmission:
4) Sexual transmission
5) Donor-derived infection
6) urine and blood transmission Clinical presentation:
v In immunocompromised patients, particularly in renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
v Outside renal transplantation, it is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC whereas in HIV infected patients, it may disseminate leading to severe viremia with multiorgan involvement and death. BK virus and malignancy: thoughts on viral oncogenesis:
It has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation. BK virus and urothelial tumors:
It may have a role in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors. Risk factors:
Immunosuppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion. Screening and diagnostic tools:
The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears. Timing of screening:
BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year. American Society of Transplantation Infectious Diseases Guidelines and KDIGO guidelines had recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years. Screening tests:
DNA-PCR in urine and blood Monitoring of the urine:
Include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA. Serology:
Serum BK-PCR of more than 4 logs copies/ml correlates strongly with BKVN, and has sensitivity of 100% with specificity of 88% Virus culture:
BKV can be isolated from a urine sample before any rise in antibody titers; however, virus culture is hardly used .It grows slowly in tissue culture Kidney biopsy:
Gold standard to diagnose BKVN, to be performed if BK viral load is more than 10000 copies/ml insistently with or without graft dysfunction.
Macroscopically shows streaky fibrosis of the medulla with circumscribed cortical scars , whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BK viral inclusions within tubular epithelium can be identified via the conventional hematoxylin and eosin (H&E) and PAS staining. Suggested algorithm for screening:
Hirsch et al. screened patients for BKV, first with urine cytology for decoy cells every 3 months. most transplant centers, recommend BK surveillance with plasma BK-PCR. Screening for BKV should be performed on periodic intervals, starting after 1 month, monthly for 3–6months, and then every 3months for the initial 1–2 years after transplantation. Differential diagnosis:
1) Allograft rejection:
The distinction of BKVN from acute rejection is challenging as the histological appearance is often similar. Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN.it differentiated by n by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells.
2) Others includes any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction. Treatment strategy of BK virus nephropathy:
The aim of treating BKV is to eradicate the virus while saving the kidney function
Reduction in immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response
No standard strategy for modifying immunosuppressant’s therapy.
Strategies used include withdrawal of antimetabolites, or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, or reducing the dose of calcineurin inhibitor (CNI) by 25-50%. Even in setting of graft dysfunction, immunosuppression reduction is important treatment option. Drugs with antiviral activities:
1. Leflunomide: is an immunomodulator, prodrug, and antirheumatic disease-modifying drug with dose of 100 mg daily for 3-5 days followed by 20-40 mg/day has been used as its metabolite A77 1726 inhibits BKV replication but it is associated with hemolysis, thrombocytopenia, hepatitis, and worsening hypertension.
2. Cidofovir: is a cytosine analog and viral DNA polymerase inhibitor that is used to manage other viral infections such as CMV.dose of 0.25 mg/kg every 2-3 week for 10-15 weeks has been used but it may cause acute kidney injury, renal tubular acidosis, proteinuria, and anterior uveitis.
3. mTOR inhibitors:restore downregulation of translation and inhibits BKV-specific T cell proliferation.
4. Intravenous immunoglobulin:has potent neutralizing antibodies and immunomodulatory properties, helping in BKVN management (with concurrent immunosuppression reduction)
5. Other therapeutic options for treating BK virus nephropathy:like quinolones, artesunate, pravastatin and rituximab have also been used. Short-term and long-term allograft survival:
Short-term improved by reduction in immunosuppression therapy but long-term need to be evaluated. BK nephropathy with concurrent acute rejection:
A combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection. Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN. Post infection monitoring:
Close observation with serum creatinine every 1-2 weeks and plasma BKV-PCR every 2-4 weeks for 8 weeks should be done, followed by monthly BKV-PCR till viremia gets cleared. If viremia persists despite RIS, then consider changing to sirolimus, or adding leflunomide. Re transplantation:
Can be done successfully following graft loss owing to BKVN.
Pretransplant clearance of BK viremia is essential after minimizing immunosuppression
BKV viruria, viremia, and BK nephropathy can recur and cause allograft loss which might reflect a previous BK variant or a new infection (de-novo BKV). Conclusion:
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment. What is the level of evidence provided by this article?
It is level V
BKV is identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients in the first year after transplantation. It usually presents with asymptomatic gradual rise in creatinine and tubulointerstitial nephritis.
It may mimic acute rejection therefore making its diagnosis and treatment more difficult.
belongs to the polyomaviridae (PyV) virions, a subgroup of papovavirus. It is a family of small, non-enveloped DNA viruses with icosahedral capsid and a double stranded DNA.
It usually infects humans. Primary infection takes place during early childhood, and then the virus stays dormant throughout life in the immune-competent population.
categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1. The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined. BKV replication occurs during a state of immune suppression, for example in pregnancy, diabetes, HIV infection, cancer, and post-transplantation period. It usually begins early in the posttransplant period and can follow antirejection therapy because of intense immunosuppression.
There are possible factors that contribute to the pathogenesis of BKV nephropathy (BKVN), such as:
Defective immune surveillance by the host T-lymphocytes
Absence of humoral immunity to BKV
Alloimmune activation
Viral variation in molecular sequences.
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity and aid to clear BKV. T cells react against both nonstructural and BK capsid proteins. Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA. Without appropriate immunological regulation, progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination into the interstitium. Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation. The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis. Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss.
Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, sometimes manifests as a mild respiratory symptom in childhood. It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria. During the use of immune suppressive medications, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria. The outcome relies on the level of damage, inflammation, and fibrosis.
The route of transmission of the infection may be via respiratory, faecal-oral, transplacental, or from donor tissues.
Clinical manifestations
usually presents as BKVN, ureteric stenosis, and late-onset haemorrhagic cystitis.
Other clinical manifestations include neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome and vasculopathy. Clinical signs may include headache, dizziness, confusion, paraplegia, ataxia, and seizures. Pulmonary disease may be reactivated, and the acute respiratory infection may lead to severe interstitial pneumonitis.
Risk factors
degree of immune suppression
male sex
older recipient age
previous rejection episodes
degree of HLA mismatching
prolonged cold ischemia
BK serostatus
certain ethnic groups
lower total lymphocyte percentage
ureteral stent insertion.
Screening
screening should start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood. However, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml, with or without allograft dysfunction.
Histology
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically, whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BKV affects the kidney allograft in an erratic, multifocal manner; hence, false-negative biopsies may occur, specifically at early stages of the disease, therefore a repeat biopsy may be warranted.
Differential diagnosis
Differential diagnosis include allograft rejection, and any other disease associated with early (1–12 weeks after transplantation) and late ( ≥ 3 months transplantation) renal allograft dysfunction.
Treatment
The aim of treating BKV is to eradicate the virus while saving the kidney function. Unfortunately, BKVN has limited treatment options. Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response. However, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection. Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI.
Drugs with antiviral activities
Leflunamide
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug. It can inhibit pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects. However, being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; thus, treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages. Therefore, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage. Additionally, leflunomide has a higher rate of adverse effects such as haemolysis, aplastic anaemia, thrombocytopenia, and probably thrombotic microangiopathy, hepatitis, and worsening of hypertension.
Cidofovir
Cidofovir is a cytosine analogue and viral DNA polymerase inhibitor that is used to manage other viral infections such as CMV. It has shown inhibitory action against polyomaviruses in vitro. Cidofovir is excreted through urine, resulting in high renal tubular cell concentrations. Hence, vigorous intravenous rehydration is needed with dose adjustment if renal dysfunction is present. Cidofovir is a nephrotoxic drug, it may cause acute kidney injury, renal tubular acidosis, and proteinuria. It may also cause severe anterior uveitis which may lead to permanent visual impairment.
mTOR Inhibitors
inhibitors have shown effectiveness in in-vitro analysis in inhibiting BK replication and early gene expression. Similar to other therapeutic options, the administration of mTOR inhibitors was concomitantly used with lowering immunosuppression, questioning its clinical efficacy against BKV.
IVIG
Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes. However, the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression.
Other therapeutic options include quinolones, artesunate, pravastatin and rituximab.
Allograft survival
The renal allograft survival for recipients with BKVN has improved considerably in the past years. The documented acute rejection rates following a reduction in immunosuppression varies from 6 to 12%. Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening. However, 27% had experienced permanent allograft dysfunction and 18% ultimately lost their allograft secondary to BKVN.
BK nephropathy with concurrent acute rejection
Management of acute rejection with concomitant BKVN is debatable. More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection. Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN. In the absence of typical features, such as strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial haemorrhage, which could be indicators for acute rejection, the management should be tailored for each patient individually. The delayed improvement in renal functions following a reduction in immunosuppression is likely to reflect the slow resolution of the cellular infiltrate.
Post-infection monitoring
Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome. Based on different literature, BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression. If viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide. Inability to clear BKV can lead to worse allograft outcomes.
Re-transplantation
Re-transplantation following graft loss owing to BKVN is possible and can be done successfully. Generally, pre-transplant clearance of BK viremia is essential after minimizing immunosuppression. The patient may get infected with BKV after re-transplantation. Recurring BKV might reflect a previous BK variant or a new infection (de-novo BKV) acquired, because of the long period, in the post-transplantation stage.
Level Of Evidence:
This is a narrative review,level V
IV. BK virus infection in renal transplant recipients: an overview
· BK polyomavirus (BKV) was first detected in both urine and ureteral epithelial cells, in 1971 by Gardner et al.
· BKV was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipients.
· BKV, is a ubiquitous virus that infects most humans around the world.
· Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people.
· BKV-DNA genome can be divided into three parts: 1) The early viral gene region. 2) The late viral gene region (LVGR). 3) The capsid protein VP1 in the LVGR.
· BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and post-transplantation period.
· Primary BKV infection is usually subclinical, it goes into the circulation via tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
· After resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
· In the presence of immunosuppressive therapy, the virus activates and proliferates in the interstitium and crosses into the peritubular capillaries, leading to tubular cell lysis and viruria.
Routes of transmission of primary BK virus
1) Respiratory route: suspected to be the primary route for transmission, but it was not isolated on respiratory samples.
2) Gastrointestinal transmission: BKV detected in saliva and stool.
3) Vertical transmission: via the transplacental passage.
4) Sexual transmission: but primary infection happens before the age of sexual activity
5) Donor-derived infection.
6) transmission through the urine and blood
Clinical manifestations
· in renal allograft recipients, BKV induces BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
· in patients with hematopoietic stem cell transplant (HSCT) recipients, BKV induces hemorrhagic and non- hemorrhagic cystitis.
· in HIV-infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement and death. BK virus and renal disease
· BK virus-associated nephropathy: begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
· Ureteric stenosis: prevalence 2-6%, but rarely lead to hydronephrosis and Allograft dysfunction
· Hemorrhagic cystitis: Rare in renal allograft recipients
· BK nephropathy in the native kidney: described in HSCT recipients, heart and lung transplant recipients, and HIV-infected patients. BK virus and autoimmune diseases
· BKV viruria can be seen in patients with systemic lupus erythematosus
BK virus and malignancy: thoughts on viral oncogenesis
· The BKV-DNA has been identified in tissue samples of different neoplasms
BK virus and urothelial tumors
· BKV may have a role in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors.
· But BKV-DNA was discovered by PCR in only 5.5% of urothelial tumors
Timing of screening
· KDIGO guidelines recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening tests
· Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
Monitoring of the urine
· Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients
· Presence of decoy cells is strongly suggestive of polyomavirus infection and considered a useful marker of BKV reactivation
· Presence of Haufen bodies, which corresponds to upper levels of BK viremia, had a higher sensitivity and specificity for biopsy-proven BKVN
· molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity
· BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication
Serology: Serum BK-PCR
· BK viremia is noticed only among immunocompromised patients, with an estimated prevalence of 7–30% in the initial 6 months and 5–10% after that among kidney recipients
· Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis
· not all recipients with BK viremia will develop nephritis (BK-PCR has a PPV for BKVN of 50–60% and an NPV of 100%) Serum antibodies
· BK D+/R− have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients. Virus culture
· BKV grows slowly in tissue culture, which may take from weeks to months Kidney biopsy
· allograft biopsy is the gold standard to diagnose BKVN, which should be performed when BKV-PCR load persistently exceeds more than 10 000 copies/ml with or without allograft dysfunction
· BK viral inclusions within tubular epithelium can be identified via the conventional (H&E) and PAS staining Suggested algorithm for screening
· Screening for BKV should be performed on periodic intervals, starting after 1 month,monthly for 3–6months, and then every 3months for the initial 1–2 years after transplantation.
· American Society of Transplantation guidelines recommended further annual screening till the fifth year after transplant
Differential diagnosis
· BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells.
· Absence of endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease
Treatment strategy of BK virus nephropathy Treatment of presumptive BK virus nephropathy
· The first treatment of BKV disease is reduction/or modifications in immunosuppressive therapy with or without antiviral medications. Examples:
1) withdrawal of antimetabolite drugs
2) or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide,
3) reducing the dose of calcineurin inhibitor (CNI) by 25–50% or converting tacrolimus to cyclosporine or discontinuing CNI
Treatment of BK virus nephropathy in the setting of allograft dysfunction
· The best renal allograft outcomes in the acute BKV infection were reported when immunosuppression reduction had started early upon detection of BK viremia Drugs with antiviral activities Leflunomide
· Leflunomide (antirheumatic disease-modifying drug) metabolite can inhibit BKV replication in vitro and, to a minor degree, the level of virion assembly and release
· leflunomide cannot be combined with MMF or azathioprine; thus, they should be stopped and reduced CNI dosages during use of leflunomide.
· factors that limited its use: (a) higher dosage of the drug is necessary to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity;
(b) trough level is not accessible in all laboratories
(c) the immunosuppressive effectiveness of leflunomide is weak
Cidofovir
· It had in-vitro inhibitory action against polyomaviruses, and exclusively excreted through urine, resulting in high renal tubular cell concentrations
· It is a nephrotoxic drug; it may cause acute kidney injury, renal tubular acidosis, and proteinuria mTOR inhibitors
· mTORi inhibits BK replication and early gene expression and inhibits the proliferation of BKVspecific T cells and controls the differentiation of memory CD8 T cells
Intravenous immunoglobulin
· IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes, and it has been used for BKVN
Other therapeutic options for treating BK virus nephropathy
· Quinolones have been found beneficial in combination with leflunomide for treating BKVN, with a significant decrease in BK viremia
· Artesunate has anti-viral influence on BK viral proliferation in a primary human renal cell culture.
· statins (pravastatin) were found to reduce the percentage of BKV-infected cells
· Rituximab
Short-term and long-term allograft survival
· the renal allograft survival for recipients with BKVN had improved considerably in the past years.
· The documented acute rejection rates following a reduction in immunosuppression varied from 6 to 12%
BK nephropathy with concurrent acute rejection
· Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.
Post-infection monitoring
· BKV-PCR and renal function with any treatment, mainly post- treatment of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome
· BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression. Re-transplantation
· Re-transplantation following graft loss owing to BKVN is possible and can be done successfully Conclusion
· An early diagnosis of BKVN has resulted in significant improvement in allograft outcomes despite a lack of specific treatment.
Introduction: Two human polyoma viruses (BK virus and JC virus) were discovered in 1971, with BK virus causing interstitial nephritis and graft failure, while JC virus being responsible for progressive multifocal leukoencephalopathy (PML). BKV infection may present with asymptomatic gradually increasing creatinine within first year of transplant.
BKV and renal transplantation: historical perception: BKV was first detected in 1971 in a Sudanese renal transplant recipient with ureteric stenosis and renal failure, showing large cells with intranuclear inclusions in the urine (decoy cells). Histological changes of BKV infection were described first in 1978.
Polyomaviridae variants: Polyomaviridae subgroup of papovaviruses comprises of BKV, JCV and simian virus 40 (SV40), which are nonenveloped DNA viruses. 12 additional human polyomaviruses have been identified till now.
Epidemiology of BKV: Polyomavirus hominis-1 or BKV is ubiquitous, affecting primarily during early childhood (seroprevalence 60-85%) and then remaining dormant throughout life.
BKV structure: BKV-DNA genome can be divided into 3 parts: Non coding control region (NCCR) is responsible for regulation of virus early and late gene expression; early viral gene region (EVGR) which encodes small T antigen (STA, causes viral replication cell cycle progression and transformation) and large T antigen (LTAg, drives cell into S phase); and late viral gene region (LVGR) which encodes capsid proteins VP1 (leading to receptor binding to host cell, entering the cell and causing dormant or lytic infection), VP2, VP3, and cytoplasmic protein agnoprotein (having regulatory function).
BKV variants:4 genotypes of BKV are seen. Genotype I (a, b-1, b-2, and c subgroups) is most common (>80%), with 15% prevalence of genotype IV (a-1, a-2, b-1, b-2, c-1, c-2 subgroups) and genotype II and III being rare. Genotype Ic is prevalent in Asia while IVc and Ib-2 are prevalent in USA and Europe.
Immunological response to BKV: BKV replication occurs in immunosuppressed states (pregnancy, diabetes, HIV, cancer, and post-transplant due to intense immunosuppression). Pathogenesis of BKV nephropathy (BKVN) includes (a) defective immune surveillance by host T-cells: Cytotoxic T cells kill BK-infected cells leading to viral leakage into tubular lumen and urine as well as dissemination into renal interstitium further causing tubular cell necrosis and tubular capillary wall damage leading to basement membrane denudation, cast formation, tubulitis and inflammatory interstitial infiltrates with collateral destruction of non-infected tubular cells responsible for graft dysfunction; (b) absence of humoral immunity to BKV: Patients with prior immunity to BKV do not show manifestations of the disease irrespective of the viral load, while those receiving kidney from seropositive donor have increased likelihood of getting BK viremia; (c) alloimmune activation: allo-HLA reactivity and heterologous immunity has a role with lack of HLA matches showing better outcomes in recipients with BKVN; and (d) viral variation in molecular sequences and BKV tropism to renal tubular epithelial cells colocalizing with caeolin-1.
Pathogenesis of BK infection: BKV infection leads to childhood mild respiratory symptoms infecting tonsils and then spreading to the circulation infecting peripheral blood mononuclear cells, disseminating further to kidneys (uroepithelium and tubular cells), leukocytes, lymph nodes, and brain tissue, remaining latent there. Immunosuppression leads to BKV proliferation in interstitium, peritubular capillaritis, and tubular cell lysis with viruria.
Routes of transmission of primary BK virus: These can be respiratory, feco-oral, transplacental, or donor-tissue derived. Urine and blood have also been proposed as mode of transmission.
Clinical manifestations: Although BK viruria is seen in 7% of immunocompetent individuals, it is not associated with clinical disease. Immnucompromised patients present with BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (in renal transplant recipients), hemorrhagic and non-hemorrhagic cystitis in HSCT recipients, and multiorgan involvement in HIV. BK viruria is seen in 30-40% or renal transplant recipeints, progressing to viremia (seen in 10-15%), eventually leading to BKVN (seen in 2-15%). BKV nephritis onset can occur within 6 days to as late as 5 years. Ureteric stenosis is seen in 2-6%, and is treated with percutaneous nephrostomy followed by ureteral dilatation and reduction in immunosuppression. Hemorrhagic cystitis causes bladder cramps, painful voiding, hemturia, and flank pain. 4 grades include grade I (microscopic hematuria), grade II (macroscopic hematuria), grade III (hematuria with clots), and grade IV (hematuria with clots, clot retention and obstructive nephropathy associated renal failure). Treatment involves suprapubic catheter insertion, continuous bladder irrigation, and local cidofovir instillation. Other clinical manifestations include encephalitis, Guillian-Barre syndrome, interstital pneumonitis, atypical retinitis, retinal necrosis, hepatitis, colitis, associated autoimmune disease like SLE, polymyositis, and rheumatoid arthritis.
BK virus and malignancy: BKV-DNA has been seen in different brain tumors, pancreatic islet cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors. Agnoprotein and LTAg inhibit the cell cycle arrest driving the infected cell into a continuous dividing state. LTAg inhibits Rb and p53 tumor suppressor gene products. BKV is associated with urothelial malignancy, especially bladder carcinoma.
Risk factors for BKVN: These include degree of immunosuppression, male, older recipient age, HLA mismatching, increased cold ischemia time, BK serostatus, lyphopenia, acute rejction, and ureteral stent insertion.
Screening and diagnostic tools: KDIGO recommends BKV screening monthly for first 6 months and then at 9-, 12-, 15-, 18-, 21-, and 24-months post-transplant. BK viruria precedes BK viremia by 4 weeks and BKVN by 12 weeks.
Urine monitoring for BKVN is highly sensitive includes urine cytology showing decoy cells (infected tubular epithelial cells with single enlarged basophilic intranuclear inclusion body in an enlarged nucleus, or Haufen (cast-like 3-dimensional icosahedral aggregate of BKV particles and Tomm-Horsfall protein) can be seen under electron microscope. sensitivity and specificity for BKVN with Haufen is 100% and 99% respectively, while it is 100% and 71% respectively with decoy cells. Urinary BKV-PCR has 100% sensitivity and 78% specificity while urinary BKV mRNA has 100% sensitivity with 97% specificity.
Serology: Serum BK-PCR of more than 4 logs copies/ml correlates strongly with BKVN, and has sensitivity of 100% with specificity of 88%. Serial estimation of BK viral load is better to demonstrate BK resolution after immunosuppression reduction, and in cases under consideration for re-transplantation post BKVN-associated graft loss. These tests have high interlaboratory variations, and most of the tests are designed against genotype I, hence may not give accurate results in infections with other genotypes. There is no clinical relevance in assessing serostatus except BK D+/R- being risk factor for BKV disease development. As BKV grows slowly, viral culture is not useful in routine clinical settings.
Kidney biopsy: It remains the gold standard to diagnose BKVN, to be performed if BK viral load is more than 10000 copies/ml insistently with or without graft dysfunction. Macroscopic appearance of streaky fibrosis of medulla with circumscribed cortical scars, and microscopic appearance of sclerosed glomeruli, atrophied tubules, and interstitial fibrosis can be seen. Histological findings can be focal, hence can be missed leading to false-negative biopsies. Different gradings of histopathological changes have been described by Banff working group, University of Maryland, and American Society of transplantation. BK viral inclusions can be seen with H&E and PAS staining. Positive immunohistochemistry (IHC) using SV40 LTAg has nearly 100% specificity for polyomavirus nephropathy.
Suggested algorithm for screening: Hirsch et al advised to screen with urine cytology for decoy cells every 3 months, and if present, get serum BKV-PCR. Kidney biopsy to be done in presence of graft dysfunction. Most transplant centres perform plasma BKV-PCR monthly for 3-6 months, then 3 monthly for 1-2 years, then annual screening till 5 years post-transplant.
Differential diagnosis: Allograft rejection needs to be ruled out in view of diametrically opposite treatment. Presence of urinary and blood BKV aids in diagnosing BKVN in presence of equivocal biopsy findings. Biopsy positive for BKV inclusion bodies and SV40 stain help in diagnosing BKVN, in addition to absence of endotheliitis, extensive tubulitis and C4d deposits. Other causes of graft dysfunction like pre-renal causes, sepsis, post-renal causes also need to be ruled out.
Treatment strategy of BKVN:Reduction in immunosuppression is the only validated treatment option for BKVN. There is no standard strategy for immunosuppression modification. Reduction in immunosuppression (RIS) can lead to acute rejection in 6-12% patients. Strategies used include withdrawal of antimetabolites, or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, or reducing the dose of calcineurin inhibitor (CNI) by 25-50%. Even in setting of graft dysfunction, immunosuppression reduction is important treatment option. Leflunomide in dose of 100 mg daily for 3-5 days followed by 20-40 mg/day has been used as its metabolite A77 1726 inhibits BKV replication but it is associated with hemolysis, thrombocytopenia, hepatitis, and worsening hypertension. Intravenous cidofovir in dose of 0.25 mg/kg every 2-3 week for 10-15 weeks has been used but it may cause acute kidney injury, renal tubular acidosis, proteinuria, and anterior uveitis. mTOR inhibitors restore downregulation of translation and inhibits BKV-specific T cell proliferation. Intravenous immunoglobulin (IVIG) has potent neutralizing antibodies and immunomodulatory properties, helping in BKVN management (with concurrent immunosuppression reduction). Other therapeutic options like quinolones, artesunate, pravastatin and rituximab have also been used.
Short-term and long-term graft survival: Documented acute rejection following RIS occurs in 6-12% cases. Short-term improvements have taken place with RIS, but long-term effects need to be evaluated.
BKVN with concurrent acute rejection: A combination of antirejection therapy, with subsequent RIS should be done in such cases, with management to be tailored individually for each patient.
Post-infection monitoring: Close observation with serum creatinine every 1-2 weeks and plasma BKV-PCR every 2-4 weeks for 8 weeks should be done, followed by monthly BKV-PCR till viremia gets cleared. If viremia persists despite RIS, then consider changing to sirolimus, or adding leflunomide.
Re-transplantation: It can be done successfully post- graft loss due to BKVN. Pre-transplant BK viremia clearance is essential and allograft nephrectomy is not necessary. BKV might recur post-transplant, which could be either due to the previous BK variant, or due to a de-novo infection. The 1- and 3-year graft survival post-retransplant are excellent.
Conclusion: Screening for BKV infection post-transplant is important part of post-transplant surveillance. An early diagnosis with timely RIS has led to improved graft outcomes in BKVN.
2. What is the level of evidence provided by this article?
BK virus and renal transplantation:
Polyomavirus BK shared a high degree of similarity with JCV, which is responsible for progressive multifocal leukoencephalopathy. In kidney transplant recipients, BKV has been linked to severe interstitial nephritis and allograft failure. Human BKV is a member of the Polyoma viridae (PyV) virions, a subgroup of papovaviruses that includes BKV, JCV, and simian virus 40. (SV40).
Polyoma is derived from the words many (poly) and tumors (oma). Several viruses have been recognized. Epidemiology of BK virus
Primary infection occurs during childhood, and the virus remains dormant in immune-competent people throughout life.
The BKV-DNA genome is divided into three parts and classified into four genotypes.
The immune response to BK viral replication occurs after a state of immune suppression; thus, it has been reported to occur during pregnancy, diabetes, HIV infection, cancer, and the post-transplantation period.
Possible factors that add to the pathogenesis of BKVN might be a combination of
(a) defective immune surveillance by the host T lymphocytes
(b) absence of humoral immunity to BKV
(c) alloimmune activation
(d) viral variation in molecular sequences .
It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Additionally, BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
In the presence of immunosuppressive therapy, the virus gets activated causing tubular cell lysis and viruria. The outcome relies upon the level of damage, inflammation, and fibrosis .
Routes of transmission of primary BK virus: might be respiratory, fecal-oral, transplacental, or from donor tissues. Clinical manifestations
BKV does not cause disease in immunocompetent people
In immunocompromised patients, particularly in renal allograft recipients it can cause BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC) .
The virus can dormant in the uroepithelial cells then it shed in to the urine causing viruria , few weeks later in it disseminate to the blood causing viremia responsible for BKVN
· BK viruria generally affects 30–40% of renal transplant recipients.
· whereas 10–15% of recipients develop BK viremia .
Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
· The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years
· Ureteric stenosis 2–6% , if severe causing hydronephrosis will requires a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications .
· Hemorrhagic cystitis rarely observed among renal allograft recipients. The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain . if severe requires hydration and continuous bladder irrigation
· Other rare manifestations include Neurological , Pulmonary , Ophthalmologic, hepatic disease
· BK virus is associated with certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, in non-transplant immune-compromised individuals .
· BKV-DNA has been identified in tissue samples of different neoplasms such as brain tumors , pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
· There are some reports found association between BK virus and urothelial tumors. Risk factors implicated in the pathogenesis of BKVN
· Degree of immunosuppression,
· Others include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion;
BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year . the incidence of viremia and viruria showed bimodal peaks. 3rd then 12 month post transplant.
KDIGO recommends screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Diagnosis:
· Cytological analysis of urinary smear may reveal characteristic abnormal BK-infected cells, termed as decoy cells. Decoy cells are infected tubular epithelial cells, with an enlarged nucleus that contains a single, large basophilic intranuclear BK inclusion body and looks similar to those cells seen frequently in uroepithelial malignancy . Presence of decoy cells is strongly suggestive of polyomavirus infection and considered a useful marker of BKV reactivation, though it is not a real diagnostic tool for BKVN.
· Urine electron microscopy (EM Haufen): in contrast to decoy cells, Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, forming cast-like three-dimensional aggregates, which can be noticed in a urinary smear of kidney recipients using negative-staining electron microscopy . it requires further validation.
· Quantitative measurements of urinary BK virus-viral loads using urinary BKV-PCR .
· BK virus mRNA levels in urine viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication
1. BK viral loads (PCR) . Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis is the preferred screening technique at most transplant institutions
2. A serial estimate of viremia is the best technique to date to demonstrate resolution of BK activity following reduction of immunosuppression.
3. Furthermore, serial determinations of viremia are required to follow-up patients who lost their allograft because of BKVN and considered for re-transplantation Kidney biopsy
allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction .
Positive IHC using specific antibodies against BKV or the cross-reacting SV40 LTAg has a specificity of nearly100% for polyomavirus nephropathy;
AST guidelines recommended further annual screening till the fifth year after transplant; nevertheless, generally screening beyond 2 years is not recommended in most centers unless allograft dysfunction is present. Differential diagnosis
The distinction of BKVN from acute rejection is challenging as the histological appearance is often similar; therefore, it should be aided by analysis of blood or urine PCR.
Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN. Nevertheless, BKVN may exist concurrently with acute rejection .
BKVN can be distinguished from acute rejection by
1. The presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells.
2. Absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease
3. IHC staining of renal tissues or urinary sediments anti-HLA DR, which has been related to acute rejection
4. Higher quantity of CD20+ cells in the tissue infiltrates has been associated with BKVN as opposed to acute rejection.
The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of concurrent acute rejection Treatment strategy of BK virus nephropathy
1. Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; There is no standard strategy for modifying immunosuppressant’s therapy; such as withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance .
Such approaches can include withdrawal of antimetabolite drugs(MMF) or change to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI .
Treatment of BK virus nephropathy in the setting of allograft dysfunction Favorable renal allograft However, allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy .
2. Cidofovir, brincidofovir .
3. The mTOR inhibitors (sirolimus and everolimus) are thought to produce their inhibitory effect on BKV replication hence, it improves the immune reaction following BKV infection .
Similar to other therapeutic options, the administration of mTOR inhibitors was concomitantly used with lowering immunosuppression, generating contradictory results.
4. Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN
The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection;
Other therapeutic options for treating BK virus nephropathy
(1) Quinolones
(2) artesunate (an antimalarial drug)
(3) statins (pravastatin)
(4) Rituximab with cidofovir had no graft failure during follow-up of 17 months, Short-term and long-term allograft survival
The proposed current management have revealed substantial short-term improvements, however it influence on long term outcome such as late acute and chronic rejections need to be further evaluated.
The documented acute rejection rates following a reduction in immunosuppression varied from 6 to 12%. BK nephropathy with concurrent acute rejection
Most of the biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in 10–30% of the cases .
Though some reported either clinical improvement, steady or worse allograft outcomes, following steroid pulses .
It is recommended once BKVN is diagnosed in concurrence with acute rejection, an initial decrease in immunosuppression without steroid pulses . Upon clearance of viremia and BKVN, the advantage of up-titrating immunosuppression to avoid further late acute rejection or chronic rejection remains obscure Post-infection monitoring
Close observation of
· BKV-PCR and
· Renal function
The most common approach is to follow serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks after immunosuppressant reduction. Subsequently, it should be done on a monthly bases until clearance of BK viremia and stabilization of renal function achieved.
Reports showed BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression.
If viremia persists despite reducing the maintenance therapy, then switching to sirolimus, or adding leflunomide is advisable. Retransplantation
Retransplantation post BKVN can be successful. Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression . Allograft nephrectomy is not necessary before retransplantation; however, elimination of infection prior re transplantant is most sensible but there is no evidence to support this.
Recurring BKV might reflect a previous BK variant or a new infection.
● BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
● It is often occurring within the first year after transplantation.
● It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection
● Decoy cells are Abundant large cells with intranuclear inclusions present in the urine, resembling malignant cells
● Can bear heating up to 50°C for 30 min
● Double-stranded DNA of ∼5000
● New group members were termed based on the site of discoveey or the diseases they might cause, or an order of discovery
Epidemiology of BK virus
☆ BKV is Polyomavirus hominis-1
☆ Primary infection predominantly takes place during early childhood, then stays dormant throughout life in immune-competent people
☆ 60–85% of the general population is seropositive for BKV
BK virus structure
● The noncoding control region (NCCR) regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell.
(1) The early viral gene region encodes two proteins called small T antigen (STA) and (LTAg, large tumor antigen) which drives the cell into S phase, whereas STA is involved in viral replication, cell cycle progression, and transformation.
(2) The late viral gene region (LVGR): encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus.
* Release around virions through cell lysis.
* Encodes a small cytoplasmic protein called agnoprotein, which assistance in regulating viral replication and interrupt host cell processes.
(3) The capsid protein VP1 in the LVGR is
* Responsible for receptor binding to the host cells, facilitating virus entry into the cell.
* It is highly immunogenic and Once it gets inside the cell, the virus travels to the nucleus and establishes a dormant or lytic infection
BK virus variants
☆ Four genotypes/subtypes
* Genotype I is the predominant > 80% and has 4 subgroups
* Genotype IV found in 15% and has six subgroups
* Genotypes II and III are rare
☆ Variant viruses resulted due to deletion and duplication in the NCCR sequences during activation process
Immunological response to BK virus
● BK viral replication follows a state of immune suppression so it occurs in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period
● BKV begins early in the posttransplant period and can follow antirejection therapy
● The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN)
● Factors that participate pathogenesis of BKVN :
* Defective host T- lymphocytes
* Absence of humoral immunity to BKV
* Alloimmune activation
* Viral variation in molecular sequences
● The role of cell-mediated immunity
☆ CD4+ and CD8+ T cells are the main components that control the BKV and play a role in BK clearance.
☆ LTAg and VP1 gene products contain epitopes responsible for CD4+ and CD8+ cells identification
☆ Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA
☆ Lysis of an infected cell lead to viral leakage into the tubular and interstitium causing necrosis, casts formation, tubulitis and interstitial infiltrate
☆ Continued intragraft inflammation, tubular injury and up-regulation of profibrotic mediators ends with allograft dysfunction and loss
● The role of antibody-mediated immunity was also validated in BKV infection as patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels
● Role of alloimmune activation
☆ Higher degree of HLA mismatches increases incidences of BKVN, which hypothesizes the role of alloimmune activation.
● The role of other factors
☆ BKV tropism to the renal tubular epithelial cells
● The pathogenesis of BKV disease is related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium.
Pathogenesis of BK infection
● Primary infection is usually subclinical or a mild respiratory symptom in childhood
● BKV goes through infected tonsils then infect mononuclear cell that disseminated to secondary places including kidneys then virus stays dormant in the uroepithelium and renal tubular cells with intermittent reactivation
● Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses
Routes of transmission of primary BK virus
☆ Respiratory
☆ Fecal-oral
☆ Transplacental
☆ Donor tissues
☆ Sexual transmission
☆ Other as urine and blood
Clinical manifestations
☆ BKV does not cause disease in immunocompetent people
☆ In immunocompromised patients BKV has been correlated with BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis
☆ In HIV-infected patients, BKV disseminate leading to severe viremia with multiorgan involvement that leads to death
☆ Virus proliferate uroepithelial cells followed viruria which progress to viremia then BKVN
☆ BK viruria affects 30–40% of KTRs but
viremia develop in 10–15% and in 2 -15% progress to BKVN
BK virus-associated nephropathy
☆ Nephritis occurs early (6 days after KTx) or late (5 years after Tx)
☆ Ureteric stenosis secondary to ureteric stricture seen in 2-6% and treatment should involve a percutaneous nephrostomy and percutaneous ureteral dilatation, with concurrent RIs
☆ Hemorrhagic cystitis
* classically noticed in HSCT recipients and rarely in renal allograft recipients
* Four degrees of disease severity:
grade I: microscopic hematuria
grade II: macroscopic hematuria
grade III: hematuria with clots
grade IV: hematuria with clots, clot retention, and obstructive renal failure
* Management involves intravenous hydration. In Severe cases insertion of a supra-pubic catheter with continuous bladder irrigation with locally cidofovir and remission needs 2 to 7 weeks
BK nephropathy in the native kidney
● Occurs in HSCT recipients, heart and lung transplant recipient, and HIV-infected patients.
● Patients present with AKI (characteristic histological findings on kidney biopsy)
without significant proteinuria
● Other manifestations include:
* Neurological manifestations:
meningoencephalitis, encephalitis,Guillain–Barre syndrome, and vasculopathy.
* Pulmonary diseases:
reactivated acute respiratory infection, severe interstitial pneumonitis
* Ophthalmologic manifestations:
bilateral atypical retinitis
* Hepatic disease:
hepatitis, elevations of liver enzymes
BK virus and autoimmune diseases
● There is a relationship between BKV and certain autoimmune diseases, mainly SLE, polymyositis, and RA in nontransplant immunecompromised individuals
● BKV infection can induce antidouble-stranded DNA and histone antibodies
BK virus and malignancy:
● BKV has an oncogenic property owing to expression (LTAg) and Agnoprotein which can drive the cell into a neoplastic state by binding to suppressor gene products
● Tumor cells are likely more vulnerable to BKV than normal urothelium, so positivity of BKV is a result instead of a reason for neoplastic transformation
BK virus and urothelial tumors
● BKV-DNA was isolated in these tumors particularly bladder carcinoma
● High level of BKV-LTAg was noted in the nucleus of almost every tumor cell For both the primary tumor and its metastasis
Risk factors for BKVN:
☆ Degree of immunosuppression.
☆ Male sex
☆ Older recipient age
☆ Previous rejection episodes
☆ Degree of HLA mismatching
☆ Prolonged cold ischemia
☆ BK serostatus
☆ Certain ethnic groups
☆ Lower total lymphocyte percentage
☆ Ureteral stent insertion
Screening and diagnostic tools
● BKV screening to start at first month after transplant, then monthly for 3-6 months, and then every 3 months 12-24 months then annually for 2-5 years
● Viral replication starts by viruria then viremia followed by nephropathy.
● Viuria precedes BK viremia by ∼4 weeks, and Histological changes of BKVN are observed 12 weeks after BK viruria
● Screening for active BKV replication includes:
☆ Decoy cells
* Sensitivity 25% and Specificity 84%
* Widely available, useful marker in identification of BKV infection
* It is a poor diagnostic tool in predicting BKVN.
* Not useful for monitoring decline in viral load
☆ Haufen
* Sensitivity 100% and Specificity 99%
* Highly predictive for BKVN
* Not practical for routine practice as it
requires electron microscopy with interpretation from a pathologist
* It is absent in recipients with a lower BK viremia
☆ Urinary BK-PCR
* Sensitivity 100% and Specificity 78%
* Measurement variations between laboratories limit its use
☆ Urinary BK-mRNA
* Sensitivity 100% and Specificity 97%
* Still under assessment and requires further validation
* Raised mRNA levels >11 mRNA copies/μg total RNA) are usually present in recipients with acute cellular rejections.
☆ Plasma BK-PCR
* Sensitivity 100% and Specificity 88%
* Broadly available but costly.
* Has good sensitivity and specificity but
low PPV for BKVN
● Not all recipients with BK viremia will
develop nephritis that it depend on :
* Viral load > 10^4
* Genotype as sesitivity differs according to genotype
● Virus culture
☆ BKV can be isolated from a urine before antibody titers rise
☆ It needs weeks to months So rarely used
● Kidney biopsy
☆ It is the gold standard to diagnose BKVN
☆ It should be performed when BKV-PCR exceeds >10^4 without allograft dysfunction
☆ Positive of BK viral inclusions within tubular epithelium SV40 LTAg has a specificity of nearly100% for polyomavirus
nephropathy
☆ It can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result
☆ If the initial biopsy did not confirm BKVN, then pre-emptive treatment or a repeat biopsy must be considered.
☆ BK-PCR of allograft biopsy tissue can
identify a latent virus, even in asymptomatic recipients
Differential diagnosis
● Allograft rejection
☆ BKVN has presence of BKV inclusion bodies and immunohistology SV40
☆ Acute cellular rejection : endotheliitis and extensive tubulitis and absence of C4d
☆ Positive C4d stainingreported in some BKV cases and is linked with aggressive disease
☆ IHC staining of renal tissues or urinary sediments with anti-HLA DR
☆ BKVN and acute rejection can present concurrently.
● Any disease associated with early and late renal allograft dysfunction.
Treatment strategy of BK virus nephropathy
● Reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
● Leflunomide
☆ Pyrimidine depletion and tyrosine kinase inhibition
☆ Teriflunomide is a metabolite of leflunomide can inhibit BKV replication
☆ Orally (a loading dose of 100 mg daily for 3–5 days then 20–40 mg/day
☆ MMF or azathioprine should withdrawal and CNi should reduce
☆ Limitaitions :
* Higher dosage is necessary
* Liver toxicity
* Monitoring level is not accessible in all laboratories
* AEs (Hemolysis, aplastic anemia, TMA, hepatitis, thrombocytopenia, HTN)
● Cidofovir
☆ Inhibits viral replication; mechanism unknown
☆ Slow intravenous infusion (over 2 h) at an initial dose of 0.25 mg/kg/dose every
2–3 weeks for a period of 10–15 weeks.
☆ Cidofovir has AEs as:
* Nephrotoxicity: AKI, RTA, and proteinuria.
* Severe anterior uveitis
● mTOR inhibitors :
☆ Inhibits proliferation of BKV-specific T-cell and controls the differentiation of memory CD8 T cells
☆ AEs include: Hyperlipidemia, bone marrow toxicity, mucositis and oral ulcerations, and lymphedema
● Intravenous immunoglobulin
☆ Contain neutralizing antibodies against BKV and are immunomodulatory
☆ Dosage 2–3.5 g/kg over 2–5 days
☆ May lead to paradoxical increase in viral load
● Fluoroquinolones
☆ Inhibit BKV replication in vitro and inhibit the large T antigen helicase activity
☆ AEs: gastritis, C difficile, hepatoxicity, neurological adverse effects, and altered mental status
☆ It has been found beneficial in combination with leflunomide
● Artesunate (an antimalarial drug)
☆ Inhibit BK viral proliferation in a primary
human renal cell culture
☆ AEs:Anorexia, dizziness, nausea,diarrhea
● Statins
☆ Prevent caveolae-mediated endocytosis
☆ AEs: muscle events , hepatic dysfunction
● Rituximab
☆ As an adjuvant therapy with cidofovir to improve graft survival
Short-term and long-term allograft survival
● BKVN caused allograft damage in 30-60% of cases.
● Graft survival had improved recently
● Acute rejection following RI 6 to 12%
● Improvement is due to:
☆ Early therapeutic intervention
☆ Routine surveillance biopsies
BK nephropathy with concurrent acute rejection
● Management should be tailored for each patient individually
● Steroid pulses combind with RI
● Cidofovir combinde with Rituximab
Retransplantation
● It is possible and can be successfully
● The 1- and 3-year graft survival was excellent at 98.5 and 93.6%, respectively
● Allograft nephrectomy is not necessary before retransplantation
● BKV viruria, viremia, and BKVN can recur and cause allograft loss
● Recurring BKV might be a previous BK variant or a (de-novo BKV) acquired
IV. BK virus infection in renal transplant recipients: an overview
Summarise this article
Introduction
– BK infection is an early complication of kidney transplantation
– mostly occurs within the first year after transplantation
– the increase in BKV incidence is as a consequence of the use of more potent immunosuppressive agents
– untreated BKV infection causes kidney graft dysfunction and subsequent graft loss
– use of screening protocols help in early recognition of asymptomatic BKV infection resulting in better graft outcomes
Pathogenesis
– BKV replication occurs in states of immunosuppression like post-transplantation, HIV, cancer, pregnancy, diabetes
– BKV replication starts early in the post-transplant period and can also occur after antirejection treatment due to the intense immunosuppression
– the immune system plays an important role in controlling BKV replication and resolution of BKVN
– other factors that play a role in the pathogenesis of BKVN include:
·absence of humoral immunity against BKV,
·defective immune surveillance by the host T lymphocytes
·alloimmune activation
·viral variation in molecular sequences
·BKV tropism in the renal tubular epithelial cells
– primary BKV infection is mostly subclinical manifesting as a mild respiratory syndrome in childhood
– BKV gets into circulation through infected tonsils then infects peripheral blood mononuclear cells which get disseminated to secondary places like the kidneys
– following resolution of the primary infection, BKV remains dormant in the uroepithelium and renal tubular cells for life with intermittent reactivation which manifests as asymptomatic viruria
– BKV can also remain latent in lymph nodes, brain tissue, leucocytes
– in the presence of immunosuppressive drugs, BKV gets activated and starts proliferating in within the interstitium then crosses into the peritubular capillaries causing tubular cell lysis and viruria
– the outcome depends on level of damage, inflammation and fibrosis
– tissue damage is a result of direct viral cytolytic effects and secondary inflammatory responses
Routes of transmission of primary BKV
– include respiratory route, GI transmission (fecal-oral route), vertical transmission (transplacental), donor-derived infection, through blood and urine since BKV has been detected in peripheral blood leucocytes and in urine samples
Clinical manifestations
– presents as an asymptomatic gradual increase in serum creatinine with interstitial nephritis which mimics acute rejection posing a diagnostic and therapeutic treatment dilemma
– clinical features that have been described include: BKVN, ureteric stenosis (2-6%), hemorrhagic cystitis
– BKV infection starts as the virus proliferates in the uroepithelial cells followed by viral detachment in the urine (viruria) which progresses in a few weeks to blood (viremia) and eventually to BKVN
– 30-40% of KTRs have BKV viruria while 10-15% develop viremia and another 2-15% develop BKVN
– BKVN:
·begins with asymptomatic hematuria or viruria and culminates in extensive irreversible injury and graft failure
·the nephritis can occur as early as 6 days post- transplant or as late as 5 years
– ureteric stenosis:
·graft dysfunction due to ureteric stricture leading to hydronephrosis is not common
·treatment involves reduction of immunosuppressive medication, percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation
– hemorrhagic cystitis (HC):
·BKV associate HC and non-HC is common in HSCT recipients, rare among KTRs
·patients present with hematuria, dysuria, bladder cramps, flank pains
·4 grades of disease severity have been described: Grade I: microscopic hematuria; Grade II: macroscopic hematuria; Grade III: hematuria with clots; Grade IV: hematuria with clots, clot retention and kidney failure secondary to obstructive nephropathy
– Management: IV hydration, for severe cases, insert a suprapubic catheter for continuous bladder irrigation, cidofovir (given locally through the bladder hence reducing cumulative drug nephrotoxicity)
– other reported manifestations include: nonspecific URTI, interstitial pneumonitis, encephalitis, meningoencephalitis, GBS, atypical retinitis, colitis, hepatitis
– there is a relationship between BKV and autoimmune diseases like SLE, RA, polymyositis
– BKV-DNA has been identified in tissue samples of different neoplasms including brain, pancreatic islet cell tumors, KS, prostate cancer, urothelial tumors
Risk factors in the pathogenesis of BKVN
– overall degree of immunosuppression, previous rejection episodes, degree of HLA mismatch, prolonged CIT, BKV serostatus, ureteral stent insertion, lower total lymphocyte count, male sex, older recipient age, certain ethnic groups
Screening and diagnostic tools
– screening allows for early detection of viruria and viremia enabling the clinician to act before graft dysfunction appears
– BKVN is an early complication of kidney transplantation with most cases occurring in the 1st year posttransplant
– the incidence of viruria na viremia has bimodal peaks, the 1st one being in the 3rd month and the 2nd one in the 12th month
– BKV screening should start in the 1st month posttransplant, then monthly for the first 6 months and then every 3 months for up to 2 years
– BKV replication starts early after transplant and progresses to viruria, viremia and eventually BKVN
– viruria precedes viremia by ~4weeks, histological changes of BKVN are observed 12 weeks after BK viruria
– screening for active BKV replication involves identification of viral DNA-PCR in blood and urine
Monitoring of urine
– this involves: –
urine cytology i.e., detection of decoy cells, urine electron microscopy (EM haufen)
quantification of urinary BKV viral load by BKV DNA or
quantification of urinary BKV viral load by RT-PCR for BKV mRNA levels in urine
– decoy cells (BKV infected tubular epithelial cells with intranuclear BK inclusion bodies): are strongly suggestive of polyomavirus infection, it is a useful indicator of BKV reactivation although it is not a real diagnostic tool for BKVN, sensitivity 100%, specificity 71%, PPV 29% and NPV 100% when matched with graft-biopsy samples as a diagnostic standard
– urine electron microscopy (EM haufen): presence of haufen bodies (BKV virion aggregates) corresponds to high levels of BKV viremia, sensitivity and specificity for BKVN is 100%; however, this method cannot be used routinely due to the expense and inaccessibility to electron microscopy and the need for a pathologist to interpret the findings
Serology: – Serum BK-PCR and serum antibodies
Serum BK-PCR:
– has a sensitivity 100%, specificity 88%, PPV 50-60%, NPV 88% for the development of BKVN than BK viruria therefore it is the preferred screening tool
– a quantitative BKV-PCR of >10,000 copies/ml correlates strongly with BKVN findings on graft biopsy
– serial BKV-PCR viral load helps monitor resolution of BK activity following immunosuppression reduction as well as in patients considering re-transplantation after graft loss
– serum BK viral load measurements have significant interlaboratory variations and lack international standardization
Serum antibodies
– the relevance of assessing BK antibodies serostatus pre- and post- transplant on routine basis remains uncertain
– it has no clinical significance in diagnosing acute BKV infection affecting KTRs
– BK D+/ R- serostatus is a risk factor for the development of clinically significant BKV disease in KTRs
Virus culture
– BKV can be isolated from a urine sample even before the antibody titers rise
– BKV grows slowly in tissue culture and may take weeks to months hence viral culture is rarely used outside research settings
Kidney biopsy
– presumptive BKVN refers to patients with significant viruria (indicating viral proliferation in the urinary tract) and persistent viremia of >10,000copies/ml for more than 3 weeks
– graft biopsy is the gold standard diagnostic tool for BKVN
– should be done in KTRs with BKV viremia of >10,000copies/ml with or without graft dysfunction
– immunohistochemistry (IHC) uses specific antibodies against BKV or the cross-reacting SV40 Ag
– positive IHC has a specificity of ~100% for polyomavirus nephropathy but it does not differentiate between BKV and JCV although JCV-related nephropathy is extremely rare
– persistent BKVN results in renal parenchymal scarring with advanced IFTA
– 2 biopsy cores preferably including medulla should be obtained since the biopsy findings can be focal or isolated in the medulla, and this can be missed on 1/3rd of biopsies giving a false negative report
– false negative biopsies can also occur at the early stages of the disease, in such cases consider pre-emptive treatment or a repeat biopsy
– BK-PCR of graft biopsy is not applicable since it can identify latent BKV even in asymptomatic KTRS
Screening algorithm for BKV post-kidney transplantation
– screen for BKV using plasma BKV PCR:
· routinely, monthly for 3-6months then every 3months for 12-24months then annually for 2-5years
· any time there is an unexplained increase in serum creatinine
· following treatment of acute rejection
– in any of the 3 scenarios, if plasma BKV-PCR is <10,000copies/ml consider monthly monitoring as well as reduction in immunosuppression
– however, if plasma BKV-PCR is >10,000copies/ml consider a graft biopsy
Differential diagnosis
· graft rejection:
– histologically similar to BKVN hence the need for blood or urine PCR to differentiate the two, nevertheless BKVN can co-exist with acute rejection
– presence of BKV inclusion bodies and a positive IHV for SV40 favour a diagnosis of BKVAN
– a positive C4d staining is linked with a more aggressive BKV disease
– presence of endarteritis, glomerulitis, fibrinoid vascular necrosis and C4d deposits along peritubular capillaries is conclusive of acute rejection
· any disease associated with early (1-12 weeks post-transplant) and late (>3months post-transplant) graft dysfunction
Treatment strategy for BKVN
– the aim of treatment is to eradicate the virus while preserving graft function
– BKV viremia and BKVN indicate over-immunosuppression hence reduction of immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response
– rapid reduction in BKV viral load is associated with a steady or improved graft function
– however, reduction in immunosuppression ought to be balanced against the risk of triggering an acute or chronic rejection
Treatment of presumptive BKVN
– 1st step is to reduce or modify the immunosuppressive therapy ± antiviral drugs
– there is no standard strategy for this but some approaches have been described e.g.,
· withdrawal of antimetabolite drugs e.g., MMF – this is the most usual strategy
· change from MMF to azathioprine, sirolimus, or leflunomide
· reducing the CNI dose by 25–50% (to achieve a target trough level of tacrolimus 3-4ng/ml and cyclosporine 50-100 ng/ml, or even less) or
· converting tacrolimus to cyclosporine or
· discontinuing CNI
– tacrolimus and cyclosporine have been shown to inhibit anti-BKV-specific T-cell reaction
– MMF may limit the proinflammatory and profibrotic cytokines
Treatment of BKVN in the setting of graft dysfunction
– in advanced disease, reduction of immunosuppression is less effective, and it is not clear if modification of the immunosuppressive medications will alter the prognosis
– graft function may stabilize following modification of immunosuppressive or may still advance to end-stage disease
– reduction of immunosuppression in the setting of graft dysfunction may result in clearance of viremia, raise the BKV-specific IgG AB titers, increase BKV specific cellular immunity with steadiness of the graft function
Drugs with antiviral activities
Leflunomide
– has antiproliferative and anti-inflammatory properties since it inhibits pyrimidine synthesis
– inhibits BKV replication in vitro, level of virion assembly and release
– should not be combined with other antiproliferative agents like MMF, azathioprine
– adverse effects: aplastic anaemia, hemolysis, thrombocytopenia, TMA, hepatitis, worsening hypertension
Cidofovir
– a viral DNA polymerase inhibitor used in management of other viral infections e.g., CMV
– has inhibitory activity against polyomaviruses, given as a slow IV infusion
– nephrotoxic hence requires vigorous IV prehydration and adjust dose depending on kidney function
– can cause AKI, proteinuria, renal tubular acidosis, severe anterior uveitis
Brincidofovir
– a prodrug of cidofovir, given orally, not nephrotoxic but still in the experimental stage
mTOR inhibitors
– inhibit BKV replication and early gene expression, inhibits BKV-specific T-cell proliferation
– requires conversion of CNI to mTORi and concomitant withdrawal of MPA, this results in BKV viral load reduction and improvement in eGFR
– adverse effects: hyperlipidemia, mucositis, oral ulcers, lymphedema, bone marrow toxicity
Intravenous immunoglobulin (IVIG)
– has immunomodulatory effects, has potent neutralizing antibodies hence is able to neutralize all major BKV genotypes
– IVIG plus concurrent reduction in immunosuppression has successfully managed BKVN with concurrent acute rejection
– can cause paradoxical increase in viral load
Other therapeutic options for treating BKVN
Quinolones
– inhibit BKV replication in vitro, thought to be beneficial when combined with leflunomide
Artesunate
– associated with a decrease in BKV replication in a dose-dependent way
Statins (pravastatin)
– reduce the percentage of BKV-infected cells
Rituximab
– prospective RCTs are required to validate the benefit of rituximab in BKVN
Short-term and long-term allograft survival
– previously, lack of awareness, misdiagnosis, delayed diagnosis, use of escalated immunosuppression for possible acute rejection management resulted in permanent graft damage
– this has improved considerably due to early therapeutic intervention
BKVN with concurrent acute rejection
– management remains debatable, reduction in immunosuppression can precipitate rejection
– steroid pulses can result in either clinical improvement, steady or worse graft outcomes
– different studies have used different approaches hence the need to individualise the management
– once BKVN is diagnosed concurrently with acute rejection, a combination of antirejection therapy with a subsequent reduction in immunosuppression should be attempted
– the benefit of up-titrating immunosuppression upon clearance of viremia and BKVN to avoid further late acute rejection or chronic rejection remains largely unknown
Post-infection monitoring
– monitoring of BKV-PCR and kidney function following management of acute rejection of reduction of immunosuppression is crucial to improve graft outcome
– for patients who have had a reduction in immunosuppression due to BKVAN, monitor serum creatinine every 1-2weeks and BK-PCR level every 2-4weeks for 8weeks then thereafter monthly until BK viremia clears (or falls below the threshold values) and the kidney function stabilizes
– BKV viremia clears in 7-20weeks
– if BKV viremia persists despite reduction in immunosuppression consider reducing the immunosuppression further, or switching to sirolimus or adding leflunomide
– failure to clear BKV leads to worse graft outcomes
Re-transplantation
– re-transplantation after graft loss secondary to BKVN is possible and is associated with successful outcomes
– pretransplant clearance of BKV viremia following reduction of immunosuppression is important
– graft nephrectomy is not necessary before re-transplantation unless there is active viral replication in which case it would be prudent to remove the infected graft before re-transplanting, however there is no evidence to support this approach
– recurrent BKV may be due to a previous BK variant or a new infection (de novo BKV) acquired due to the long period post-transplant
Conclusion
– early diagnosis of BKVN via molecular techniques and tissue analysis, has resulted in improvement of the graft outcomes despite the lack of specific treatment
Level of evidence provided by this article
– Level V
· BKV and JCV were discovered in 1971, but their negative effect was poorly understood until three decades later when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
· It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection.
BK virus and renal transplantation: historical perception
· Gardner et al. were the first to detect BK polyomavirus (BKV) in 1971, and Mackenzie et al. in 1978 defined histological changes consistent with polyomavirus nephritis. · Since then, numerous reports have been reported, and BKV has been identified as a cause of severe interstitial nephritis and allograft failure in kidney transplant recipients.
Polyomaviridaevariants
· Polyomaviridae (PyV) virions are small, nonenveloped DNA viruses with icosahedral capsids present in the urine, named ‘decoy cells’ for their resemblance to malignant cells.
Epidemiology of BK virus
· BKV is a widespread virus that infects most humans, with up to 60% of the general population being seropositive. · Variations in prevalence can be explained by age, sample size, and antibody threshold.
BK virus structure
· The BKV-DNA genome is divided into three parts: NCCR, EVGR, and LVGR, with VP1 being the main capsid protein responsible for receptor binding to host cells.
BK virus variants
· Genotype I is the predominant subtype of BKV, with genotype IV being the second most frequent. · Phylogenetic analysis has identified four subgroups of subtype I (I/a, I/b-1, I/b-2, and I/c) and six subgroups of subtype IV (IV/a-1, IV/a-2, IV/b-1, IV/b-2, IV/c-1, and IV/c-2). · Subgroup IV/c-2 is predominant among Americans and Europeans, while other subgroups are more common in Asian populations.
Immunological response to BK virus
· BK viral replication follows a state of immunosuppression, and the immune system plays an essential role in controlling BKV replication and resolution of BKVN.
The role of cell-mediated immunity
· CD4+ and CD8+ T cells are key components of cellular-mediated immunity to control the BKV and play a role in BK clearance. · Epitopes in the viral genome identify CD4+ and CD8+ cells. Cytotoxic T cells (CTL) kill BK-infected cells after the recognition of damaged segments of viral DNA. · Without appropriate immunological regulation, progressive lytic infection arises and results in large nuclear and peri-nuclear viral inclusion in the tubular cells.
The role of humoral immunity
· Humoral immunity and antibody-mediated immunity play a role in BKV infection, with kidney recipients from a seropositive donor more likely to develop viremia.
Role of alloimmune activation
· Allo-HLA-reactivity and heterologous immunity are important factors in the development of BKVN, allowing BKV to escape immunological surveillance. · CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been linked to an increase in the incidence of BKVN, suggesting alloimmune activation.
The role of other factors
· The pathogenesis of BKVN is likely related to a combination of cellular and humoral immune deficiencies, alloimmune activation, and BKV’s tropism to the renal tubular epithelium.
Pathogenesis of BK infection
· BKV primary infection is usually subclinical or has mild respiratory symptoms in childhood, and can remain dormant in the uroepithelium and renal tubular cells for life.
· In the presence of immunosuppressive therapy, the virus activates and proliferates, resulting in tissue damage, inflammation, and fibrosis.
Routes of transmission of primary BK virus
· The primary route of transmission of BKV is respiratory, as evidenced by the presence of BKV in the respiratory tract and tonsils of children. · Gastrointestinal transmission is also proposed, as evidenced by 45% of stool samples and rectal swabs testing positive for polyomavirus DNA. · Vertical transmission, (crossing the placenta), Sexual transmission, and Donor-derived infection are also possible.
Clinical manifestations
· BKV does not cause disease in immunocompetent people, but in immunocompromised patients, it can cause BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
BK virus and renal disease
· BK polyomavirus-associated nephropathy (BKVN)/PyVAN affects 30-40% of renal transplant recipients, with an estimated incidence of 2-15% due to different immunosuppressive regimens and screening strategies.
BK virus-associated nephropathy
· BKV-associated nephropathy causes viruria, hematuria, and allograft failure.
Ureteric stenosis
· The prevalence of ureteric stenosis is 2–6%.
· Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen
· Treatment of ureteric stenosis involves nephrostomy and dilatation.
Neurological manifestations, Pulmonary diseases, and Ophthalmologic manifestations: are less apparent
Hemorrhagic cystitis
· BKV-associated HC is rare in renal transplant, presenting with bladder cramps, painful voiding, hematuria, and/or flank pain. · Management involves vigorous intravenous hydration and Cidofovir given locally through bladder installation for remission.
BK nephropathy in the native kidney
· BKVN has been reported in transplant recipients and HIV-infected patients.
BK virus and hepatic disease
· BKV and hepatitis associated with a bone marrow transplant.
BK virus and autoimmune diseases
· BKV has been linked to certain autoimmune diseases, such as systemic lupus erythematosus, polymyositis, and rheumatoid arthritis. · Taguchi and colleagues reported the isolation of BKV from a urine sample of two patients with lupus, and there is a prevalence of 16% in patients with systemic lupus erythematosus.
BK virus and malignancy: thoughts on viral oncogenesis
· BKV-DNA has been identified in tissue samples of neoplasms, including brain tumors, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors. · BKV-LTAg can bind and inhibit cell cycle regulators, leading to urothelial malignancies in experimental mice. · BKV has variable DNA locations inside cells, but tumor cells are more vulnerable to BKV than normal urothelium.
BK virus and urothelial tumors
· BKV may have a role in the pathogenesis of urothelial malignancy, particularly bladder carcinoma, as evidenced by high levels of BKV-LTAg, p53, p16, and Ki-67 in tumor cells.
Risk factors
· Risk factors for BKVN include immunosuppression, male sex, older recipient age, previous rejection episodes, HLA mismatching, cold ischemia, BK serostatus, ethnic groups, lower lymphocyte percentage, and ureteral stent insertion.
Screening and diagnostic tools
· Early identification of viruria/viremia to prevent graft dysfunction.
Timing of screening
· BKVN is an early complication of a kidney transplant, with bimodal peaks in the third and ninth months. · BKV screening should start at the first month, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening tests
· Viral replication in the urine precedes BK viremia and histological changes of BKVN are observed 12 weeks after BK viruria.
Monitoring of the urine
· Detection of BKV-infected epithelial cells or viral load.
Urine cytology
· Decoy cells are useful markers of BKV reactivation, but sensitivity varies.
Urine electron microscopy (EM Haufen):
· Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, which has a higher sensitivity and specificity for biopsy-proven BKVN than decoy cells. · It requires further validation and cannot be applied for routine clinical practice.
Quantitative measurements of urinary BK virus-viral loads
· Urinary BKV-PCR has 100% sensitivity and 78% specificity, but difficulty standardizing for diagnosis.
BK virus mRNA levels in urine
· BKV-VP1 mRNA derivative from urinary cells can be used as a biomarker to detect active viral replication, but further validation is needed.
Serology
Serum BK-PCR
· BK viremia can be detected with real-time PCR and quantitative BKV-DNA in plasma, but not all recipients will develop nephritis.
Serum antibodies
· Positive donor BKV serostatus and negative recipient serostatus (BK D+/R) are risk factors for clinically significant BK disease in kidney allograft recipients.
Virus culture
· BKV can be isolated from urine samples but grows slowly in tissue culture.
Kidney biopsy
· The Banff classification system was shown to correlate with clinical outcomes in 178 patients with biopsy-proven PVN. · Plasma BK-PCR has high sensitivity and specificity, but allograft biopsy remains the gold standard. · Histologically, streaky fibrosis of the medulla with cortical scars can be seen.
Suggested algorithm for screening
· BKV screening in renal transplant recipients should be performed at periodic intervals with plasma BK-PCR and allograft biopsy in individuals with persistent high viral loads.
Differential diagnosis
Allograft rejection
· BKVN and acute rejection can be distinguished by BKV inclusion bodies, positive immunoperoxidase staining, anti-HLA DR, CD20+ cells, and increased expression of genes.
Another differential diagnosis
· Early and late renal allograft dysfunction are differential diagnoses.
Treatment strategy of BK virus nephropathy
· Reduced immunosuppression is the only valid therapy to treat BKVN and restore antiviral immune response, but should be balanced against risk of rejection.
Treatment of presumptive BK virus nephropathy
· The first treatment of BKV disease has focused on reduction/modifications in immunosuppressive therapy with or without antiviral medications. · Different regimens have been attempted, such as withdrawal of antimetabolite drugs, switching a drug class, and steroid avoidance. · Switching tacrolimus to cyclosporine may reduce MMF levels, but the total withdrawal of MMF may be essential if BK viremia remains.
Treatment of BK virus nephropathy in the setting of allograft dysfunction
· Reducing immunosuppression is a rational option in the context of acute BKV infection, as it can lead to clearance of viremia and increase BKV-specific IgG-antibodies titer and cellular immunity. · It may also stabilize allograft function or advance to end-stage despite therapy.
Drugs with antiviral activities
Leflunomide
· Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug used in rheumatoid arthritis to inhibit pyrimidine synthesis and reduce CNI dosages.
Cidofovir
· Cidofovir is a cytosine analog and viral DNA-polymerase inhibitor used to manage other viral infections, but it is a nephrotoxic drug and should be used carefully in kidney recipients.
mTOR inhibitors
· mTOR inhibitors inhibit BKV replication and early gene expression, but clinical efficacy is questionable.
Intravenous immunoglobulin
· IVIG has the most potent antiviral influence, with a selectivity index of 1000, and has been successful in treating BKVN with concurrent acute rejection, but its effectiveness is uncertain.
Other therapeutic options for treating BK virus nephropathy
· Quinolones, artesunate, statins, and rituximab have been found to inhibit the LTAg helicase activity and have in-vitro and in-vivo activity against BKV. · Rituximab has also been found to reduce the percentage of BKV-infected cells and LTAg expression in human renal proximal tubular epithelial cells. · Further prospective randomized trials are needed to validate the benefit of this therapy for BKVN.
Short-term and long-term allograft survival
· BKVN caused permanent allograft damage in the late 1990s and
the early 2000s, but renal allograft survival has improved significantly.
· Therapeutic approaches have improved viremia, but long-term
outcomes need further evaluation.
· Management should be tailored for each patient individually, with delayed improvement in renal functions likely due to slow resolution of cellular infiltrate.
Postinfection monitoring
· USA-OPTN registry data showed 126 retransplants lost their graft due to BKVN, with excellent 1- and 3-year graft survival. · Pretransplant clearance of BK viremia is essential after minimizing immunosuppression, and allograft nephrectomy is not necessary before retransplantation. · Monitoring BKVN using quantitative plasma BKV-PCR is important to improve allograft outcomes. · BK viremia clears in 7-20 weeks, but the initial decline may be delayed for 4-10 weeks.
Conclusion · After over three decades of study, we now somewhat’ understand the pathogenesis of BKV. · A larger “known unknown” just serves to highlight how elusive BKV is.
· Despite the lack of a particular therapy, an early identification of BKVN based on a combination of genetic · methods and tissue analysis has significantly improved allograft results. ================= Level of Evidence 5
Week 9, 10 : BK virus infection in renal transplant recipients: an overview
Summary:
· 3 Human polyomaviruses involved in diseases in kidney transplant recipients (KTRs) include: BK virus (BKV), JC virus (JCV) and simian virus 40 (SV40). The name polyoma represents the viruses’ ability to induce many (poly) tumors (−oma).
· JCV was discovered as a cause of progressive multifocal leukoencephalopathy.
· BK is named after the 1st Sudanese KTR case with viral detection in both urine and ureteral epithelial cells and he was presented with ureteric stenosis and graft failure.
· BK infection early Posttransplant (1st year) is a prominent cause of acute graft dysfunction (found shredded in urine + histopathological evidence of damage in allograft biopsy).
· BKV can be categorized into four genotypes/subtypes, type 1 is the most common (> 80% worldwide), followed by type 4 (15% of the healthy population). While types II and III are relatively rare.
· The incidence of BK infection increased with use of potent IS medications as tacrolimus and MMF in addition to the enhanced microbiological diagnostic techniques.
· Route of infection: respiratory, fecal-oral (viral isolated from saliva and stool), transplacental, or from donor tissues, and may be through the urine and blood (viruses detected in urine and peripheral blood leukocyte).
· BK infection is mostly acquired in early childhood and remains dormant in the urinary tract (60–85% of the general population is seropositive for BKV), till the patient become immunocompromised (pregnancy, DM, HIV infection, cancer, and Posttransplant), it becomes reactivated.
· The main mechanism of immune defense against BK infection is cellular-mediated immunity (CD4+ and CD8+ T cells). Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA. In addition, humoral immunity might have a role in the pathogenesis of BKVN, so BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
· Pathogenesis of BK infection; 1. defective immune surveillance by the host T lymphocytes, (b) absence of humoral immunity to BKV, (c) alloimmune activation (d) viral variation in molecular sequences.
· Pathogenesis of BKVN:
1. Impaired immune response either cell mediated or humoral.
2. Alloimmune activation means cross-reactivity against allo-HLA antigens and BKV in humans. This can be explained by increase in the incidences and severity of BKVN in those with higher degree of HLA mismatches. The higher the degree of HLA mismatch, the worse the prognosis of BKN.
3. BKV tropism to the proximal renal tubular epithelial cells may play an additional role in BKN.
· Clinical presentation of 1ry infection: mild respiratory symptom in childhood (BKV goes into the circulatory system through infected tonsils >> peripheral blood mononuclear cell >> disseminated to the kidneys >> dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
· In case of immunosuppression as KTRs: BKV reactivation >>lysis of infected tubular cells >> viral leakage into the tubular lumen and urine (viruria), as well as dissemination into the interstitium. Then, damage of tubular capillary walls will cause the vascular spread of the virus (viremia),leading to dense inflammatory interstitial infiltrate and tubulitis.>> up-regulation of profibrotic mediators and ends with allograft dysfunction and loss. Mechanism of tissue injury direct viral cytolytic effects and secondary inflammatory responses and the prognosis depends on the degree of tissue damage.
· Time frame:
o Viruria (diagnosis by viral DNA-PCR in urine)
o Then after 4 weeks viremia develop
o Then after 12 weeks of viral shedding in urine >>BKN develops.
· Presentation in transplant patients (immunocompromised host):
o Infection with this virus starts as the virus proliferate in the uroepithelial cells then detached in urine (viruria) >> then in blood (viremia) and eventually to BKVN (2 and 15% of allograft).
o Clinical presentation varies from asymptomatic hematuria up to extensive irreversible injury and allograft failure.
· It usually presents as asymptomatic gradual rise in creatinine with severe tubulointerstitial nephritis that mimics AR presentation.
o BKV has different clinical features, BKVN (ureteric stenosis and late-onset hemorrhagic cystitis).
o Hemorrhagic cystitis is common in patients with hematopoietic stem cell transplant (HSCT) (may be related to pretreatment with cyclophosphamide), but it is rare in KTR.
o HIV infected patients, BKV may disseminate leading to severe multi organ failure (retinitis, encephalitis, GBS, URTI, interstitial pneumonia, hepatitis, pancreatitis, colitis), BKN and death. Most of invasive disease occurs in HSCT.
o Ureteric stenosis is 2–6% allograft dysfunction, treatment by percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent decrease of IS medications.
o Hemorrhagic cystitis is rare in kidney transplantation (mostly in HSCT), grade I: microscopic hematuria; grade II: macroscopic; grade III: hematuria with clots; grade IV: hematuria with clots, clot retention, renal failure secondary to obstructive nephropathy. Treatment by vigorous intravenous hydration. Severe cases might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation + Cidofovir
· The risk of BKV infection is increased in KTRs especially after ttt of AR episodes (aggressive immunosuppression), male gender, older age, degree of HLA mismatching, prolonged cold ischemia, BK serostatus (D+/R-), certain ethnic groups, lower total lymphocyte percentage and ureteral stent insertion.
· Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss. Hence, routine screening protocol for early detection of asymptomatic BKV infection results in better allograft outcomes.
· ‘Decoy cells’ are large cells with intranuclear inclusions present in the urine (resembling malignant cells).
· Oncogenesis properties of BKV:
o It remains a matter of debate.
o BKV-DNA has been identified in tissue samples of different neoplasms, as brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
o However, it is not conclusive that it has a causative role or just coexisting infection in malignant cells.
o It is suggested that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as high level of BKV-LTAg was noted in the nucleus of almost every tumor cell and none of the non-neoplastic urothelium.
· Screening during 1st year posttransplant: first month, then monthly for the first 6 months, and then every 3 months for up to 2 years after transplantation then annually thereafter.
· Screening by viruria/ viremia or decoy cells in urine.
o BK PCR in urine and blood (if viral titer <10,000 just FU viral titer monthly and consider decrease IS while, if plasma PCR > 10,000 copies …do allograft biopsy)
o Decoy cells are identified in 15–30% of KTRs, by Cytological analysis of urinary smear. It indicates active BKV reactivation, but it is not a real diagnostic tool for BKVN.(sensitivity 100%, specificity of 71%, positive predictive value (PPV) 29% and negative predictive value (NPV) 100%), compared to graft biopsy as a diagnostic standard.
o Urine electron microscopy (EM Haufen): Haufen represents cast-like three-dimensional aggregates (BKV particles + Tamm-Horsfall protein), visualized in a urinary smear of kidney recipients using negative-staining electron microscopy, but it is not always available in all health care settings.
· Suggested step wise approach for BKV screening:
o Start with decoy cells in urine (persistence of decoy cells ≥ 3 months).
o Proceed to plasma PCR-for BK (quantitative).
o Consider renal biopsy (some suggest it only if graft dysfunction is present, others suggest it when viral load > 10,000 copies/ml)
· Serum antibodies have no value (present in healthy population, none confident in such immunocompromised patients), (D+/R-) may be associated with higher risk of infection posttransplant.
· Allograft biopsy is the golden standard to diagnose BKN, is indicated if significant viruria (suggesting viral proliferation in the urinary tract), persistent viremia of more than or equal to 104 copies/ml for > 3 weeks.
o Pros and cons of biopsy:
o Findings can be focal or isolated to the medulla and missed on 1/3 of biopsies (false-negative), a minimum of two biopsy cores involving the renal medulla, to make the correct diagnosis.
· Differential diagnosis:
1. AR (BKVN can be distinguished from AR by presence of BKV inclusion bodies and immunohistology (positive immunoperoxidase staining for SV40).
2. Other causes of graft dysfunction (CMV infection, UTI, sepsis, etc)
· Treatment of BKVN: (No specific therapy for BKN) 1. Reduction of IS (with balance against AR), effective mainly in early stages of BKN, while in advanced disease with graft damage the benefit is debatable.
· No consensus, but many suggestions are considered as:
· Withdrawal of antimetabolites as MMF or shift to azathioprine, sirolimus, or leflunomide.
· Leflunomide is an immunomodulatory used in rheumatoid arthritis, used after stoppage of MMF/aza (cannot be used with antiproliferative drugs). Its use has many limitations (adverse effects as hemolysis, aplastic anemia, thrombocytopenia, TMA, hepatitis, and hypertension worsening).
· Reducing the dose of CNI by 25–50% (to achieve Lower window of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml).
· Converting tacrolimus to cyclosporine (might reduce MMF levels even with same dose of MMF) or discontinuing CNI
2. Cidofovir: antiviral used in CMV, can be useful, adverse effects include severe anterior uveitis and nephrotoxicity that requires adequate prehydartion).
3. Conversion from CNI to mTORi: improves the recovery of BKVN and GFR. 4. IVIG (dose 2–3.5 g/kg divided over 2–5 days) + reduction of IS medications: preferred especially if BKVN is associated with AR, but the effect is still questionable as reduction of IS was done in all patients. 5. Quinolones
6. Artesunate (an antimalarial drug) may have dose dependent anti-viral activity.
7. Rituximab (Although it can increase the risk of viral infection in KTR as BKVN, CMV viremia, herpes zoster, and septic shock, it may be beneficial in ttt of BKVN.
· Treatment of BKVN with concomitant AR (or with anticipated AR with the reduction of IS medications):
o Reduction of IS in BKVN can precipitate AR in 30 % of cases.
o Initial reduction of IS (with or without pulse steroids) can be used.
o The timing of uptitration of IS after clearance of BKV is still debatable.
o Close monitoring of the graft function every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks then monthly thereafter until clearance of BK viremia.
o The initial decline of BKV viral load might be delayed for 4–10 weeks following reduction of IS and virus clears in 7–20 weeks.
o Retransplantation is feasible with excellent graft outcome at 3 years posttransplant. However, recurrent or devo BKVN can occur posttransplant. Consideration of graft nephrectomy to eliminate the source of replicating virus is rationalized, but not standard practice.
· Prognosis of BKVN:
o It is associated with graft loss if diagnosed late after graft dysfunction.
o Early diagnosis through screening protocols and surveillance biopsy is associated with better graft outcome.
Introduction:
This paper discusses BK virus infection and how it affects renal transplant recipients. Infection with BKV is a complication that can occur during the first year following a transplant. It presents similarly to acute rejection, making it difficult to distinguish both of them. associated with tubulointerstitial nephritis and asymptomatic creatinine rise. increased overall immunosuppression is the main common risk factor. Pathogenesis:
BKV primary infection rarely causes lung symptoms in children. BKV enters the circulatory system through diseased tonsils and infects peripheral blood mononuclear cells, which spread to secondary sites like kidneys. The virus remains latent in the uroepithelium and renal tubular cells for life, occasionally reactivating as asymptomatic viruria.
BKV can also hide in leukocytes, brain cells, and lymph nodes. In immunosuppressive therapy, the virus initiates and proliferates in the interstitium and enters the peritubular capillaries, causing tubular cell lysis and viruria. Damage, inflammation, and fibrosis determine outcomes. Viral cytolysis and secondary inflammatory reactions damage tissue.
Different BKV disease symptoms arise from complex immune system-BKV interactions. Routes of transmission of primary BK virus:
(1) Respiratory route
(2) Gastrointestinal transmission
(3) Vertical transmission: during pregnancy
(4) Sexual transmission
(5) Donor-derived infection
(6) Others:through the urine and blood c/p: BK virus renal disease
This virus proliferates in uroepithelial cells, causing viruria, viremia, and BKpolyomavirus-associated nephropathy (BKVN)/PyVAN . 30–40% of renal transplant recipients develop BK viruria, while 10–15% develop viremia.
BKVN is reported in 2–15% of kidney allograft recipients. BK-related nephropathy
BKV-associated nephropathy starts with viruria or asymptomatic hematuria and progresses to irreversible damage and allograft failure. Nephritis can start 6 days or 5 years after renal transplant. Uretric stenosis
prevalence 2–6%.
Allograft dysfunction due to ureteric stricture and hydronephrosis is rare. Treatment involves temporary percutaneous nephrostomy and ureteral dilatation, along with immunosuppressive medication reduction. Hcccccccccc cystitis:
HSCT recipients commonly develop BKV-associated HC or non-HC, but renal allograft recipients rarely do. Bladder cramps, painful voiding, hematuria, and flank pain may occur.
Grade I: microscopic hematuria; grade II: macroscopic; grade III: hematuria with clots; and grade IV: clot retention, renal failure, and obstructive nephropathy. Intense intravenous hydration is required. Supra-pubic catheters with bladder irrigation may be needed for severe BKV-HC. Cidofovir given locally through bladder installation reduced cumulative drug nephrotoxicity and caused HC remission in 2 to 7 weeks after hematuria. Native BK nephropathy
BKVN has been found in native kidneys of HSCT, heart, and lung transplant recipients and immunocompromised HIV-infected patients. All those patients had acute kidney injury without significant proteinuria and typical kidney biopsy histology. Neurological manifestations:
BKV rarely causes primary or reactivated CNS disease. Patients with HIV or HSCT usually get such infections. Meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy may present clinically. Headache, dizziness, confusion, paraplegia, ataxia, and seizures may occur .
BKV and neurological symptoms are still debated. Pulmonary diseases:
reactivated acute respiratory disease leading to severe interstitial pneumonitis in association with BKV has been reported twice in HIV-infected patients, with prominent histopathological lung features with distinctive BK cytopathic changes and a positive BK viral DNA test in the autopsy. Ophthalmologic manifestations:
reported one case of bilateral atypical retinitis in an AIDS-positive homosexual white male. The eye autopsy showed several retinal necrosis areas. PCR found retinal BKV-DNA. Autopsy revealed BKV infection in the brain, kidneys, and peripheral blood smear. Since it’s a single case, BKV’s ophthalmological effects need more evidence. Plenty of believe that BKV plays a major role in urothelial carcinoma etiology. BKVN detection and screening:
Crucial for preventing graft dysfunction is the early diagnosis of viremia and viuria through screening.
The AST and KDIGO guidelines recommend the following screening intervals: the first month after transplantation, every month for six months, every three months for one to two years, annually for two to five years, any presentation with an unexplained rise in creatinine, and following treatment of rejection episodes.
If PCR is 10,000, monitoring and/or immunosuppression reduction should be considered; if PCR is greater than 10,000, graft biopsy should be considered.
Urine cytology for decoy cells is used for screening and diagnosis (sensitivity 100%, specificity 71%, PPV29%, NPV100%).
Sensitivity and specificity are both 100% for urine electron microscopy (EM Haufen).
Urine BKV-PCR has a specificity of 78% and a sensitivity of 100%.
Level of mRNA in the urine with a sensitivity of 100 percent and a specificity of 97%.
100% sensitivity and 88% specificity for BKV-PCR in serum(preferred screening test).
A kidney biopsy should be performed when the viral load exceeds 100,000 copies per milliliter, with or without a transplant dysfunction.
D.D.: Allograft rejection
BKVN and acute rejection have similar tissue appearances, so blood or urine PCR can help distinguish them. Differentiating these two entities is important because immunosuppression for the assumed rejection may cause BKVN progression. BKVN may coexist with acute rejection.
BKV inclusion bodies and SV40 immunoperoxidase staining separate BKVN from acute rejection. Though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease, absence of definitive features of acute cellular rejection, such as endotheliitis, extensive tubulitis, and C4d deposits in peritubular basement membrane, are valuable. Anti-HLA DR IHC staining of renal tissues or urine sediments can distinguish acute rejection from BKVN. BKVN has more tissue infiltrate CD20+ cells than acute rejection.
BKVN and acute rejection can coexist.
Endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries prove acute rejection. Additional differential diagnoses include any medical condition linked with early (1-12 weeks post-transplantation) and late (≥3 months post-transplantation) dysfunction of the renal allograft. management options:
-Reduction of immunosuppression is the main factor (risk of rejection should be balanced with immunosuppression reduction).The recommended action involves the discontinuation of anti-metabolite and a reduction of 25-50% in the dose of calcineurin inhibitor.
-Additionally, mTOR inhibitors have been observed to effectively inhibit BK virus replication.
-Certain antiviral medications, such as leflunomide and cidofovir, have been found to exhibit nephrotoxic effects.
-There is a conflicting body of evidence regarding the effectiveness of quinolone.
-Artesunate (anti malarial) has been observed to exhibit a dose-dependent reduction in viral proliferation.
-ciprofloxacin & leflunamide
-IVIG
-rituximab
Further evaluation is required to assess the long-term outcomes, including instances of late acute and chronic rejection.
-The incidence of acute rejection subsequent to the reduction of immunosuppressive therapy ranges from 6% to 12%. Acute rejection and BK nephropathy
Proven allograft biopsies of acute rejection with BKVN or expected rejection after immunosuppression reduction to treat BKVN are controversial. Over half of biopsies show tubulitis, and any drop in immunosuppression can cause rejection in 10–30%.
Steroid pulses usually enhance clinical outcomes but worsen allograft outcomes. Celik et al. [215] found that immunosuppression reduction reduces viral load better than steroid pulses in BKVN and tubulitis biopsies.
After BKVN finding, immunosuppression should be reduced without steroid pulses.
However, in the lack of typical features, such as strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage, acute rejection should be managed individually. The cellular infiltrate may slow renal function recovery after immunosuppression reduction. Up-titrating immunosuppression after viremia and BKVN clearing is unclear. Post-infection monitoring
BKV-PCR and renal function monitoring during and after therapy.
Most centers use quantitative plasma BKV-PCR to assess BKVN.
Most transplant patients who have their immunosuppression reduced for BKVAV are monitored with serum creatinine tests every 1–2 weeks and plasma BK-PCR levels every 2–4 weeks for 8 weeks. It should be repeated monthly until BK viremia is cleared or viral burden falls below threshold levels and renal function stabilizes.
BK viremia clears in 7–20 weeks. Immunosuppression reduction may delay early decline by 4–10 weeks. If viremia remains after reducing maintenance therapy, consider sirolimus, leflunomide, or further reduction. level of evidence:
narrative review, level 5
discovered in 1971, BKV belongs to the Polyomaviridae a subgroup comprising JCV, BKV and SV40.
Their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma.
There are 4 genotypes of BKV, with genotype 1 being the most prevalent followed by genotype 4;
Pathogenesis:
Primary infection with BKV is usually subclinical, manifests as a mild respiratory symptom in childhood.
The virus remains dormant in the urothelium and renal tubular cells. It can also remain dormant in the lymph nodes, brain tissue and leukocytes.
In the presence of immunosuppressive therapy, the virus replicates and spreads to the peri-tubular capillaries leading to tubular cell lysis and viruria. Reaction between the BKV and immune system leads to various presentation of BK disease. Routes of transmission of primary BK virus:
Several routes for the primary BKV virus transmission have been implicated.
The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestation
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals but BKV does not cause disease in immunocompetent people.
Diseases include BKV nephropathy, ureteric stenosis, and late onset hemorrhagic cystitis.
·BKV and renal disease: Begins with viral replication in the uroepithelial cells, then viruria that progresses to viremia and later BK associated nephropathy.
·BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
·Ureteric stenosis: Prevalence is 2-6%, rarely does it lead to hydronephrosis and allograft dysfunction. Treatment of ureteric stenosis involves placement of a percutaneous stent, percutaneous ureteral dilatation with concurrent reduction of immunosuppression.
Four degrees of disease severity are recognized:
– Asymptomatic hematuria
– Symptomatic hematuria
– Hematuria with clots
– Hematuria with clots, clot retention and renal failure secondary to obstructive uropathy.
Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection.
BKV and malignancy: BKV DNA has been detected in tissue samples of different neoplasms. It has been proposed that BKV has oncogenic properties owing to its LTAG and STAG proteins.
Screening tests
Viruria precedes viremia by approximately 4 weeks while BKVN occurs 12 weeks after viruria.
· 1) Urine cytology: Decoy cells, they are infected tubular cells with with an enlarged nucleus with basophilic intranuclear inclusions.
Presence of decoy cells is strongly suggestive of polyomavirus infection and is considered as a marker of BKV reactivation.
It has sensitivity ranging between 25-100% and specificity 71-84% to diagnose BKVN.
· 2) Urine viral loads: PCR has a sensitivity of 100% and specificity of 78%.
Persistent high viral loads can predicting patients at risk of BKVN.
· 3) Serum BK PCR: sensitivity of 100% and specificity of 88% thus it is the preferred screening tool in most transplant centers.
· 4) Kidney biopsy: Gold standard for diagnosing BKVN.. Treatment:
Decreasing immunosuppression is the only validated therapy to treat BKVN and restore immune response to viruses; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Withdrawal of the antimetabolite such as MMF is the most usual method. Drugs with antiviral activities:
Leflunomide: It’s an immune modulator given orally, loading dose of 100mg daily for 3–5 days followed with a maintenance dose of 20–40mg/day
Cidofovir: Cytosine analog and viral DNA- polymerase inhibitor. Mechanism of action is unclear as BKV lacks the viral polymerase gene the known target of cidofovir. It’s exclusively excreted through urine, resulting in high renal tubular cell concentrations.
mTOR inhibitors: Inhibits the proliferation of BKV- specific T cells and controls the differentiation of memory CD8 T cells; hence, it improves the immune reaction following BKV infection.
Intravenous immunoglobulin: Potent neutralizing antibodies and is able to neutralize all major BK viral genotypes. IVIG in a dosage of 2–3.5g/kg divided over 2–5 days with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection.
Others: Quinolones, antimalarial, statin
Post infectious monitoring:
Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome. S. creatinine every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks then monthly until clearance of BK viremia or at viral burden falls below threshold value and stabilization of renal function achieved.
Conclusion:
Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment. Level of evidence: level V
In 1971, Gardner et al were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. They named the virus ‘BK’ after the initials of this patient.
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life .
Studies showed as much as 60–85% of the general population is seropositive for BKV .BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and post transplantation period .
The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN)
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood. It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Routes of transmission of primary BK virus
Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Risk factors
Several risk factors were implicated in the pathogenesis of BKVN. The most consistent risk factor identified in the literature is the overall degree of immunosuppression.
Screening and diagnostic tools
The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears
Treatment strategy of BK virus nephropathy
The aim of treating BKV is to eradicate the virus while saving the kidney function. Unfortunately, BKVN has limited treatment options . As BK viremia and BKVN signify excessive cumulative immunosuppression, hence, decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Postinfection monitoring
There are different protocols in different centers for monitoring BKVN, mostly using quantitative plasma BKV-PCR. The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
Retransplantation
Retransplantation following graft loss owing to BKVN is possible and can be done successfully
BK virus infection in renal transplant recipients: an overview. Please summarise this article.
INTRODUCTION.
BKV is a key player in causing interstitial nephritis and allograft failure in KTR.
BKV discovered in a sudanese KTR who had ureteric stenosis and renal failure.
Epidemiology and BKV structure.
Initial infection occurs in early childhood then it establishes latent infection until pt gets immunocompromised. A prevalence of 41.8% has been reported in Iran.
The viral genome is divided into 3 regions; early viral gene region, late viral gene region and capsid protein.
BKV classified into 4 genotypes with genotype 1 and 4 accounting for most of the infection and 2 and 3 causing less infection.
Immunological response to BKV and Pathogenesis.
Replication occurs in immunosuppressed state; pregnancy, DM, HIV, Ca and post transplantation(Common during intense immunosuppression).
CD4 and CD8 all play key role in clearing BKV and when they are dysregulated, progressive lytic infection occurs with varied manifestation.
Those with prior immunity don’t manifest severe infection while D+/R- pair develop dx in comparison to D-/R- pair.
HLA alloreactivity i.e either T cells that cross react to BKV and alloantigen or the increase in BKVN in those with higher HLA mismatches all point to alloimmune activation as a cause of BKV infection.
BKV tropism in renal epithelial cells also play a role in BKV infection.
Following initial infection, it establishes a latent infection in uroepithelial cells and reactivates once the immune system is dysregulated with varied manifestation.
Route of transmission of primary BKV.
Respiratory -found in tonsils of children.
Gastrointestinal -Found in salivary glands and oral secretions.
Vertical -BK viruses increase by > 35% in pregnancy and can cross the placenta and be latent in fetal organs.
Sexual -Detected in one study in 57% of genital tissue and 95% of sperm specimens.
Donor derived.
Urine and blood.
Clinical Manifestations.
7% of immunocompetent shed BKV in urine asymptomatically.
BKV and renal dx- viruria precedes viremia then BKVN.30-40% of KTR get viruria with 10-15% get viremia and BKVN estimated at 2-15% of KTR.
BKVN -viruria, viremia and later hematuria and allograft failure btn 6/7 post op to 5 yrs post op.
Ureteric stenosis -ocurs in 2-6% and tx with RIS, nephrostomy and ureteral dilatation.
Hemorrhagic cystitis -Mostly in HCST compared to KTR. .Presents as bladder cramps, dysuria, hematuria +/- flank pains. Mgt involves hydration +/- suprapubic catheter for bladder irrigation.
BKVN in native kidney – can occur in anyone who is immunocompromised.
Other manifestation;
CNS- Meningoencephalitis,encephalitis,GBS and vasculopathy.
Resp – Interstitial pneumonitis.
Eye -atypical retinitis.
GIT -hepatitis.
Autoimmune dx – SLE,RA and polymyositis have been associated with BKV activation and replication.
BKV and Malignancy.
Early coding protein ;LTAg and STA can induce neoplastic transformation, Agroprotein and LTAg arrest cell cycle and lead to continuous replication with resultant malignancy.
It has also been reported in a few cases though not conclusive of bladder and urothelial malignancies.
Risk factors to BKV infection.
Immunosuppression.
Male sex.
Older recipient.
Previous rejection episode.
Degree of HLA mismatches.
Prolonged cold ischemia.
Low total lymphocyte percentage.
Ureteral stent.
Screening and diagnostic tools.
BKV occurs early esp in 1st 1 yr post transplantation.
Viruria precedes viremia by 4 weeks with BKVN occurring 12/52 after viruria.
Monitor urine;urine decoy cells, haufen cells or urinary BKV DNA PCR.BKmRNA levels is more sensitive but needs more validation.
Serum BK PCR can be used to identify those at risk of BKVN but the cut off points are not clear. It is the preferred screening tool. BKVPCR >4logs copies/ml has a high likelihood of BKVN on allograft biopsy.
BKV antibodies not routinely doe as has no clinical relevance.
BKV culture from urine can be done but is hardly used due to long wait time.
Renal biopsy is gold standard and should be done with VL >10000 COPIES/ML +/- graft dysfunction. BKVN is associated with sclerosis, interstitial nephritis and BKV inclusion bodies. IHC using antibodies against BKV or SV40 has ~100% specificity for polyomavirus nephropathy but cant differentiate BKV from JCV.
Screening algorithm -Screen at 1 month then monthly for 3-6/12,then every 3/12 for 1-2 yrs then annually for 2-5 yrs. Screening beyond 2 yrs not recommended though AST guidelines recommend upto 5 yrs. Biopsy to be done in those with high VL for > 3/52.
Ddx;
Allograft rejection.
Diseases associated with early (1-12/52) and late (>3/12) renal allograft dysfunction.
Tx of BKVN.
–RIS is the only validated approach.
Presumptive BKVN.
RIS -Withdraw ,decrease or switch drugs within same class and steroids avoidance. OR
Withdraw antimetabolite or switch from MMF to AZA/sirolimus/leflunomide. OR
Decrease CNI by 25-50% OR
Convert tac to cyclosporine or discontinue CNI.
TX of BKVN in setting of allograft dysfunction.
RIS -withdraw or discontinue immunosuppressive meds.
Drugs with antiviral activity.
Leflunomide-its metabolite A77 1726 inhibits BKV replication. It is a pyrimidine synthesis inhibitor and cant be combined with an antimetabolite. Efficacy not clear. We need to monitor LFTS and A77 1726 levels and other SE ;Hemolysis, aplastic anemia, thrombocytopenia TMA and HTN.
Cidofovir- Reestablishes p53 and pRB function and induce apoptosis of BKV infected cells. Needs to be renal doses and pt to be well hydrated to avoid nephrotoxicity.Brincidofovir is its pro drug without nephrotoxicity and hopefully it gets approved.
MTORi -Delays viral replication and inhibits proliferation of BKV specific T cells and thus decreases BKV replication. It is not yet approved.
IVIG-Has neutralizing antibodies and neutralizes major BK viral genotypes.
Others;
Quinolones – used in combination with leflunomide.
Artesunate.
Pravastatin.
Rituximab
BKVN and Concurrent acute rejection.
Approach differ and should be individualized with some authors suggesting combined anti rejection therapy and later RIS.
Post infection monitoring.
Serum creatinine every 1-2 weeks.
Plasma BK PCR – 2-4 weeks for 8/52 then monthly until BK viremia cleared.
If viremia persists despite RIS, further reduction to be considered or switch to sirolimus or add leflunomide.
Re-transplantation.
Pre-transplant clearance of viremia essential.
Allograft nephrectomy not necessary but can be done.
Recurrence can still ocur.
What is the level of evidence provided by this article?
Introduction
The human Polyomavirus (BKV) and JC virus (JCV) were first discovered in 1971 by Gardner et al (1). The human BKV belongs to the Polyomaviridae (PyV)
virions, a subgroup of papova viruses comprising BKV, JCV, and simian virus 40 (SV40), its nonenveloped circular double-stranded DNA virus. The name polyoma stated to the virus’s capacity to create many(poly)tumors(-oma). There are 12 human BKVs have been isolated from 2007-2017 with four genotypes identified. The seroprevalence of BKV in the general population was found in the range of 60-85% as per reports however limited data about the BKV prevalence in the middle east& Africa but one study from Iran shows that BKV prevalence is around 41%.BKV is one of the important causes of early allograft dysfunction, usually in the first year after transplantation and after treatment of acute rejection with intense immunosuppression, and can manifest as an asymptomatic increase in creatinine level that is similar to acute rejection presentation and can lead to diagnostic and management problems. Structure of the BKV
BKV- DNA genome has three regions. The noncoding control region (NCCR): it regulates the expression of the virus’s early and late genes
regarding differentiation and activation of the host cell. 1. The early viral gene region with it encodes the controlling nonstructural proteins called small T antigen (STA) and large T antigen (LTAg), large tumor antigens which interact and binds to cellular antigens and plays role in viral replication at the S phase cycle.
2 The late viral gene region (LVGR): it converts the capsid proteins VP-1, VP-2, and VP-3 within the nucleus and also encodes a small cytoplasmic protein called agnoprotein, assisting in regulating viral replication and interrupting the host cell processes.
3) The capsid protein VP1 in the LVGR is the chief capsid protein present on the surface and is responsible for receptor binding to the host cells, VP1 is immunogenic as well& it’s the target for the neutralizing antibodies and immune cell recognition. facilitating virus entry into the cell once it gets inside the cell, the virus travels to the nucleus and establishes dormant or lytic infection. BKV variant
BKV have so far four genotypes based on DNA VP1 genomics sequences, genotype 1 is the predominate type with 80% of BKV infection followed by genotype 1V, and both have further subtypes in each genotype with predominate subtypes to certain populations like USA and Europe have more predominate subtype for genotype 1 I (I/b-2) while 1lc1 in Asian patients. Immunological response to BK virus BKV replication can be started early post-kidney transplantation due to immune suppression as in the general population it reported during pregnancy, DM, HIV patients also in cancer patients, and after sold organ transplantation, so the immune system plays a vital role in promoting the viral replication and triggering BKV nephropathy
T cell defect and absence of humoral immune response, alloimmune response, and BKV variation on a molecular level The role of cell-mediated immunity
CD4 and CD8 play key roles in the eradication or clearance of BKV, T cells react against both nonstructural and BK capsid proteins and can be measured by the enzyme-linked immunosorbent spot
(ELISPOT) and tetramer staining. Cytotoxic T cells (CTL) kill the BK-infected cells after the recognition of damaged segments of viral DNA. The defective cellular immune response resulted in viral replication and the infective lytic stage can infect the tubule epithelial cells with viral shedding in the urine and can progress to tubule interstitial nephritis
The alloimmune activation is an immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity. The role of humoral immunity patients with past immunity to BKV may not demonstrate the manifestation of the disease, regardless of the number of viral copies, D+ve /R- ve is at high risk to get BKV Viremia in addition patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels. Clinical manifestations of BKV in renal transplantation The clinical manifestation varies from viruria with viral cells (decoy cells ) shedding in the urine is reported in between 30-40% usually asymptomatic or can result in ureteric stenosis, obstruction, late-onset hemorrhagic cystitis (HC), and if progresses to viremia in the blood then BKV nephropathy with viral interstitial inflammation and progressive interstitial inflammation/fibrosis
HC related to BKV is more seen in ALLO-HCT, rare after kidney transplantation with 4 grades of severity from grade one microscopic painful hematuria with abd cramps, grade two hematuria b visible, and grade 3 gross hematuria with clots, and grade 4 hematuria with obstruction and renal impairment, treatment with aggressive hydration with SPC insertion, bladder irrigation, and cidofovir local infusion for 2-7 weeks BKV in native kidneys
BKV infection of native kidneys with biopsy-proven IB invasion have been reported in recipients of lung and heart transplantation, HIV infections, and also post HCTwith clinical manifestations of nonproteinuric AKI
BK virus and malignancy: thoughts on viral oncogenesis
BKV has an oncogenic property owing to the expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation, many reports correlate the BKV association with certain urothelial tumors, Kaposi sarcomas Ewings sarcoma, CNI malignancies like meningioma. Early coding regions in BKV like Agnoprotein and LTAg will make infected cells incapable of arresting the cell cycle and may energy the cell into a continuous dividing status. Screening for BKV after transplantation
BKV viruria and viremia usually occur early after transplantation with a peak in 3 months then 9 months and another peak after 1 year, many risk factors associated with BKV risk include mainly the intensity of IS therapy, male sex, older age, ethnic background, HLA mismatches, and DGF prolonged cold ischemia time, BKV serostatus and ureteric stenting
As per KDIGO guidelines had recommended BKV screening start in the first month after the transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years
What is the level of evidence provided by this article?
Introduction
The two human polyomaviruses, BK virus (BKV) and JC virus(JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation.
It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma
BK virus and renal transplantation: historical perception
In 1971, Gardner et al, were the first to detect BK polyomavirus(BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure.
They named the virus ‘BK’ after the initials of this patient.
The relationship between kidney transplants and shedding of a polyomavirus in the urine was confirmed with subsequent studies by Lecatsas, BK virus (BKV) was discovered in 1971, it took almost three decades for this virus to be routinely considered as a possibility among a plethora of causes of renal dysfunction in a kidney transplant recipient.
Increased awareness among nephrologists to recognize BKVdisease at an earlier stage and the development of better diagnostic laboratory techniques contributed to the ever-increasing incidence of BKV infection.
Polyomaviridae variants
The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40).
It is a family of small, nonenveloped DNA viruses with icosahedral capsid of.
A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017.
These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV; HPyV6, HPyV7, HPyV9, and HPyV12; New Jersey polyomavirus (NJPyV, known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14).
BK virus structure
BKV-DNA genome can be divided into three parts The noncoding control region (NCCR): it regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell
BK virus variants
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1.
The subgroup of subtype I (I/b-2) has been noticed mostly in American and European populations, whereas subgroup I/c dominates in Asians.
Among subtype IV isolates, subgroup IV/c-2 is predominant among Americans and Europeans, whereas the other subgroups are more common in Asian populations [16,31].
Apart from the genotypic variations of VP1 region, additional two other forms of BKV present secondary to variations in the NCCR, namely, rearranged and archetype variants.
Continuous duplication of BK genome during activation process can result in deletion and duplication in the NCCR sequences, with subsequent generation of rearranged variant viruses.
The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined.
Immunological response to BK virus
BK viral replication follows a state of immune suppression; it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period. BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
The immune system plays an essential part in controlling BKVreplication and resolution of BK virus nephropathy (BKVN).
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
Progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination
The role of humoral immunity
Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies.
Bohl and colleagues found the kidney recipients from a seropositive donor were more likely to develop BK viremiacompared with others who had a kidney from a seronegative donor .
The role of antibodymediated immunity was validated in BKVinfection.
The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
Role of alloimmune activation
Another possible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen(HLA)-reactivity and heterologous immunity.
The latter concerns with T cells, which cross-react to both BKVand allo-antigens.
One can propose that the host BKV-specific effector memory T cells cannot identify the allo-HLA molecules representing BKV-peptides; it allows BKV to escape the immunological surveillance.
Murine kidney allografts were more susceptible to polyomavirusinfection, which cause an increase in allo-reactive T cells that lacked crossreactivity to the virus.
The role of other factors
In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role.
Moriyama et al [56] had demonstrated that a blockage of caveolin-induced endocytosis, either directly or through small interference RNA depletion of caveolin-1, produced substantial reduction in BKV infectivity as measured by immunofluorescence, as BKV particles were found in vitro to colocalize with caveolin-1, and not to a clathrin, in the human renal proximal tubular epithelium.
The pathogenesis of BKV disease is probably related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium
Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
It has been proposed that BKV goes into the circulatory system through infected tonsils, and infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
The sophisticated reactions between the BKV and the immune system result in different clinical features of BKV disease.
Routes of transmission of primary BK virus
Several routes for the primary BKV virus transmission have been theorized.
The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Respiratory route: several authors had speculated the primary route of transmission to be respiratory, as evident by the presence of BKV in the respiratory tract and tonsils of children.
The supportive studies are mainly epidemiological, and none of them had isolated BKV on respiratory samples.
Clinical manifestations
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals; BKV does not cause disease in immunocompetent people.
In renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC).
BKV is commonly encountered in patients with hematopoietic stem cell tnsplant (HSCT) recipients as hemorrhagic and non-HC. whereas in HIV- infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement and eventually leads to death.
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine, which can progress a few weeks later to blood and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN).
BK viruria generally affects 30–40% of renal transplantrecipients, whereas 10–15% of recipients develop BK viremia.
The estimated incidence of BKVN in different literature ranges between 2 and 15% of kidney allograft recipients.
The variations in these figures can be explained by different immunosuppressive regimens and different screening strategies, including a performance of biopsy surveillance in some centers, which can detect BKVN at earlier stages.
BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% . Allograftdysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen , and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen , and treatment should involve a percutaneous nephrostomy and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Hemorrhagic cystitis
BKV-associated HC or non-HC is classically noticed in HSCTrecipients, yet it can be rarely observed among renal allograftrecipients.
The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain.
Severe cases of BKV–HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation.
Reported manifestations of BKV in immunocompromised patients, including renal transplant recipients and patients with HSCT and HIV infection.
Locally through bladder installation was suggested as a therapeutic option for HC, the remission varied from 2 to 7 weeks following hematuria
BK nephropathy in the native kidney
BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients.
Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection.
Such infections are primarily seen in patients with HSCT or HIV infection.
Autopsy showed that BKV infection was present in the brain, kidneys, and peripheral blood smear.
As it is a single case, further data are required before labeling BKV to cause an ophthalmological manifestation.
BK virus and autoimmune diseases
A relationship between BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immunecompromised individuals.
Taguchi and colleagues were the first to report the isolation of BKV from a urine sample of two patients with lupus.
This was confirmed with high BK serum antibodies titers; they demonstrated BKV antigen by indirect immunofluorescence.
There is an increase in the prevalence with persistence/or recurrent BK viruria in patients with lupus.
Such a relationship could be explained with a compromised immune system secondary to the systemic illness or the intensified immunosuppression .
There is no article that describes BKV activation in patients with systemic lupus erythematosus at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease.
BK virus and malignancy: thoughts on viral oncogenesis
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
It has been proposed that BKV has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation.
The LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Inactivation of tumor suppressor p53 and pRb in experimental mice by BKV–LTAg can induce urothelial malignancies.
Tumor cells are likely more vulnerable to BKV than normal urothelium, as the infection happens mainly in proliferating cells, and that positivity is a result instead of being a reason for neoplastic transformation.
Regardless of whether BKV has a causative part in human cancer development or not, it will remain a topic of debate
BK virus and urothelial tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, bladder carcinoma as the BKV-DNA was isolated in these tumors.
Geetha et al. reported a bladder carcinoma with widespread metastases in a simultaneous pancreatic and kidney transplant recipient with concomitant BK interstitial nephritis.
For both the primary tumor and its metastasis, high level of BKV–LTAg was noted in the nucleus of almost every tumor cell and none in the non-neoplastic urothelium, which supports a possible role of BKV in the development of these tumors.
Alexiev et al [140] reported a similar experience, where all tumor cells had shown strong expression of BKV–LTAg, p53, p16, and Ki-67, in addition to the intranuclear virions in electron microscopy
Risk factors
Several risk factors were implicated in the pathogenesis of BKVN.
The most consistent risk factor identified in the literature is the overall degree of immunosuppression.
Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLAmismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; these risk factors have not been uniformly observed in all studies.
Screening and diagnostic tools
The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears.
Screening tests
Viral replication starts early after transplantation and progresses through noticeable phases: viruria viremia followed by nephropathy.
Viral replication in the urine precedes BK viremia by ∼4 weeks, and there have been confined cases of patients developing viremia without viruria, this is uncommon.
Histological changes of BKVN are observed 12 weeks after BK viruria.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
No single diagnostic pathway has appeared as predominant.
Monitoring of the urine
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKVvirions or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Urine cytology
Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients.
Such wide variation can be explained by screening strategies that were used in different centers and different immunosuppressive regimens.
Urine electron microscopy (EM Haufen): in contrast to decoy cells, Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, forming cast-like three-dimensional aggregates, which can be noticed in a urinary smear of kidney recipients using negative-staining electron microscopy.
Presence of Haufen bodies, which corresponds to upper levels of BK viremia, had a higher sensitivity and specificity for biopsy-proven BKVN (100 and 99% correspondingly), in a retrospective, single-center study.
Haufen particles were absent in recipients with a lower BK viremia
Advantages and limitation
Useful marker in identification of BKV infection, but a poor diagnostic tool in predicting BKVN.
Not useful for monitoring decline in viral load.
Predictive for BKVN, but not practical for routine practice as it requires electron microscopy with interpretation from a pathologist Measurement variations between laboratories limit its use
Still under assessment and requires further validation
Has good sensitivity and specificity but low PPV for BKVN.
As this method represents singlecenter data, it requires further validation.
This test cannot be applied for routine clinical practice because of the expense and inaccessibility to electron microscopy and the need for interpretation from a pathologist.
Molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity .
Persistent DNA-PCR more than 107/ml instead of episodic identification can recognize patients at risk for BKVN.
Variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis.
BK virus mRNA levels in urine
BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication.
This method is considered as highly specific and sensitive in predicting patients who might develop BKVN, using 6.5×105 BKV-VP1 mRNAs/ng RNA in urinary cells as a cutoff value.
Though this assay is encouraging as a noninvasive tool and can provide additional diagnostic and prognostic data, yet it requires further validation.
Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels
Serum antibodies
Serum antibodies against BKV are commonly present among the general public.
The significance of assessing BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain.
It has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients.
The positive donor BKV serostatus and negative recipient serostatus (BK D+/R−) have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients.
Kidney biopsy
The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks.
Allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log genome) with or without allograft dysfunction.
Such suggestion came from a prospective analysis of Hirsch et al, who demonstrated that BK viremia of more than or equal to 104 is characteristically present in recipients with proven biopsies of BKVN.
BK-PCR of allograft biopsy tissue is not an applicable investigation to diagnose BKVN, as it can identify a latent virus, even in asymptomatic recipients.
Pros and cons of kidney biopsy
Renal biopsy remains the gold standard for diagnosis of BKVN. biopsy findings can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result; a minimum of two biopsy cores, preferably including medulla, should be inspected to make the correct diagnosis.
Suggested algorithm for screening
Different screening protocols are present in the literature, reflecting the experience of several centers where they have been developed.
Hirsch et al,screened patients for BKV, first with urine cytology for decoy cells every 3 months, and whenever decoy cells were detected, additional studies were carried, including quantification of viral level in the plasma with the possibility of doing allograft biopsy only with a deterioration of renal function.
The persistence of decoy cells for more than or equal to 3 months will trigger the performance of quantitative measurement of PCR-viral loads in plasma and renal biopsy in patients with evidence of BK viral reactivation, irrespective of renal function.
Buehrig et al,and Khamash et al, had suggested routine surveillance biopsies to detect patients with silent BKVN.
Allograft biopsies were performed at third/fourth month and at 12 months after transplantation, and many patients were detected with a silent disease.
The University of Maryland
A variable number of virus-infected cells with any degree of tubular injury and significant inflammation affecting less than 25%, 25–50% or >50% of the core biopsy.
A variable number of infected cells with any degree of tubular injury and tubular atrophy/ fibrosis affecting >50% of core biopsy
American Society of Transplantation Virus infection and cytopathic effect in
Similar to the University of Maryland, except that B1, B2 and B3 are assigned progressively increasing degrees of cytopathic effect, atrophy, and fibrosis.
Same as University of Maryland System time of diagnosis .
Most transplant institutes, including our center, recommend BK surveillance with plasma BK-PCR.
Screening for BKV should be performed on periodic intervals, starting after 1 month, monthly for 3–6 months, and every 3 months for the initial 1–2 years after transplantation.
American Society of Transplantation guidelines recommended further annual screening till the fifth year after transplant; generally screening beyond 2 years is not recommended in most centers unless allograft dysfunction is present .
Allograft biopsy can be considered in individuals with persistent high viral loads for more than or equal to 3 weeks.
Is a suggested algorithm for BKV screening .
Allograft rejection
The distinction of BKVN from acute rejection is challenging as the histological appearance is often similar; it should be aided by analysis of blood or urine PCR.
Absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease.
Another useful technique to differentiate between acute rejection and BKVN is IHC staining of renal tissues or urinary sediments with.
The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of concurrent acute rejection.
Treatment strategy of BK virus nephropathy
The aim of treating BKV is to eradicate the virus while saving the kidney function.
BKVN has limited treatment options .
As BK viremia and BKVN signify excessive cumulative immunosuppression, decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection .
Rapid viral load reduction has been related to steady or improved allograft function .
Treatment of presumptive BK virus nephropathy
The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
There is no standard strategy for modifying immunosuppressant’s therapy; different regimens have been attempted upon recognition of viremia.
These include withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance .
Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% or converting tacrolimus to cyclosporine or discontinuing CNI.
Treatment of BK virus nephropathy in the setting of allograft dysfunction
Favorable renal allograft outcomes in the context of acute BKVinfection were reported when immunosuppression reduction had started early upon detection of BK viremia, permitting early and appropriate therapeutic interference.
If the identification of BKVN is made at an advanced stage when nephropathy ensues, reducing immunosuppression is probably going to be less effective, owing to the advanced disease, with severe histological changes leading to progressive, irreversible renal damage.
Allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy.
Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises BKV-specific IgG-antibodies titer and increases BKV– specific cellular immunity.
Drugs with antiviral activities
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug which was developed to be used in rheumatoid arthritis.
Being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages.
It is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppressiondosage.
The mTOR inhibitors are thought to produce their inhibitory effect on BKV replication by restoring the downregulation of translation that occurs under cellular stress, delay the viral replication
It inhibits the proliferation of BKV– specific T cells and controls the differentiation of memory CD8 T cells; it improves the immune reaction following BKV infection .
Tacrolimus and MMF were replaced with sirolimus, which resulted in reduction of the BK viral load with concurrent improvement in estimated glomerular filtration rate.
Intravenous immunoglobulin
Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN for its immunomodulatory effects.
The IVIG with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection; the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression.
Other therapeutic options for treating BK virus nephropathy,A latest study examined the anti-viral influence of artesunate on BK viral proliferation in a primary human renal cell culture.
The investigators found a decrease in BKV proliferation in a dose-dependent way with artesunate.
Therapy with anti-CD20mAb rituximab used for the treatment of antibody-mediated rejection was associated with several adverse effects including BKVN, CMV viremia, herpes zoster, and septic shock , yet Babel and colleagues had reported promising results by using rituximab in nine transplant patients with BKVN.
Patients who had received rituximab as an adjuvant therapy with
Adverse muscle events and hepatic dysfunction
Cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN.
In both groups, the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine.
In the late 1990s and early 2000s, BKVN caused permanent allograft damage in 30–60% of cases
This happened as a result of lack of awareness, delayed diagnosis, misdiagnosis, and coincidental utilization of escalated immunosuppression for possible acute rejection episodes .
Buehrig et al, reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis (8/8 patients vs 3/10, P=0.004).
Chen et al,reported 1-, 3-, and 5-year allograft survival rates following a diagnosis of BKVN (n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograftsurvival (P= 0.042)
BK nephropathy with concurrent acute rejection
Management of proven allograft biopsies of acute rejection with concomitant BKVN or management of anticipated rejection following a decrease of immunosuppression to treat BKVNremains debatable.
More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in 10–30% of the cases .
Reports have depicted clinical improvement, steady or worse allograft outcomes, following steroid pulses .
Hirsch et al,suggested a combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection.
An initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.
Upon clearance of viremia and BKVN, the advantage of up-titrating immunosuppression to avoid further late acute rejection or chronic rejection remains obscure.
Postinfection monitoring
Close observation of BKV-PCR and renal function with any treatment, following management of acute rejection or reduction of immunosuppression, is crucial to improve allograftoutcome.
The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
It should be done on a monthly bases until clearance of BK viremia and stabilization of renal function achieved .
USA-OPTN registry data for the period 2004–2008 showed 126 individuals got retransplant of 823 who lost their graft secondary to BKVN.
Recurring BKV might reflect a previous BK variant or a new infection acquired, because of the long period, in the posttransplantation stage.
Conclusion
Three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology.
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment
Findings
Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population.
Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening.
Buehrig et al,reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis (8/8 patients vs 3/10, P=0.004).
Chen et al, reported 1-, 3-, and 5-year allograft survival rates following a diagnosis of BKVN (n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograftsurvival (P= 0.042).
Celik et al,found a reduction in immunosuppression is more than capable in reducing and 18%.
LEVEL OF EVIDENCE IS 5.
BK virus (BKV) was discovered in 1971. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection. Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss. This review is aimed to discuss the most recent evidence addressing the virology, pathogenesis, clinical features, diagnostic tools, screening protocols, treatment strategy, and short-term and long-term renal allograft survival concerning BKV infection.
The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40).
Immunological response to BK virus
BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN).
Pathogenesis of BKV
It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
Routes of transmission of primary BK virus
· Respiratory route
· Gastrointestinal transmission
· Vertical transmission
· Sexual transmission
· Donor-derived infection
· Through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes
Clinical manifestations
BKV does not cause disease in immunocompetent people. In immunocompromised patients, particularly in renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
Risk factor
Risk factors
Immunosuppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion
Screening and diagnostic tools
KDIGO guidelines have recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
DNA-PCR in urine and blood
BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’)
Urine cytology Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients
Urine electron microscopy (EM Haufen)
Quantitative measurements of urinary BK virus-viral loads Compared with urine cytology, molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity
Serum BK-PCR BK viremia is noticed only among immunocompromised patients, with an estimated prevalence of 7–30% in the initial 6 months and 5–10% after that among kidney recipients
Kidney Biopsy
Streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically
BK viral inclusions within tubular epithelium can be identified via the conventional hematoxylin and eosin (H&E) and PAS staining
Fluorescence in-situ hybridization (FISH) analysis allows BKV identification in renal transplant tissues through bright nuclear fluorescence technique
Differential diagnosis
Allograft rejection
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40
Treatment strategy of BK virus nephropathy
The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy
Stop MMF
IVIG
What is the level of evidence provided by this article?
Introduction The human BK virus was first discovered in 1971 belong to Polyomaviridae comprising JC Virus, BK Virus, and Simian virus 40. BKV is one of the common early post-kidney transplant infections that could cause graft loss by BKV nephropathy if not detected timely. There are twelve more polyoma viruses that are named based on the disease they cause, geography, or their epidemiology Epidemiology of BKV a) BKV is found worldwide. b) Affect almost all people during childhood and remained dormant until there is immunosuppression status c) Studies show upto 60-85% of the population is affected d) It has three genomic region (NNCR), e) early viral gene region, late viral region (LVGR), and the capsid protein in VP1 of the late viral region f) Humoral immunity play vital role in BKVN Pathogenesis of BKV Infection
The portal of entry into circulation is infected tonsils ( primary infection)
BKV infects the peripheral blood mononuclear cell that gets disseminated to secondary places like the kidneys. Following a resolution of primary infection,
The virus stays dormant in the uroepithelium and renal tubular cells for life until reactivated by the situation that affects the immune system
The outcome relies upon damage, inflammation and fibrosis.
During reactivation, viral cytolytic effect and inflammatory response will determine the final outcome in the kidney parenchyma
The defective immune surveillance by T- cells and the absence of humoral immunity to BKV will result in viral replication and eventual disease
Route of transmission of primary BK virus
Respiratory route
Gastrointestinal transmission
Vertical transmission
Sexual transmission
Donor-derived infection
Through urine and blood.
Clinical Manifestations
BKVN
Hemorrhagic cystitis
Ureteric stenosis
Pulmonary disease
Neurological involvement eg meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
BK virus and hepatic disease in those with bone marrow transplant
BK virus and autoimmune diseases like SLE, polymyositis, and rheumatoid arthritis have been documented
BK virus and malignancy-like brain tumors of glial and neural origin such as ependymomas, meningiomas, glioblastomas, gliomas, and neuroblastoma
BKVN in Urothelial tumours might have role in pathogenesis.
Risk factions for BKV a) Immunosuppression – most common b) Male sex c) Older recipient age d) Previous rejection episode e) Degree of HLA mismatch f) Prolong cold ischemic time g) BK serostatus D+/R- h) Certain ethnic group Screening time and diagnostic tool
The aim is early detection from the urine, and blood before kidney tissues- histology
Detection of Decoy cell (urine cytology) or Haufen BK virion if electron microscope is available
A quantitative measure of urinary BK virus by PCR
Kidney biopsy – the gold standard
American Society of Transplantation Infectious Diseases Guidelines and KDIGO guidelines had recommended BKV screening start the first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years
Treatment of BKVN
Immunosuppressive reduction the main stay of treatment
Discontinue MMF, and switch to AZA, or Sirolimus
Withdrawal of steroids
Reduce the dose of CNI by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or convert tacrolimus to cyclosporine or discontinue CNI
Other medications that have been used with varying outcomes
Leflunomide
Cidofovir or Brancidofovir which is less nephrotoxic
mTORs
IVIG
Quinolone
Pravastatin
Rituximab
Conclusion Despite of three decades of research in the field of BKV, there are still remain some gaps, like lack of definitive treatment that could be curative, although some of these searches has helped the understanding of early diagnosis and some early intervention that may help to prevent the progression to BKVN. There is the challenge of difficulty in differentiating acute allograft rejection from BKVN, and sometimes both may coexist. Re-Transplantation is possible after graft loss, and the common reason is to remove the failed graft after period of undetected BKV
Introduction:
BK virus (BKV) was discovered in 1971, BKV belongs to the Polyomaviridae a subgroup comprising JCV, BKV and SV40. Their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients. BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma. There are 4 genotypes of BKV, with genotype 1 being the most prevalent followed by genotype 4; genotype 2 and 3 are rare.
Pathogenesis: Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood. The virus remains dormant in the urothelium and renal tubular cells. It can also remain dormant in the lymph nodes, brain tissue and leukocytes. In the presence of immunosuppressive therapy the virus replicates and spreads to the peri-tubular capillaries leading tubular cell lysis and viruria. Reaction between the BKV and immune system leads to varies presentation of BK disease.
Routes of transmission of primary BK virus:
Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestation Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals (but not in plasma); nevertheless, BKV does not cause disease in immunocompetent people. Include BKV nephropathy, ureteric stenosis, and late onset hemorrhagic cystitis. · BKV and renal disease: Begins with viral replication in the uroepithelial cells, then viruria that progresses to viremia and later BK associated nephropathy. · BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. · Ureteric stenosis: Prevalence is 2-6%, rarely does it lead to hydronephrosis and allograft dysfunction. Treatment of ureteric stenosis involves placement of a percutaneous stent, percutaneous ureteral dilatation with concurrent reduction of immunosuppression. · Hemorrhagic cystitis: Presentation include painful voiding, hematuria, painful bladder cramps+/- flank pains. Four degrees of disease severity are recognised: – Asymptomatic hematuria – Symptomatic hematuria – Hematuria with clots – Hematuria with clots, clot retention and renal failure secondary to obstructive uropathy. · Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection. · BKV and malignancy: BKV DNA has been detected in tissue samples of different neoplasms. It has been proposed that BKV has oncogenic properties owing to its LTAG and STAG proteins. Screening tests Viruria precedes viremia by approximately 4 weeks while BKVN occurs 12 weeks after viruria. · Urine cytology: Decoy cells, they are infected tubular cells with with an enlarged nucleus with basophilic intranuclear inclusions. Presence of decoy cells is strongly suggestive of polyomavirus infection and is considered as a marker of BKV reactivation. It has sensitivity ranging between 25-100% and specificity 71-84% to diagnose BKVN. · Urine viral loads: PCR has a sensitivity of 100% and specificity of 78%. Persistent high viral loads can predicting patients at risk of BKVN. · Serum BK PCR: sensitivity of 100% and specificity of 88% thus it is the preferred screening tool in most transplant centers. · Kidney biopsy: Gold standard for diagnosing BKVN..
Treatment: Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection. Withdrawal of the antimetabolite such as MMF is the most usual method. Drugs with antiviral activities: Leflunomide: It’s an immune modulator given orally, loading dose of 100mg daily for 3–5 days followed with a maintenance dose of 20–40mg/day and recommended target level of 40–100 μg/ml. Cidofovir: Cytosine analog and viral DNA- polymerase inhibitor Mechanism of action is unclear as BKV lacks the viral polymerase gene the known target of cidofovir. It’s exclusively excreted through urine, resulting in high renal tubular cell concentrations. mTOR inhibitors: Inhibits the proliferation of BKV- specific T cells and controls the differentiation of memory CD8 T cells; hence, it improves the immune reaction following BKV infection.
Intravenous immunoglobulin: Potent neutralizing antibodies and is able to neutralize all major BK viral genotypes. IVIG in a dosage of 2–3.5g/kg divided over 2–5 days with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection. The efficiency is uncertain, as it has been given with concomitant reduction in immunosuppression.
Others: Quinolones, antimalarial, statin Post infectious monitoring: Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome. S. creatinine every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks then monthly until clearance of BK viremia or at viral burden falls below threshold value and stabilization of renal function achieved. Conclusion:
Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology. There is a bigger ‘known unknown’ that just proves the elusive nature of BKV. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
BK virus infection in renal transplant recipients: an overview
1. The two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971. 2. BKV infection is often occurring within the first year after transplantation. 3. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma. 4. Decoy cells are abundant large cells with intranuclear inclusions present in the urine, named as ‘decoy cells’ for their resemblance to malignant cells.Polyomaviridae variants 5. The Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising human BKV, JCV, and simian virus 40 (SV40).The name polyoma represents the viruses’ capability to create many (poly) tumors (−oma). 6. The Polyomaviridae is a family of small, nonenveloped DNA viruses and has a circular double-stranded DNA. 7. A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017. MCPyV (Merkel cell carcinoma) is one of the lately isolated PyV. Epidemiology of BK virus 1. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people. 2. 60–85% of the general population is seropositive for BKV. BK virus structure
BKV-DNA genome can be divided into three parts: 1. The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen). 2. The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus. 3. The capsid protein VP1 in the LVGR: is responsible for receptor binding to the host cells, facilitating virus entry into the cell. BK virus variants
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1: 1. Genotype I: the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide. 2. Genotype IV: is the second most frequent genotype, found approximately in 15% of the healthy human population. 3. Genotypes II and III: are relatively rare and infect only a minority of patients. Immunological response to BK virus 1. BK viral replication follows a state of immune suppression(in pregnancy, diabetes, HIV infection, cancer, and post-transplantation period). 2. Possible factors that add to the pathogenesis of BKVN might be a combination of: a) defective immune surveillance by the host T- lymphocytes. b) absence of humoral immunity to BKV. c) alloimmune activation. d) viral variation in molecular sequences. 3. The role of cell-mediated immunity: a) CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance. b) Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA. c) Progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells. d) The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination into the interstitium. e) Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation. f) The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis. g) Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss. 4. The role of humoral immunity: a) the kidney recipients from a seropositive donor were more likely to develop BK viremia compared with others who had a kidney from a seronegative donor. b) The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels. 5. Role of alloimmune activation: a) CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans. b) The higher degree of HLA mismatches is linked with an increase in the incidences of BKVN, which hypothesizes the role of alloimmune activation. c) 6. The role of other factors: BKV tropism to the renal tubular epithelial cells may play an additional role.
Pathogenesis of BK infection 1. Primary infection BKV is usually subclinical. 2. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life. BKV can remain latent in leukocytes, brain tissues, and lymph nodes. 3. Intermittent reactivation may manifests as asymptomatic viruria. 4. When the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria. 5. Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses. 6. The outcome relies upon the level of damage, inflammation, and fibrosis.
Routes of transmission of primary BK virus
The route of infection might be respiratory, fecal-oral, transplacental, from donor tissues.
Clinical manifestations 1. BKV does not cause disease in immunocompetent people. 2. In immunocompromised patients(KTRs), BKV has been correlated with BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC). 3. In HSCT recipients, it manifests as hemorrhagic and non-HC. 4. In HIV- infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement and eventually leads to death. 5. BKV is linked to certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis.
BK virus and malignancy: thoughts on viral oncogenesis
1. It has been proposed that BKV has an oncogenic property. 2. The BKV-DNA has been identified in tissue samples of different neoplasms, including: a) different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas). b) pancreatic islets cell tumors. c) Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma. d) prostatic carcinoma and urothelial tumors.
Screening for active BKV replication 1. Identification of viral DNA-PCR in urine and blood. 2. BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity. 3. BK virus mRNA levels in urine(sensitivity of 100% and specificity 97%. 4. Serum BK-PCR: BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively, for the development of BKVN than BK viruria [95,181]; hence, it is the preferred screening technique at most transplant institutions. 5. Urine cytology for Decoy cells(reported a sensitivity of 100%, and a specificity of 71%). 6. Urine electron microscopy (EM Haufen) for the presence of Haufen bodies, which corresponds to upper levels of BK viremia(had a higher sensitivity and specificity for biopsy-proven BKVN (100 and 99% correspondingly)). 7. Serum antibodies against BKV has no clinical relevance in diagnosing acute BKV infection affecting post-kidney transplant recipients. 8. Virus culture: BKV grows slowly in tissue culture, which might extend from weeks to months.Virus culture is used in the setting of research. 9. Kidney biopsy: a) to anticipate the disease in presumptive BKVN(patients with significant viruria and persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks.
b) Identification of BK viral inclusions within tubular epithelium via the conventional hematoxylin and eosin (H&E) and PAS staining. H&E is specific for BKV with a sensitivity of 57.9% and specificity of 94.4%. c) Identification of BKV via in-situ hybridization:fluorescence in-situ hybridization (FISH) analysis is specific for BKV with a sensitivity of 94.7% and a specificity of 100%. d) Identification of BKV via immunohistochemistry (IHC):IHC is specific for BKV with a sensitivity of 68.4% and specificity of 100%. e) Positive IHC using specific antibodies against BKV or the cross-reacting SV40 LTAg has a specificity of nearly100% for polyomavirus nephropathy.
Differential diagnosis · Allograft rejection. · Any disease associated with early or late renal allograft dysfunction.
Treatment of presumptive BK virus nephropathy:
Reduction/or modifications in immunosuppressive therapy with or without antiviral medications. Drugs with antiviral activities · Leflunomide. · Cidofovir. · mTOR inhibitors. · Intravenous immunoglobulin Other therapeutic options for treating BK virus nephropathy · Quinolones. · Artesunate (an antimalarial drug). · statins (pravastatin). · Rituximab.
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
SUMMARY Introduction
Polyomaviruses are small DNA viruses that can infect humans and animals like rabbits.
BK polyomavirus (BKV) is considered one of the highly prevalent forms of polyomaviruses.
BK named after 1st case which was a Sudanese renal transplant patient presented with ureteral obstruction after renal transplant and histological examination showed viral particles in the lining of the ureters. Pathogenesis of BKV Infection
Primary BKV infection occurs in the first decade of life, on average at 4 to 5 years of age.
Possible routes include the following: (1) airborne transmission through air droplets (2) a feco-oral transmission (3) both through blood transfusion and vertical transmission
Primary infections are often clinically insignificant; however, the virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule.
In the immunocompetent population, BKV replication is manifested by asymptomatic viruria, and the incidence of shedding is 20%. However, in immunocompromised individuals, the risk of shedding reaches 60% and the viruria is more common.
The defective immune surveillance by T- cells and the absence of humoral immunity to BKV will result in viral replication and eventual disease
Clinical Manifestation
BKVN
Hemorrhagic cystitis seen only in BM transplant patients
Ureteric stenosis
Risk factions for BKV
Immunosuppression – most common
Male sex
Older recipient age
Previous rejection episode
Degree of HLA mismatch
BK serostatus D+/R-
screening time and test
Viuria: PCR in urine can be used in screening but viral load should be at least more than 7 log to consider significant.
Decoy cells: Cytological urine abnormalities (decoy cells) are suggestive but not specific, sensitive, or definitive for BKV infection because
(1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus).
(2) decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients. Of note, their absence does not exclude the disease.
Plasma PCR: Sustained high viral DNA levels in the plasma of renal transplant recipients who have an appropriate clinical picture can suggest BKVN.
Kidney biopsy: characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection.
A diagnosis of BKV in a renal biopsy could be missed in about 30% (sensitivity only 70%) of cases because BKV has a focal tropism in the medulla rather than in the cortex
BK virus nephropathy can be similar to cellular rejection (Or mixed with rejection).
immunohistology methods are used to differentiate between both.
Correlations between histologic findings and BK viremia is essential in patients who show ambiguous histologic features.
American Society of Transplantation Infectious Diseases Guidelines guidelines recommended BKV screening start the first month after transplant, then monthly for the first 9 months, and then every 3 months for up to 2 years
Treatment of BKVN NO RCT support any of next approachs.
Immunosuppressive reduction by 30% to 50%
Discontinue MMF and switch to Sirolimus
IVIG
Switch from MMF to leflunomide with monitoring of its trough level.
BKV is a major cause of interstitial nephritis and allograft failure in kidney transplant recipients, presenting as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis. BK polyomavirus (BKV) was detected for the first time in 1971 in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure .
BK virus structure:
BKV-DNA genome is divided into three parts: NCCR, late viral gene region, and capsid protein VP1. BKV can be divided into four genotypes based on DNA sequence variations in the VP1 region, with genotype I accounting for 80% worldwide and genotype IV being the second most frequent.
Immunological response to BK virus:
The immune system plays an essential role in controlling BKV replication and resolution, with CD4+ and CD8+ T cells being the major components. Humoral immunity, antibody mediated immunity, allo-human leukocyte activation, and polyomavirus infection all play roles in the pathogenesis of BKVN.
Pathogenesis of BK infection:
BKV infection is usually subclinical and manifests as a mild respiratory symptom in childhood. After primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation. Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
Routes of transmission of primary BK virus:
Routes of transmission of primary BK virus have been theorized, such as respiratory, fecal-oral, transplacental, or from donor tissues. Vertical transmission is also proposed, as BK viruria can increase up to 35% during pregnancy and BKV can cross the placenta and stay dormant in fetal organs.
Clinical manifestations:
BK virus (BKV) is a virus that causes urinary shedding in 7% of healthy individuals, but does not cause disease in immunocompromised patients. It is associated with different clinical features, such as BKVN,ureteric stenosis, and late-onset hemorrhagic cystitis (HC). Outside renal transplantation, BKV is commonly encountered in patients with HSCT and HIVinfected patients. BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. BK nephropathy in the native kidney has been reported in HSCT recipients, heart and lung transplant recipients, as well as immunocompromised HIV-infected patients. Neurological manifestations include meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy. Pulmonary diseases include reactivated acute respiratory infection leading to severe interstitial pneumonitis, and ophthalmologic manifestations include bilateral atypical retinitis. Further data are needed before labeling BKV to cause an ophthalmological manifestation.
BK virus (BKV) has been linked to hepatic disease and autoimmune diseases, including systemic lupus erythematosus, polymyositis, and rheumatoid arthritis. BKV infection can induce antidouble-stranded DNA and histone antibodies, and there is an increase in the prevalence of persistence/or recurrent BK viruria in lupus. However, there is no article that describes BKV activation in postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease.
BK virus and malignancy:
BKV has an oncogenic property due to expression of early coding region-encoded proteins such as LTAg and STA, which can drive the cell into a neoplastic transformation. BKV-LTAg may have a role in the pathogenesis of urothelial tumors, but evidence is limited.
Risk factors and screening :
Risk factors for BKVN include overall immunosuppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion. Screening and diagnostic tools are used to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears. Viral replication starts early after transplantation and progresses through noticeable phases: viruria then viremia followed by nephropathy.
Monitoring of the urine may detect BKV-infected epithelial cells, aggregates of BKV virions, or quantification of urinary BKV viral load. Cytological analysis of urinary smear may reveal characteristic abnormal BK-infected cells, termed as decoy cells. Decoy cells are infected tubular epithelial cells with an enlarged nucleus that contains a single, large, basophilic intranuclear BK inclusion body and looks similar to those seen frequently in uroepithelial malignancy. Reported a sensitivity of 100%, and a specificity of 71% when they matched graft-biopsy samples as a diagnostic standard.
Quantitative measurements of urinary BK virus-viral loads using urinary BKV-PCR have 100% sensitivity and 78% specificity. However, variability in laboratory measurements has created difficulties in standardizing this technique for definite diagnosis. Recently, BK viral capsid (VP1) protein 1-mRNA derived from urinary cells has been analyzed as a biomarker to detect active viral replication. This assay is highly specific and sensitive, but requires further validation. Additionally, raised mRNA levels for granzyme B (>11 mRNA copies/μg total RNA) are usually present in recipients with acute cellular rejection, which may overestimate the prevalence of BKVN.
Serology serum BK PCR :
BK viremia is mainly seen in immunocompromised patients, with an estimated prevalence of 7-30% in the initial 6 months and 5-10% after that among kidney recipients. Quantitative BKV-DNA in plasma has been successful in identifying early infection before nephritis. Nephritis can be seen with plasma BKVDNA of less than 7000 copies/ml, The BKV-PCR test has high sensitivity and specificity, but there are interlaboratory variations in measuring BK viral loads. Serum antibodies against BKV are commonly present.
Kidney biopsy:
Kidney biopsy is the gold standard to diagnose BKVN, but different threshold values have been proposed to anticipate the disease. BK viral inclusions within tubular epithelium can be identified via conventional hematoxylin and eosin (H&E) and PAS staining, while in-situ hybridization (FISH) analysis allows for BKV identification in renal transplant tissues through bright nuclear fluorescence technique.
Suggested algorithm for screening:
Different screening protocols have been developed for BKV screening in renal transplant recipients, with Hirsch et al. recommending a step-wise methodology and Ramos et al. recommending periodic screening of urine cytology for decoy cells. Buehrig et al. and Khamash et al. recommended routine surveillance biopsies to detect silent BKVN, and American Society of Transplantation guidelines recommended further annual screening till the fifth year after transplant. Most transplant institutes, including our center, recommend BK surveillance with plasma BK-PCR. Screening should be performed on periodic intervals, starting after 1 month, monthly, and every 3 months for the initial 1-2 years after transplantation.
Differential diagnosis:
Differential diagnosis of BKVN from acute rejection is important as treating the presumed rejection with increased immunosuppression may result in progression, but it can also occur concurrently with acute rejection. Differentiation between these two types of rejection is aided by blood or urine PCR and IHC staining of renal tissues or urinary sediments with anti-HLA DR, as well as a higher quantity of CD20+ cells in the tissue infiltrates and increased expression of genes related to inflammation and acute rejection. The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of coexistence.
Treatment :
Reducing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response, but should be balanced against risk of rejection.
Treatment of BK virus nephropathy in the setting of allograft dysfunction:
Reducing immunosuppression is a rational option for treating BK virus nephropathy in the setting of allograft dysfunction.
Cidofovir : Cidofovir is a cytosine analog and viral DNApolymerase inhibitor used to manage other viral infections, but its mechanism of action is unclear.
mTOR inhibitors: MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression, but lack clinical efficacy.
Intravenous immunoglobulin: IVIG has the most potent antiviral influence, but its efficiency is uncertain.
Other therapeutic options for treating BK virus nephropathy:
Quinolones and statins have been found to inhibit LTAg helicase activity and have in-vitro and invivo activity against BKV. Artesunate has been found to decrease BKV proliferation in a dose-dependent way, and rituximab has been reported promising results in nine transplant patients with BKVN. The standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine.
Short-term and long-term allograft survival:
BKVN caused permanent allograft damage in 30-60% of cases, but the renal allograft survival for recipients with BKVN had improved considerably in the past years. Therapeutic approaches have revealed substantial short-term improvements, but long-term outcomes such as late acute and chronic rejections need to be further evaluated. Buehrig et al. reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis.
BK nephropathy with concurrent acute rejection:
Management of proven allograft biopsies of acute rejection with concomitant BKVN or anticipated rejection following a decrease of immunosuppression is debatable. Steroid pulses can reduce viral load, but antirejection therapy may be more effective.
Postinfection monitoring:
Postinfection monitoring of BKV-PCR and renal function is essential to improve allograft outcome. Retransplantation is possible and can be done successfully.
Conclusion:
Early diagnosis of BKVN has improved allograft outcomes despite lack of specific treatment.
level of evidence provided by this article?
level V
Please summarise this article. The term BKVN has been created to recognize recipients with
(a) significant viruria, suggesting viral proliferation in the urinary tract
(b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks
BK-PCR has high sensitivity and specificity in anticipating BKVN different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN
Thus, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction .
. Ultimately, a persistent BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis Three grades of histopathological severity have been identified grade A includes viral cytopathic changes of near-normal renal parenchyma, with no or minimal tubular atrophy, interstitial fibrosis, or inflammation, to stage C, which signifies diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation.
screening protocols had recommended
a step-wise methodology for BKV screening in renal transplant recipients. screened patients for BKV, first with urine cytology for decoy cells every 3 months, and whenever decoy cells were detected, additional studies were carried, including quantification of viral level in the plasma with the possibility of doing allograft biopsy only with a deterioration of renal function.
. Buehrig et al. and Khamash et al. had suggested routine surveillance biopsies to detect patients with silent BKVN. Allograft biopsies were performed at third/fourth month and at 12 months after transplantation, and many patients were detected with a silent disease
Differential diagnosis
Allograft rejection is challenging as the histological appearance is often similar; aided by analysis of blood or urine PCR.
Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN. Nevertheless, BKVN may exist concurrently with acute rejection
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells.
Furthermore, absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported in someBKV cases and islinked with more aggressive disease
Another useful technique to differentiate between acute rejection and BKVN is IHC staining of renal tissues or urinary sediments with anti-HLA DR, which has been related to acute rejection
Besides, a higher quantity of CD20+ cells in the tissue infiltrates has been associated with BKVN as opposed to acute rejection . Moreover, the expression of genes related to inflammation and acute rejection (such asCD8, interferon-gamma,CXCR3, and perforin) was higher in patients with BKVN compared with acute rejection.
Another differential diagnosis includes any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction.
Treatment strategy of BK virus nephropathy
decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection Rapid viral load reduction has been related to steady or improved allograft function
Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI
Withdrawal of the antimetabolite such as MMF is the most usual method
Treatment of BK virus nephropathy
Drugs with antiviral activities A metabolite of leflunomide teriflunomide (A77 1726) can inhibit BKV replication in vitro and, to a minor degree, the level of virion assembly and release . Leflunomide is given orally, with a loading dose of 100 mg daily for 3–5 days followed with a maintenance dose of 20–40 mg/day and recommended target level of 40–100 μg/ml. ; thus, treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages .
Cidofovir showed in-vitro inhibitory action against polyomaviruses though the mechanism of action is unclear as BKV lacks the viral polymerase gene, the known target of cidofovir . Cidofovir is exclusively excreted through urine, resulting in high renal tubular cell concentrations. Hence, vigorous intravenous prehydration is needed
Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes
The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection;
Quinolones
It has been found beneficial in combination with leflunomide for treating BKVN
with a significant decrease in BK viremia
Rituximab Although therapy with anti-CD20mAb rituximab used for the treatment of antibody-mediated rejection was associated with several adverse effects including BKVN, CMV viremia, herpes zoster, and septic shock
yet Babel and colleagues had reported promising results by using rituximab in nine transplant patients with BKVN. Patients who had received rituximab as an adjuvant therapy with cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN. In both groups,
the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine. The viral load had normalized in most within 18.3±6.8 weeks . This is a single report, and further prospective randomized trials are required to validate the benefit of this therapy for BKVN
Retransplantation following graft loss owing to BKVN is possible and can be done successfully
Ramos et al. described successful retransplantation in 9/ 10 patients without recurrent BKVN,
An analysis of the USA-OPTN registry data for the period 2004–2008 showed 126 individuals got retransplant of 823 who lost their graft secondary to BKVN
All kinds of induction and maintenance therapy have been used for all recipients as per their center’s protocols. Of the 126 retransplants, BKV was reported in 17.5% of the cases; however, just a single kidney was lost because of repetitive BKVN.
The 1- and 3-year graft survival among the retransplanted individuals was excellent at 98.5 and 93.6%, respectively Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression
Allograft nephrectomy is not necessary before retransplantation; however, in the background of active viral replication, it appears sensible to eliminate the infected graft before getting a new transplant, though there is no evidence to support this approach
What is the level of evidence provided by this article? the level of evidence is 5
Please summarise this article. Introduction: – Two human polyomaviruses, BK virus (BKV), simian virus 40 (SV40) and JC virus (JCV), were discovered in 1971, since that time BKV infection is a major cause of interstitial nephritis and allograft failure in kidney transplant recipients, presenting a diagnostic and therapeutic treatment dilemma. – Gardner et al. and Mackenzie et al. were the first to detect BKpolyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient. This virus was found to have high homology with JCV, the other human polyomavirus, and was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipient.
Polyomaviridae variants: The human BKV belongs to the Polyomaviridae (PyV) virions, are small, nonenveloped DNA viruses with icosahedral capsids that can withstand heating up to 50°C for 30 min and have a circular double-stranded DNA of ∼5000 base pairs. 12 additional human polyomaviruses have been isolated since 2007.
Epidemiology of BK virus: BKV is a widespread virus that infects most humans around the world (60-85% of the general population), with primary infection occurring in early childhood and remaining dormant throughout life.
BK virus structure: The BKV-DNA genome is divided into three parts: (1) NCCR – ( The non-coding control region) (2) Early viral gene region (EVGR) (3) Late viral gene region (LVGR). The NCCR regulates the expression of the early and late genes, while the LVGR encodes the capsid proteins VP-1, VP-2, and VP-3. VP1 is highly immunogenic and is the target for neutralizing antibody, cellular immune recognition, and required for virion assembly and hemagglutination of human-erythrocytes.
BK virus variants: Based on the differences in the DNA sequence of the VP1 region, BKV can be classified into four genotypes or subtypes. The most common subtype is genotype I, followed by genotype IV, genotypes II and III, and genotype IV. Four more subgroups of subtype I (I/b-2) and six subgroups of subtype IV (IV/a-1, IV/a-2, IV/b-1, and IV/c-1) have been discovered by phylogenetic research. These groupings might represent various migratory and geographic trends in the human population. Other forms of BKV, such as the rearrangement (rr) and archetypal (ww) variants, appear secondary to differences in the NCCR in addition to the genotypic variations of VP1. These genotypes’ clinical and immunological effects on the clinical features and progress of the disease are still unknown.
Immunological response to BK virus:
BKVN can develop during pregnancy, diabetes, HIV infection, cancer, and the post-transplantation phase. BK virus replication occurs after a condition of immunological suppression, which can also happen during pregnancy. The pathogenesis of a virus may be influenced by elements such as poor immune surveillance, a lack of humoral immunity, alloimmune activation, and molecular variations in the virus.
– Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA, leading to lytic infection and viral leakage. Collateral destruction with necrosis and apoptosis of noninfected tubular cells can lead to intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators. – Humoral immunity may play a role in the pathogenesis of BKVN, as kidney recipients from asero-positive donors are more likely to develop BK viremia. – The role of allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity in the development of BKVN is unclear, but CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been found in humans. – BKV tropism to the renal tubular epithelial cells may play an additional role in the pathogenesis of BKVN, with a blockage of caveolin-induced endocytosis producing a substantial reduction in infectivity.
Pathogenesis: BKV is usually sub-clinical or manifests as a mild respiratory symptom in childhood, and can remain latent in leukocytes, brain tissues, and lymph nodes for life. In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, leading to tubular cell lysis and viruria.
Routes of transmission: The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations: – BK viruria affects 30-40% of renal transplant recipients, while 10-15% develop BK viremia. – BKV-associated nephropathy can occur as early as 6 days- 5 years post transplant, with incidence range of 2-15%. – Ureteric stenosis, with prevalence of ureteric stenosis is 2–6%, Treatment should involve apercutaneous nephrostomy and dilatation, with concurrent reduction of immunosuppressive medications. – Hemorrhagic cystitis, is extremely rare in SOT recipients, with 4 clinical grades from microscopic hematuria grade 1 to gross hamtauira with clots grade 4, treatment is by vigorous intravenous hydration and trans-urethral Cidofovir installation to reduce cumulative drug nephrotoxicity. – Other rare manifestation: primary central nervous system disease or reactivated central nervous system infection, it has been linked to pulmonary diseases, ophthalmologic manifestations, hepatic disease, and autoimmune diseases. Taguchi and colleagues were the first to report the isolation of BKV (decoy cells) from a urine sample of two patients with SLE.
BK virus and malignancy: – Brain tumors of glial and neural origins have been found to have BKV-DNA in tissue samples from various neoplasms. Because early coding region-encoded proteins such the large tumor antigen (LTAg) and STA are expressed. – It has been suggested that BKV possesses an oncogenic characteristic. Agnoprotein and LTAg makes the infected cells incapable of stopping the cell cycle. – Urothelial cancers can be brought on by the inactivation of the tumor suppressors p53 and pRb. Yet, because tumor cells are more susceptible to BKV than normal urothelium, positive does not cause neoplastic transformation; rather, it is a consequence of it.
BK virus and urothelial tumors: Only a few cases have been reported. Rollison et al. found BKV-DNA by PCR in 5.5% of Urothelial tumors, but Roberts et al. reported no evidence of BKVLTAg in 20 immunocompetent patients.
Risk factors: Overall immunosuppression, male sex, recipient age, previous rejection episodes, HLA mismatching, cold ischemia, BK sero-status, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion.
Screening and diagnostic tools: – BKV screening: starts at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years. – Screening for active BKV replication may include detection of viral DNA-PCR in urine and blood. – Viral replication in the urine precedes BK viremia by ∼4 weeks, and BKVN are observed 12 weeks after BK viruria.
Monitoring of the urine: – Decoy cells are tubular epithelial cells with an enlarged nucleus that contains a single, large basophilic intra-nuclear BK inclusion body and look similar to those seen in uro-epithelial malignancy. (sensitivity of 100%, and a specificity of 71%) – EM Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein that can be detected in a urinary smear of kidney recipients. However, it requires further validation and cannot be used in routine clinical practice due to the expense and difficulty of electron microscopy.( senisitivity of 100% and specificity of 99% in BKVN with very high viral load) – Molecular analysis of urinary BKV-PCR has 100% sensitivity and 78% specificity, but variability in laboratory measurements made it difficult to diagnose. – BK virus mRNA levels in urine, this assay is highly sensitive and sensitive, but requires further validation and may overestimate the prevalence of BKVN.
Serology: – Serum BK-PCR is the preferred screening technique for BK viremia, prevalence 6-30% in first 6 months post transplant. – Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis. – BK-PCR has high sensitivity and specificity, but there are substantial inter-laboratory variations in measuring BK viral loads. – Serum antibodies have no clinical relevance, but (BK D+/R−) is a risk factor for the development of clinically significant BK disease in allograft recipients. – Virus culture can be isolated from a urine sample before any rise in antibody titers, but is hardly used.
Kidney biopsy: – Allograft biopsy is the gold standard to diagnose BKV, with a sensitivity of 94.7% and specificity of 100% for detecting BKV. Histologically, streaky fibrosis of the medulla with cortical scars can be seen, while microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates – Three different histological grading systems are available, with the Banff grading system having a moderately good intra-observer agreement. – Tissue BK PCRis not an applicable investigation to diagnose BKVN.
Suggested algorithm for screening: Different types of screening are there: – Stepwise methodology: when decoy cell detected in urnie microscopy then other modalities for diagnosis. – Routine surveillance biopsies to detect silent BKVN. – Rourtine surveillance eith plasma BK-PCR. American Society of Transplantation guidelines recommend further annual screening till the fifth year after transplantation, but screening beyond 2 years is not recommended in most centers unless allograft dysfunction is present. Allograft biopsy can be considered with persistent high viral loads for more than 3 weeks. Differential diagnosis: Allograft rejection. Other viral infections.
Treatment strategy of BK virus nephropathy: Treatment is by restoring antiviral immune response/ by reduction of IS, and saving the graft from rejection. – Treatment of BK virus nephropathy is by reducing or modifying immunosuppressive therapy -/+ antiviral medications. This can include withdrawal of antimetabolite drugs, changing from mycophenolate mofetil (MMF) to azathioprine,sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI), or converting tacrolimus to cyclosporine or discontinuing CNI. – Frequent graft function monitoring and biopsy when needed. Drugs with antiviral activities: Leflunomide: is an immunomodulator, prodrug, and antirheumatic disease-modifying drug developed to treat rheumatoid arthritis, Adverse effects include hemolysis, aplastic anemia, thrombocytopenia, and probablythrombotic microangiopathy, hepatitis, and worsening of hypertension, it is un known is it the drug working on BK viremia or the reduction of immunosppressives. Cidofovir: is a cytosine analog and viral DNA polymerase inhibitor, given intravenously every 2-3 weeks, it is nephrotoxic (AKI,RTA, and proteinuria). Brincidofovir: is a new antiviral drug with less toxicity and given orally. mTOR inhibitors: may be effective in reducing viral replication. Intravenous immunoglobulin: IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain. Quinolones: ? have been found to inhibit LTAg helicase activity and have in-vitro and in-vivo uncertain activity against BKV. Artesunate: ? antimalarial drug, decreases BKV proliferation in a dose-dependent way. Statins (pravastatin): ? reduce BKV-infected cells and LTAg expression in renal proximal tubular epithelial cells. Rituximab: ? in nine patient received rituximab – no graft loss were observed.
Short-term and long-term allograft survival: BKVN caused permanent allograft damage in 30-60% of cases, Buehrig et al. reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis. Chenet al. reported 1-, 3-, and 5-year allograftsurvival rates following a diagnosis of BKVN as 99.2, 90.7, and 85.7%, respectively. BK nephropathy with concurrent acute rejection: Anti-rejection therapy with subsequent IS reduction, is suggested.
Postinfection monitoring: – Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is essential to improve allograft outcome. – The transplant recipients who have their immuneosuppression reduced for BKVAV, with a serum creatinine test every 1-2weeks and plasma BK-PCR level at 2-4-week intervals for 8 weeks. BK viremia clears in 7-20weeks. – If viremia persists despite reducing the maintenance therapy, further reduction should be considered or changing to sirolimus, or adding leflunomide. Inability to clear BKV can lead to worse allograft outcomes.
Retransplantation following BKV induced graft loss: An analysis of the USA-OPTN registry data for the period 2004-2008 showed 126 individuals got retransplant of 823 who lost their graft secondary to BKVV, with BKV reported in 17.5% of the cases. The 1- and 3-year graft survival among the retransplanted individuals was excellent at 98.5 and 93.6%, respectively. Conclusion: Early diagnosis of BKVN has improved allograft outcomes despite lack of specific treatment.
What is the level of evidence provided by this article?Level of evidence V – erratic review.
Introduction
BK virus (BKV) is identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients in the first year after transplantation. It usually presents with asymptomatic gradual rise in creatinine and tubulointerstitial nephritis.
It may mimic acute rejection therefore making its diagnosis and treatment more difficult.
BKV belongs to the polyomaviridae (PyV) virions, a subgroup of papovavirus. It is a family of small, non-enveloped DNA viruses with icosahedral capsid and a double stranded DNA. It usually infects humans. Primary infection takes place during early childhood, and then the virus stays dormant throughout life in the immune-competent population.
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1. The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined. BKV replication occurs during a state of immune suppression, for example in pregnancy, diabetes, HIV infection, cancer, and post-transplantation period. It usually begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
Immunological response to BK virus
There are possible factors that contribute to the pathogenesis of BKV nephropathy (BKVN), such as:
Defective immune surveillance by the host T-lymphocytes
Absence of humoral immunity to BKV
Alloimmune activation
Viral variation in molecular sequences.
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity and aid to clear BKV. T cells react against both nonstructural and BK capsid proteins. Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA. Without appropriate immunological regulation, progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination into the interstitium. Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation. The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis. Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss.
Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, sometimes manifests as a mild respiratory symptom in childhood. It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria. During the use of immune suppressive medications, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria. The outcome relies on the level of damage, inflammation and fibrosis.
The route of transmission of the infection may be via respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations
In immunocompromised patients, particularly in renal allograft recipients, BKV usually presents as BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis. Other clinical manifestations include neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome and vasculopathy. Clinical signs may include headache, dizziness, confusion, paraplegia, ataxia, and seizures. Pulmonary disease may be reactivated, and the acute respiratory infection may lead to severe interstitial pneumonitis.
Risk factors
Risk factors for BKVN include degree of immune suppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion.
Screening
It is recommended that BKV screening should start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years. Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood. However, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml, with or without allograft dysfunction.
Histology
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically, whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BKV affects the kidney allograft in an erratic, multifocal manner; hence, false-negative biopsies may occur, specifically at early stages of the disease, therefore a repeat biopsy may be warranted.
Differential diagnosis
Differential diagnosis include allograft rejection, and any other disease associated with early (1–12 weeks after transplantation) and late ( ≥ 3 months transplantation) renal allograft dysfunction.
Treatment
The aim of treating BKV is to eradicate the virus while saving the kidney function. Unfortunately, BKVN has limited treatment options. Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response. However, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection. Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI.
Drugs with antiviral activities Leflunamide
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug. It can inhibit pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects. However, being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; thus, treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages. Therefore, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage. Additionally, leflunomide has a higher rate of adverse effects such as hemolysis, aplastic anemia, thrombocytopenia, and probably thrombotic microangiopathy, hepatitis, and worsening of hypertension.
Cidofovir
Cidofovir is a cytosine analog and viral DNApolymerase inhibitor that is used to manage other viral infections such as CMV. It has shown inhibitory action against polyomaviruses in vitro. Cidofovir is excreted through urine, resulting in high renal tubular cell concentrations. Hence, vigorous intravenous prehydration is needed with dose adjustment if renal dysfunction is present. Cidofovir is a nephrotoxic drug, it may cause acute kidney injury, renal tubular acidosis, and proteinuria. It may also cause severe anterior uveitis which may lead to permanent visual impairment.
mTOR Inhibitors
mTOR inhibitors have shown effectiveness in in-vitro analysis in inhibiting BK replication and early gene expression. Similar to other therapeutic options, the administration of mTOR inhibitors was concomitantly used with lowering immunosuppression, questioning its clinical efficacy against BKV.
IVIG
Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes. However, the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression.
Other therapeutic options include quinolones, artesunate, pravastatin and rituximab.
Allograft survival
The renal allograft survival for recipients with BKVN has improved considerably in the past years. The documented acute rejection rates following a reduction in immunosuppression varies from 6 to 12%. Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening. However, 27% had experienced permanent allograft dysfunction and 18% ultimately lost their allograft secondary to BKVN.
BK nephropathy with concurrent acute rejection
Management of acute rejection with concomitant BKVN is debatable. More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection. Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN. In the absence of typical features, such as strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage, which could be indicators for acute rejection, the management should be tailored for each patient individually. The delayed improvement in renal functions following a reduction in immunosuppression is likely to reflect the slow resolution of the cellular infiltrate.
Post-infection monitoring
Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome. Based on different literature, BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression. If viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide. Inability to clear BKV can lead to worse allograft outcomes.
Re-transplantation
Re-transplantation following graft loss owing to BKVN is possible and can be done successfully. Generally, pre-transplant clearance of BK viremia is essential after minimizing immunosuppression. The patient may get infected with BKV after re-transplantation. Recurring BKV might reflect a previous BK variant or a new infection (de-novo BKV) acquired, because of the long period, in the post-transplantation stage.
Level Of Evidence:
This is a narrative review, therefore the LOE is level V
Treatment In kidney transplant recipients with detectable BKPyV viremia or biopsy-proven BKPyVAN, recommended reducing maintenance immunosuppression.
•Several agents have been shown to have in vitro anti-BKPyV activity, including intravenous immune globulin (IVIG), leflunomide, cidofovir, and quinolone antibiotics.
However, not routinely use any of these agents for the treatment of BKPyV infection, given that the efficacy of these agents has not been established and use of these therapies has not been clearly shown to be superior to reduction in immunosuppression alone.
In patients who are on a triple immunosuppression therapy consisting of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate mofetil/sodium or azathioprine), and prednisone, we initially reduce the dose of the antimetabolite by 50 percent. If the BKPyV viral load does not decrease within two to four weeks, we completely discontinue the antimetabolite. If there is still no decrease in viral load after another two weeks, we decrease the dose of the calcineurin inhibitor by 25 to 50 percent, targeting a whole blood tacrolimus trough level of 4 to 6 ng/mL or a whole blood cyclosporine trough level of 60 to 100 ng/mL.
An alternative approach that is used by others is to first decrease the dose of the calcineurin inhibitor by 25 to 50 percent in one or two steps, followed by reducing the antimetabolite by 50 percent, followed by discontinuing the antimetabolite
●In patients who are on a glucocorticoid-free maintenance regimen with a calcineurin inhibitor and an antimetabolite without prednisone, a similar approach as described above for patients on triple immunosuppression therapy may be used. However, transplant centers may feel less inclined to use monotherapy with either a calcineurin inhibitor or antimetabolite. An alternative approach is to reduce both the calcineurin inhibitor and the mycophenolate, which allows both the targeting of two pathways and lower total immunosuppression.
The two words are “Restore immunity.”
This will be achieved by careful reduction of the immune suppression (as explained by my colleagues) to allow the recipient’s immune system to deal with the infection.
Decrease maintain immunosuppressive in recipients of kidney transplants who have biopsy-proven BKPyVAN or detectable BKPyV viremia, but avoid using in vitro anti-BKPyV medicines on a regular basis.
Reduction of immunosuppression MMF by 50% or even stop, second CNI by 25% is the first step in treating BKV infection and closely monitoring for risk of rejection, if no response will consider IVIG 0.4mg /kg every 3 weeks ( based on limited evidence)
Balance modifying /reducing the power of immunosuppression to increase immunity against the virus.
MMF withdrawal is the most common practice.
Many centres do this plus givingLeuflomide
…
We managed a 20-year-old female who was just discharged yesterday. She presented with haemorrhagic cystitis and developed post-renal aKI due to ureter stenosis despite Leflomide and MMF withdrawal. BK was proven by biopsy (bladder and kidney), nephrostomy was applied for 8 days. We gave both iv and intravesical cidofovir. No need to DJ stent, and the nephrostomy was removed. A second dose (cidofovir plus probenecid) is planned for next week
MMF can be stopped and Tac dose reduced and mTORI m-TOR inhibitors (m-TORIs) have been shown to have antiviral properties in vitro
Reference Jouve T, Rostaing L, Malvezzi P. Place of mTOR inhibitors in management of BKV infection after kidney transplantation. J Nephropathol. 2016;5(1):1-7.
BKV infection at the level of viruia or viremia or graft invasion??
only 40% kidney transplant patients develop viruria ,20% will develop viremia but only 10% will develop BK nephropathy and less than 5% with develop graft loss because of BKN.
there is no strong evidence in the management of BKV infection in each stage.
immunosuppression reduction (MMF or azathiopurine) is the corner stone for managment but after some consideration like date of transplant, history of graft rejection, immunological risk, stability of CNI level and stability of kidney function because of probability of misdiagnosis of underlying rejection.
individualized management from case to another should be considered with frequent monitoring of kidney functions during slowly withdrawal of immunosuppression with early kidney biopsy if AKI happened at any stage.
The human BK virus named after the initials of the person it was first discovered in 1971 belong to Polyomaviridae comprising JCV, BKV, and Simian virus 40. BKV is one of the common early post-kidney transplant infections that could lead to graft loss by BKV nephropathy if not detected early enough. Moreso, there are twelve more polyomaviruses that are named based on the disease they cause, geography, or their epidemiology
Epidemiology of BKV
BKV is very common globally
Affect almost most people in childhood and remained dormant until there is immunosuppression
Studies show 60-85% of the population is affected
It has three genomic stages that are, early viral gene region, late viral region, and the capsid protein in VP1 of the late viral region
Pathogenesis of BKV Infection
Generally believed that the portal of entry into circulation is infected tonsils
BKV infects the peripheral blood mononuclear cell that gets disseminated to secondary places like the kidneys. Following a resolution of primary infection,
The virus stays dormant in the uroepithelium and renal tubular cells for life until reactivated by the situation that affects the immune system
During reactivation, viral cytolytic effect and inflammatory response will determine the final outcome in the kidney parenchyma
The defective immune surveillance by T- cells and the absence of humoral immunity to BKV will result in viral replication and eventual disease
Route of transmission of primary BK virus
Respiratory route
Gastrointestinal transmission
Vertical transmission
Sexual transmission
Donor-derived infection
Through urine and blood.
Clinical Manifestation
BKVN
Hemorrhagic cystitis
Ureteric stenosis
Neurological manifestations like meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
BK virus and hepatic disease in those with bone marrow transplant
BK virus and autoimmune diseases like systemic lupus erythematosus, polymyositis, and rheumatoid arthritis have been documented
BK virus and malignancy-like brain tumors of glial and neural origin such as ependymomas, meningiomas, glioblastomas, gliomas, and neuroblastoma
Urothelia tumours like bladder cancer
Risk factions for BKV
Immunosuppression – most common
Male sex
Older recipient age
Previous rejection episode
Degree of HLA mismatch
Prolong cold ischemic time
BK serostatus D+/R-
Certain ethnic group
screening time and test
The aim is early detection from the urine, and blood before kidney tissues- histology
Detection of Decoy cell (urine cytology) or Haufen BK virion if electron microscope is available
A quantitative measure of urinary BK virus by PCR
Kidney biopsy – the gold standard
American Society of Transplantation Infectious Diseases Guidelines and KDIGO guidelines had recommended BKV screening start the first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years
Treatment of BKVN
Immunosuppressive reduction
Discontinue MMF, and switch to AZA, or Sirolimus
Withdrawal of steroids
Reduce the dose of CNI by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or convert tacrolimus to cyclosporine or discontinue CNI
Other medications that have been used with varying outcomes
Leflunomide
Cidofovir or Brancidofovir which is less nephrotoxic
Immunoglobulin
Quinolones
Artesunate
Pravastatin
Rituximab
Conclusion
In spite of three decades of research in the field of BKV, there still remain some unanswered question like definitive treatment that could bring a cure, although some of these searches has helped the understanding of early diagnosis and some early intervention that may help to prevent the progression to BKVN. There is also challenge of difficulty in differentiating acute allograft rejection from BKVN, and sometimes the two may coexist. Retransplantation is possible after graft loss, and the common reason is to remove the failed graft after period of undetected BKV
Prevalence: Primary infection occurs mainly in childhood and account up to 85% of the general population is seropositive for BKV
BK virus structure The BKV-DNA genome is divided into three parts: the noncoding control region NCCR, the early viral gene region, and the late viral gene region (LVGR).
The later encodes the capsid proteins VP-1, VP-2, and VP-3. VP1 is the main capsid protein present on the surface and is responsible for receptor binding to the host cells, facilitating virus entry into the cell. BK virus variants: (according to VP1) They are four variants, the most common is genotype 1 ( 80%) followed by genotype 4 (15%)
Immunological response to BK virus: BKV replication and resolution of BKV Nephropathy is caused by defective immune surveillance, absence of humoral immunity, alloimmune activation, and viral variation in molecular sequences.
Pathogenesis of BK infection o Primary infection is usually subclinical and rarely manifests as a mild respiratory symptom in childhood o Infect tonsils first then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys o Stay dormant in the uroepithelium, renal tubular cells, leukocytes, brain tissues, and lymph nodes o In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitial and peritubular capillaries
Routes of transmission of primary BK virusmight be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations 1.BK virus and renal disease
BK virus-associated nephropathy: begins with viruria or asymptomatic haematuria and ends with extensive irreversible injury and allograft failure
Ureteric stenosis up to 6%.
Haemorrhagic cystitis.
BK nephropathy in the native kidney in other immunosuppressed population.
3- malignancy: It associated with urothelial tumours in particular bladder Ca, brain tumors of glial and neural origin, Kaposi sarcoma.
Risk factors o Overall degree of immunosuppression (the most important risk) o Other risk factors include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion
Screening and diagnostic tools Timing of screening: at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years A) Urine: cytology for Decoy cells and EM for Haufen (PPV 95%)
B) Serology: BK-PCR (100% sensitivity and 88% specificity)
Serum antibodies
C) Kidney biopsy: (the gold standard to diagnose BKVN) – should be performed when BKV-PCR load 4 log with or without allograft dysfunction. Biopsy findings can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result; therefore, a minimum of two biopsy cores, preferably including medulla, should be inspected to make the correct diagnosis.
BANFF histological grading systems for BK virus nephropathy: Class A: A variable number of virus-infected cells with NO or MINIMAL injury to tubular epithelial cells Class B: Tubular epithelial cell necrosis or lysis with denudation of basement membrane across a length of more than two cells Class C: Any degree of tubular injury with interstitial fibrosis affecting >50% of the cortex
Differential diagnosis between rejection and BKVN Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN 1. SV 40 staining: BKV inclusion bodies 2. Absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane, IHC staining of renal tissues or urinary sediments with anti-HLADR (acute rejection) 3. A higher quantity of CD20+ cells in the tissue infiltrates (BKVN) Treatment strategy Treatment of presumptive BK virus nephropathy: o Reduction/or modifications in immunosuppressive therapy with or without antiviral medications o Withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance
Drugs with antiviral activities: – Leflunomide: inhibit viral replication and have to be given with removal of antimetabolites as MMF or azathioprine and decreasing CNI dose. – Cidofovir (nephrotoxic) and Brincidofovir (prodrug) – mTOR inhibitors: inhibits BK replication and it improves the immune reaction after BKV infection – IVIG: It has immunomodulatory effect, it’s use alongside with Immunosuppressives reduction medications in treating BKVN with concurrent acute rejection – Others (quinolones, artesunate, pravastatin, and rituximab)
BK nephropathy with concurrent acute rejection: Management is debatable
Postinfection monitoring: Cr test every 1–2 weeks and plasmaBK-PCR level at 2–4-week intervals for 8 weeks then monthly bases until clearance of BK viremia
= BK viremia clears in 7–20 weeks (the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression). If viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide
Retransplantation can be done successfully
What is the level of evidence provided by this article? Level 5
Introduction;
-The two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971,
-The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and Simian virus 40 (SV40). Epidemiology of BK virus;
-Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
-Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people.
-60–85% of the general population is seropositive for BKV as showed in Studies. BK virus variants;
-BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1.
-Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population.
-Alternatively, genotypes II and III are relatively rare and infect only a minority of patients. The role of cell-mediated immunity;
-CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
-From immunological factors involved in the development of BKVN are Humoral immunity and another possible is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity. Pathogenesis of BK infection;
-Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
-It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
-Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria. Risk factors; –The most consistent risk factor is the overall degree of immunosuppression.
-Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion. Routes of transmission of primary BK virus;
-Several routes for The primary BKV virus transmission have been theorized.
-The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
-Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes. Clinical manifestations;
-Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals (but not in plasma); nevertheless, BKV does not cause disease in immunocompetent people. -BK virus-associated nephropathy; Clinically, it begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
-The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
–Ureteric stenosis;The prevalence of ureteric stenosis is 2–6% .
-Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
–Hemorrhagic cystitis; BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients. -Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy. Screening and diagnostic tools; –The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears.
-KDIGO guidelines had recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years. Monitoring of the urine:
-Including detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
-Urinary tests are highly sensitive for detecting active BKV infections. However, they lack specificity for BKVN as the detected viral particles could originate anywhere along the urinary tract.
-Different laboratory assays have created difficulty in standardizing the cutoff values for a definite diagnosis.
-Although decoy cells are suggestive but not definitive in diagnosing BKVN, their absence does not exclude the disease.
-Additionally, it can be confused with other viruses, such as cytomegalovirus (CMV) and adenovirus infection, though CMV can cause cytoplasmic besides the intranuclear inclusions Serology; –Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis.
-Plasma DNA-PCR has high sensitivity and specificity in anticipating BKVN; however, there is substantial interlaboratory variations in measuring BK viral loads with lack of international standardization.
-Moreover, the sensitivity and specificity of PCR seems to be assay dependent and should be interpreted in the light of clinical condition.
-Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels. Serum antibodies , Virus culture -Kidney biopsy; –Allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log 10 genome (copies/ml)) with or without allograft dysfunction.
-However, biopsy findings can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result; therefore, a minimum of two biopsy cores, preferably including medulla, should be inspected to make the correct diagnosis. Treatment strategy of BK virus nephropathy; –The aim of treating BKV is to eradicate the virus while saving the kidney function.
-The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
-There is no standard strategy for modifying immunosuppressant’s therapy; however, different regimens have been attempted ;
-Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI. Drugs with antiviral activities;
-Leflunomide , Cidofovir , brincidofovir (CMX001). Other therapeutic options for treating BK virus nephropathy;
-Quinolones , Artesunate (an antimalarial drug) , statins (pravastatin) , Rituximab BK nephropathy with concurrent acute rejection;
-Management of proven allograft biopsies of acute rejection with concomitant BKVN or management of anticipated rejection following a decrease of immunosuppression to treat BKVN remains debatable.
-There was study suggested; combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection.
-Follow the transplant recipients who have their immunosuppression reduced for BKVAV, by
monitoring BKVN, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
-Subsequently, it should be done on a monthly bases until clearance of BK viremia (or at least viral burden falls below threshold values) and stabilization of renal function achieved. Retransplantation;
-Retransplantation following graft loss owing to BKVN is possible and can be done successfully.
-pre-transplant clearance of BK viremia is essential after minimizing immunosuppression.
-There is no evidence to support such as allograft nephrectomy is not necessary before retransplantation; however, in the background of active viral replication, it appears sensible to eliminate the infected graft before getting a new transplant.
-Although. BKV viruria, viremia, and BK nephropathy can recur and cause allograft loss.
-Recurring BKV might reflect a previous BK variant or a new infection (de-novo BKV) acquired, because of the long period, in the post-transplantation stage.
Level of evidence; -This article is a narrative review, and this (LOE V)
Summary Introduction
BKV belongs to the Polyomaviridae a subgroup comprising JCV, BKV and SV40.
Additional 12 viruses have been identified.
BKV primary infections usually occurs in childhood after the virus remains dormant in immunocompetent individuals.
Seropositivity rates in the general population range between 60-85%, however there is scarcity of data in Africa and Middle East.
There are 4 genotypes of BKV, with genotype 1 being the most prevalent followed by genotype 4; genotype 2 and 3 are rare.
Immunological response
BKV replication follows a state of immunosuppression, hence occurs in pregnancy, HIV, DM, cancer and post-transplant period.
Possible mechanisms for the pathogenesis of BKVN are:
Defective immune clearance by the host T cells
Absent humoral immunity
Alloimmune activation
Viral variation of molecular sequences
Pathogenesis of BKV infection
Primary infection is usually sub-clinical or presents as a mild respiratory infection.
BKV reaches the circulatory system through infected tonsils then disseminates to other organs.
The virus remains dormant in the uroepithelium and renal tubular cells.
It can also remain dormant in the lymph nodes, brain tissue and leukocytes.
In the presence of immunosuppressive therapy the virus replicates and spreads to the peri-tubular capillaries leading tubular cell lysis and viruria.
Reaction between the BKV and immune system leads to varies presentation of BK disease.
Clinical manifestation
Include BKVN, ureteric stenosis, and late onset hemorrhagic cystitis.
BKV and renal disease
Begins with viral replication in the uroepithelial cells, then viruria that progresses to viremia and later BK associated nephropathy.
BK viruria affects 30-40% of renal transplant recipients, while 10-15% of them get viremia and 2-15% have BKVAN.
BKVAN ends with irreversible kidney injury and allograft failure.
Ureteric stenosis
Prevalence is 2-6%, rarely does it lead to hydronephrosis and allograft dysfunction.
Treatment of ureteric stenosis involves placement of a percutaneous stent, percutaneous ureteral dilatation with concurrent reduction of immunosuppression.
Hemorrhagic cystitis
Commonly in the HSCT recipients and rare in renal allograft recipients.
Presentation include painful voiding, hematuria, painful bladder cramps+/- flank pains.
Four degrees of disease severity are recognised:
Asymptomatic hematuria
Symptomatic hematuria
Hematuria with clots
Hematuria with clots, clot retention and renal failure secondary to obstructive uropathy.
Management involve vigorous hydration.
Cidofovir given locally has been suggested as a treatment option.
Other clinical manifestations include:
Neurological-encephalitis, meningitis, GBS
Pulmonary disease-Interstial pneumonitis
Ophthalmic- One case of bilateral atypical retinitis has been reported to date.
Hepatic-hepatitis
Autoimmune-persistent BK viruria has been shown in patients with lupus.
BKV and malignancy
BKV DNA has been detected in tissue samples of different neoplasms.
It has been proposed that BKV has oncogenic properties owing to its LTAG and STAG proteins.
BKV Agnoprotein and LTAG are able to to arrest the cell cycle of an infected cell and keep it in a continuous diving state.
LTAG can also bind and inhibit cell regulators eg p53, Rb.
Risk factors
The most consistent risk factors is the degree of immunosuppression, other risk factors identified have been variable among studies and the include male gender, older age of recipient, some ethnic groups, degree of HLA mismatch, cold ischaemia time etc.
Timing of screening
Most BKVN have been reported in the first year post-transplant.
Incidence of BK viruria and viremia have a bimodal peak with the first peak in the third month post-transplant then gradual decline and the second peak in the 12 month but with few detected cases.
Screening tests
Viruria precedes viremia by approximately 4 weeks while BKVN occurs 12 weeks after viruria.
Urine cytology
Decoy cells
They are infected tubular cells with with an enlarged nucleus with basophilic intranuclear inclusions.
Presence of decoy cells is strongly suggestive of polyomavirus infection and is considered as a marker of BKV reactivation.
It has sensitivity ranging between 25-100% and specificity 71-84% to diagnose BKVN.
Thus it is a poor diagnostic tool for BKVN and can’t be used to monitor declining viral loads.
Haufen
Icosahedral aggregates of BKV particles and Tomm-Horsfall proteins that can be detected in the urine smear using negative staining EM.
They are highly predictive in diagnosing BKVN however they are not routinely done in routine clinical practise.
Urine viral loads
Urine PCR has a sensitivity of 100% and specificity of 78%.
Persistent high viral loads can predicting patients at risk of BKVN.
However variability between laboratories makes it difficult to standardise it.
Serum BK PCR
Has a sensitivity of 100% and specificity of 88% thus it is the preferred screening tool in most transplant centers.
However not all patients with viremia will develop BKVN, PPV 50-60% ,NPV 100%.
Additionally the primers were designed against genotype 1 hence may not detect other different strains.
Kidney biopsy
Gold standard for diagnosing BKVN.
BKV affects the kidney erratically hence false negative biopsy may occur thus a repeat biopsy or pre-emptive treatment may be considered.
Viral inclusions can be identified by H&E and PAS staining.
IHC using specific antibodies against SV40 has a specificity of nearly 100%,does not differentiate between BKV and JCV.
FISH has sensitivity of 94.7% compared with 57.9% for H&E and 68.4% for IHC f; and a specificity of 100% comparable to 94.4% for H&E and 100% for IHC. However its use is limited.
Suggested algorithm for screening
Persistence of decoy cells for more than or equal to 3 months will trigger the performance of quantitative measurement of PCR-viral loads in plasma and renal biopsy in patients with evidence of BK viral reactivation, irrespective of renal function.
Screening for BKV should be performed on periodic intervals, starting after 1 month, monthly for 3–6 months, and then every 3 months for the initial 1–2 years after transplantation.
Differential diagnosis
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and IHC staining for SV40, highlighting the virally infected cells.
Can also be differentiated by IHC staining of renal tissues or urinary sediments with anti-HLA DR, which has been related to acute rejection.
Treatment
BK viremia and BKVN signify excessive cumulative immunosuppression, hence, decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Withdrawal of the antimetabolite such as MMF is the most usual method; however, a study by Egli et al showed that both cyclosporine and tacrolimus could inhibit anti-BKV-specific T-cell reaction, and not so much with MMF or prednisone challenging this practice.
Leflunomide
It’s an immune modulator given orally, loading dose of 100mg daily for 3–5 days followed with a maintenance dose of 20–40mg/day and recommended target level of 40–100 μg/ml.
Being a pyrimidine synthesis inhibitor, it cannot be combined with other anti-proliferative drugs like MMF or azathioprine; thus, treatment with this drug should involve simultaneous withdrawal of anti-proliferative medication and reduced CNI dosages.
Therefore, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage.
It requires higher dosage of the drug (≥40 mg/day) to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity.
It higher rate of adverse effects such as hemolysis, aplastic anemia, thrombocytopenia, and probably thrombotic microangiopathy, hepatitis, and worsening of hypertension
Cidofovir
Cytosine analog and viral DNA- polymerase inhibitor
Mechanism of action is unclear as BKV lacks the viral polymerase gene the known target of cidofovir.
It’s exclusively excreted through urine, resulting in high renal tubular cell concentrations.
Its nephrotoxic may cause acute kidney injury, renal tubular acidosis, and proteinuria hence caution in kidney transplant recipients.
Brincidofovir prodrug of cidofovir that gets converted to cidofovir when it goes intracellular. It’s effectiveness against all DNA viruses with no documented nephrotoxicity and ease of oral administration.
M-tor inhibitors
Inhibits the proliferation of BKV- specific T cells and controls the differentiation of memory CD8 T cells; hence, it improves the immune reaction following BKV infection.
Intravenous immunoglobulin
Potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
Selectivity index of more than 1000 as opposed to cidofovir and leflunomide selectivity index of 3.8 and 2.3, respectively.
IVIG in a dosage of 2–3.5g/kg divided over 2–5 days with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection.
The efficiency is uncertain, as it has been given with concomitant reduction in immunosuppression.
Quinolones
Beneficial in combination with leflunomide for treating BKVN with a significant decrease in BK viremia.
Though some studies have shown no benefit.
Post infectious monitoring
Scr every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks then monthly until clearance of BK viremia or at viral burden falls below threshold value and stabilisation of renal function achieved.
If viremia persists despite reducing the maintenance therapy, further reduction should be considered or to consider changing to sirolimus, or adding leflunomide.
Re-transplantation following graft loss owing to BKVN is possible and can be done successfully.
Clearance of BK viremia is essential before re-transplantation.
Allograft nephrectomy is not necessary before, however, in the background of active viral replication, it is sensible to eliminate the infected graft before getting a new transplant, though there is no evidence to support this approach.
BK virus in Renal Transplant Recipients Summary of the article
BK virus according to Gardner et al; in 1971, was first discovered in urine and ureteral epithelial cells of a Sudanese KTR, who present with ureteric stenosis and renal failure.
Decoy cells abundant large cells with intranuclear inclusions were detected in the urine.
Cause severe interstitial nephritis and allograft failure in KTR.
Virus structure
a) The early viral gene region. b) The late viral gene region. c) The capsid protein VP1 in the LVGR is the main capsid protein.
4 Genotypes; VP1-4 (VP1 is the most predominant subtype), with subgroups (I/a, I/b-1, 1/B-2, and 1/C.
The BK virus replicates in cases of lower immunity
a) DM. b) Pregnancy. c) HIV. d) Cancer. e) Post transplantation. Immunological response T-cell immunity
CD4 and CD8 are the major cells in BK virus clearance.
T cell destruct both non-structural proteins and capsid proteins.
Cytotoxic T cells kill the BK-infected cells.
Viral invasion in the tubular cells leads to the formation of viral inclusions.
Tubular cell necrosis leads to casting formation.
Disseminated infection can result via vascular spread and lead to interstitial infiltration and tubulitis.
Humoral immunity
Act via antibody-mediated immunity.
Alloimmune activation
Act via HLA reactivity.
Other factors
BKV tropism to the renal tubular epithelium.
Pathogenesis
Primary infection; is usually subclinical, with mild respiratory symptoms.
Dormant stay in the uroepithelium for life (they may remain latent in the leukocytes, brain tissues, and lymph nodes).
Intermittent reactivation with asymptomatic viruria.
In the case of immunity suppression, the virus reactivates and proliferates inside the interstitium and crosses to peritubular capillaries, which leads to cell lysis and viruria, which can end with tissue damage, inflammation, and fibrosis.
Routes of transmission of primary BK virus
Respiratory route.
GIT route.
Vertical transmission.
Sexual transmission.
Donor-derived infection.
Urine and blood.
Clinical manifestation (In immunocompromised patients)
Ureteric stenosis associated with hydronephrosis in severe stricture.
BKV and autoimmune disease, (isolated from the urine of lupus patients).
BKV has an oncogenic property (isolated from many malignant tissues) and is a fundamental part of urothelial malignancy, particularly bladder carcinoma).
Risk factors
Degree of immunosuppression.
Male sex.
Older recipients.
Previous rejection.
HLA MM.
Prolonged cold ischemia.
BK serostatus.
Ethnic group.
Low total lymphocytes percentage.
Ureteral stent insertion.
Screening and diagnosis
Early screening is recommended during the 1st year.
Bimodal peaks (in the 3rd and 12th months post-Tx)
KDIGO and ASTID recommend BK screening in the 1st-month post-Tx and monthly for the 1st 6 months, and then every 3 months for up to 2 years.
Viruria precedes viremia by 4 weeks, with histological changes seen 12 weeks after BK viruria.
Viral DNA PCR in the urine and blood.
Presence of decoy cells in the urine by urine cytology.
Decoy cells;
a) cytological finding in urine examination, and it is an infected tubular epithelial cell, with an enlarged nucleus with viral inclusion. b) Useful marker of BKV reactivation. c) sensitivity varies with different centers (100% sensitivity and 71% specificity by Hirch et al), while (25% sensitivity and 84% specificity by Viscount et al).
Urine electronmicroscopy; cast like aggregates (Tamm-Horsfall protein, Haufen bodies, 100% sensitivity, and 99% specificity).
DNA PCR, (100% sensitivity and 78% specificity).
BK virus mRNA level in the urine, a biomarker for detecting viral replication in the urine.
Serology; serum BK-PCR, detect BK viremia (in immunocompromised patients), quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months has been recommended for early detection of BK infection before the development of nephritis.
No definitive cut-off level of viral load but the proposed PCR is more than 4 logs (1x10x4) copies/ml.
Serum antibodies; it has no clinical relevance in diagnosing acute BKV infection, but (BK D+/R-) have been considered as risk factors in allograft recipients.
Virus culture; is hardly used.
Kidney biopsy; is the gold standard to diagnosed BKVN, (streaky fibrosis of the medulla with circumscribed cortical scars, glomerular sclerosis, necrosis, tubular atrophy, interstitial fibrosis, and mononuclear cell infiltrate, with viral inclusion by H&E and PAS staining.
Differential diagnosis
Allograft rejection.
Other infections associated with early Tx.
Treatment
IS reduction, or modification (withdrawal of MMF or switching to AZA, sirolimus, or leflunomide), (reduce CNIs to 25-50% with target CyA 50-100 and TAC 3-4 ng/ml).
Leflunomide; an immunomodulatory, antiproliferative, and anti-inflammatory, with a loading dose of 100 mg OD for 3-5 Ds and maintenance 20-40 mg/d with target level 40-100 micro g/ml, with stopping antimetabolites.
Cidofovir 0.25 -1 mg/kg/dose every 2-3 wks for 10-15 wks, and vigorous hydration.
Brincidofovir a prodrug of cidofovir in oral form, is highly effective and has no documented nephrotoxicity (still experimental).
mTOR has shown effectiveness in inhibiting of BK replication and early gene expression.
IVIG.
Quinolones inhibit LTAg activity, effective in combination with leflunomide.
Artesunate, shown to have anti-viral activity.
Pravastatin, reduce the percentage of infected cells.
Rituximab; adjuvant with cidofovir.
Treat BKN with concomitant acute rejection
Combination of anti-rejection therapy with a subsequent reduction of IS.
Post-infection monitoring
BKV-PCR, every 2-4 wks.
Serum Cr every 1-2 wks.
Conclusion
An early diagnosis of BKVN is based on a combination of molecular techniques and tissue analysis, which results in a substantial improvement in allograft outcomes despite a lack of specific treatment.
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
I like your well-structured detailed summary.
Introduction
-BKV infection can affect KTR and lead to significant impact of kidney function. It has variable presentation producing a diagnostic and therapeutic treatment dilemma.
-It was first described in 1971, in KTR presented with ureteric stenosis and virus named from patient initial.
-The virus became more recognized and its effect on the kidney is established as a cause for interstitial nephritis and renal failure.
Polyomaviridae variants
-It belong to Polyomaviridae (PyV), a subgroup of papovaviruses comprising BKV,JCV& SV40. With 12 additional new virus identified from the same group.
– It is a family of small, nonenveloped DNA viruses with icosahedral capsid of
Epidemiology of BK virus
-Primary infection occurs mainly during childhood, and the virus remain dormant in immunocompetent
– Around 60–85% of the general population is seropositive
BK virus structure
BKV-DNA genome can be divided into three parts:
The noncoding control region (NCCR): it regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell.
(1) The early viral gene region: it encodes for small T antigen (STA) and large T antigen.
(2) The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3.
(3) The capsid protein VP1 in the LVGR
BK virus variants
– Variation in VP1 DNA sequence or in the NCCR resulted in 4 genotypes/subtypes and different subgroup in each subtype, may reflect geographic variation.
– The clinical and immunological consequences of these genotypes are still undefined
Immunological response to BK virus
The immune system plays an essential part in controlling BKV replication, virus will replicates in immunocompromised state with combination of:
– Defective immune surveillance by the host T lymphocytes:
– Absence of humoral immunity to BKV;
– Allo-immune activation;
– Viral variation in molecular sequences.
Pathogenesis of BK infection
– Primary infection is usually subclinical in childhood.
– After that, it styed dormant in the uroepithelium and renal tubular cells for life.
– Intermittent reactivation manifests as asymptomatic viruria.
– In immunosuppressed state, the virus activates and proliferate inside the interstitium and crosses into the peritubular capillaries, producing cell lysis and viruria.
– Combination of direct viral cytolytic effects and secondary inflammatory result in tissue damage and fibrosis.
Routes of transmission of primary BK virus
– Respiratory route (1ry route).
– Gastrointestinal transmission: fecal-oral transmission
– Vertical transmission: transplacental
– Sexual transmission
– Donor-derived infection; similar
– Other proposed mode for BKV transmission is through the urine and blood.
Clinical manifestations
– BK virus and renal disease: start with shedding of infected cells in the urine (viruria 30–40%), which can progress a few weeks later to blood (viremia 10–15%) and then BK nephropathy (BKVN)/ (PyVAN) 2-15%
–BK virus-associated nephropathy: Nephritis occurs as early as 6 days after KT or as late as 5 years, may ends with extensive irreversible injury and allograft failure.
– Ureteric stenosis; in 2–6%, lead to hydronephrosis and may result in allograft dysfunction.
Treated with percutaneous nephrostomy and ureteral dilatation, with concurrent reduction of IS.
– Hemorrhagic cystitis: is extremely rare in KTR, noted frequently in HSCT recipients, present with bladder cramps, painful voiding, hematuria, and/or flank pain. Four grade of severity.
Treated with IV hydration, sometime needs bladder irrigation. Local bladder Cidofovir can be tried.
–BK nephropathy in the native kidney of HSCT, HIV and non-kidney SOTR; present with AKI without significant proteinuria.
–Neurological manifestations: can cause 1ry or 2ry CNS disease in HSCT/ HIV present with meningoencephalitis, encephalitis,
Guillain–Barre syndrome, and vasculopathy.
–Pulmonary diseases: severe interstitial pneumonitis
–Ophthalmologic manifestations: bilateral atypical retinitis,
– BK virus and hepatic disease; hepatitis in BMT
– BK virus and autoimmune diseases in nontransplant immunecompromised individuals; SLE, polymyositis, and RA.
BK virus and malignancy: virus DNA found in different malignancy;
– Brain tumors of glial and neural origin.
– Pancreatic islets cell tumors
– Kaposi sarcoma.
– Ewing sarcoma.
– Osteogenic sarcoma.
– Prostatic carcinoma.
– Urothelial tumors.
Conversely, tumor cells are likely more vulnerable to BKV than normal cells, as the infection happens mainly in
proliferating cells, causation is not certain.
Risk factors
-The overall degree of immunosuppression (the main factor).
-Others; male sex, older age, previous rejection episodes, HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion Presumptive BKVN; patient with significant viruria and persistent viremia of more than or equal to 104 copies/ml for > 3 weeks. Screening and diagnostic tools Aim: early detection before significant damage occurs. Timing of screening:
AST and KDIGO guidelines recommended; start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening tests
However, no single diagnostic pathway has appeared as predominant
Monitoring of the urine
– Urine cytology Decoy cells; (occurs in 13–30%); infected epithelial cells
– Urine electron microscopy (EM Haufen); aggregates of BKV virions.
– Urinary BKV viral load PCR.
– BK virus mRNA levels in urine
Urinary tests are highly sensitive for detecting active BKV infections. However, they lack specificity for BKVN as the detected viral particles could originate anywhere along the urinary tract.
Serum
– Serum BK-PCR; it is the preferred screening, there is substantial interlaboratory variations in measuring BK viral loads with lack of international standardization.
– Serum antibodies; routine bases is uncertain, it has no clinical relevance in diagnosing acute BKV infection
Virus culture BKV growsslowly in tissue culture, hardly used outside research setting. Kidney biopsy the gold standard todiagnose BKVN, should be performedwhen BKV-PCR load insistently > 10000 copies/ml with orwithout allograft dysfunction
– Histologically, interstitial fibrosis might present with mononuclear cell infiltrates. BK viral inclusions& positive IHC using specific antibodies against SV40.
– Histopathological grading of the severity of BKAN; Banff grading has shown good intra-observer agreement.
-It affects the allograft in multifocal manner; hence, false-negative biopsies may occur (minimum of two biopsy cores including medulla).
Differential diagnosis
-Allograft rejection; differentiation is challenging for similar histological appearance, and they can present concurrently, features might help to differentiate;
* Presence of BKV inclusion bodies and IHC for SV40.
* Absence of definitive features of ACR; endotheliitis, extensive tubulitis & C4d deposition.
– Any disease associated with early (1–12 weeks post-Tx) and late (≥3 months post-Tx) renal allograft dysfunction.
Treatment strategy of BK virus nephropathy
– The only validated therapy to treat BKVN is decreasing immunosuppression should be balanced against the risk of rejection.
Treatment of presumptive BK virus nephropathy
– Reduction/or modifications in IS with or without antiviral medications.
-There is no standard strategy for modifying IS.
-Withdrawal of antimetabolite drugs or change from MMF to azathioprine, sirolimus, or leflunomide.
– Reducing the dose of CNI by 25–50%
-Converting tacrolimus to cyclosporine or discontinuing CNI
Treatment in the setting of allograft dysfunction
– Reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia in acute BKV with a steadiness of allograft functions in advanced stage BKVN
Drugs with antiviral activities
– Leflunomide; immunomodulator, can inhibit BKV replication, cannot be combined with other antiproliferative drugs
– Cidofovir; nephrotoxic drug
– Brincidofovir; new promising antiviral drug, prodrug of cidofovir, no documented nephrotoxicity
– mTOR inhibitors
-Intravenous immunoglobulin; immunomodulatory effects, has potent neutralizing antibodies
-Other therapeutic options: Quinolones, artesunate (an antimalarial drug), statins (pravastatin), Rituximab Short-term and long-term allograft survival
-Renal allograft survival for recipients with BKVN had improved considerably.
-Substantial short-term improvements, such as eliminating the circulating viremia,
-long term outcomes such as late acute and chronic rejections need to be further evaluated
BK nephropathy with concurrent acute rejection
Management remains debatable.
Suggested; combination of antirejection therapy with a subsequent reduction in immunosuppression.
Generally, an initial decrease in IS without steroid pulses should be considered upon detection of BKVN.
Postinfection monitoring
Close observation of BKV-PCR and renal function with any treatment, especially after AR or reduction of IS is crucial to improve allograft outcome
-Serum creatinine test every 1–2 weeks & plasma BK-PCR level at 2–4-week intervals for 8 weeks. Then, done on a monthly bases until clearance of BK viremia (or at least viral burden falls below threshold values) and stabilization of renal function achieved
Re-transplantation
– Re-transplantation following graft loss owing to BKVN is possible and can be done successfully [10,13]. Ramos
– The graft survival among the retransplanted individuals was excellent
– Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression
– Allograft nephrectomy is not necessary before re-transplantation
– It can recur and cause allograft loss .
Conclusion
early diagnosis of BKVN has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.Typing whole sentence in bold amounts to shouting.
I like your well-structured detailed summary.
BK virus infection in renal transplant recipients: an overview Please summarise this article: Introduction
BKV, one of two human polyomaviruses discovered in 1971, was shown to induce interstitial nephritis and allograft failure in renal transplant patients three decades later. In the first year following kidney transplantation, BKV infection is one of several possible reasons of renal failure. Asymptomatic creatinine increases with tubulointerstitial nephritis may resemble acute rejection, creating a diagnostic and management conundrum.
BK epidemics:
BKV—polyomavirus hominins-1—infects most persons worldwide. In immune-competent humans, the virus remains latent after early childhood infection. 60–85% of the general population is BKV-positive. The only study on BKV prevalence in the Middle East and Africa came from Iran, with a seroprevalence of 41.8%. The age of the studied population, sample size, and antibody threshold explain such percentage variations.
BK virus immunity:
BK virus replication occurs after immune suppression in pregnancy, diabetes, HIV infection, cancer, and post-transplantation. As a result of strong immunosuppression, BKV replication usually starts early post-transplant. BKV replication and BKVN resolution depend on the immune system [48]. BKVN may be caused by (a) inadequate immunological surveillance by host T lymphocytes, (b) lack of humoral immunity to BKV, (c) alloimmune activation, and (d) viral variation in molecular sequences.
BK pathogenesis:
BKV primary infection seldom causes respiratory symptoms in children. BKV enters the circulatory system by infected tonsils and infects peripheral blood mononuclear cells, which spread to secondary sites, including the kidneys. The virus remains latent in the uroepithelium and renal tubular cells for life, sometimes reactivating as asymptomatic viruria. BKV may also hide in leukocytes, brain tissues, and lymph nodes. In immunosuppressive treatment, the virus activates and proliferates in the interstitium and enters the peritubular capillaries, causing tubular cell lysis and viruria. Damage, inflammation, and fibrosis determine outcomes. Viral cytolysis and subsequent inflammatory responses harm tissue. Different BKV illness symptoms originate from complex immune system-BKV interactions.
BK virus renal disease:
This virus proliferates in uroepithelial cells, causing viruria, viremia, and BK polyomavirus-associated nephropathy (BKVN) or PyVAN. 30–40% of renal transplant patients develop BK viruria, whereas 10–15% develop viremia. BKVN is reported in 2–15% of kidney transplant patients. Different immunosuppressive regimens and screening strategies—including biopsy surveillance in certain centers—can explain these differences.
BK-related nephropathy:
BKV-associated nephropathy starts with viruria or asymptomatic hematuria and progresses to permanent damage and allograft failure. Nephritis might start 6 days or 5 years after a kidney transplant. Ureteric stenosis the prevalence of ureteric stenosis is 2–6%. Hemorrhagic cystitis: HSCT patients often develop BKV-associated HC or non-HC, although renal allograft recipients seldom do. Other rare manifestations: neurological manifestations; pulmonary diseases, Ophthalmologic manifestations, BK virus, urothelial cancers BKV-DNA was found in urothelial malignancies such as bladder carcinoma, and many believe BKV plays a major role in their development.
Risk factors:
There are many risk factors for BKVN. Immunosuppression is the most consistent risk factor in the research. Male sex, older recipient age, past rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, specific ethnic groups, a lower total lymphocyte percentage, and ureteral stent insertion are further risk factors for BKVN, however, not all investigations have found them.
Screening tests:
1 — Decoy cells:sensitivity: 25, specificity: 84 . Widely available, it is a useful marker in the identification of BKV infection but a poor diagnostic tool in predicting BKVN. Not useful for monitoring the decline in viral load
2-Haufen:sensitivity 100, specificity 99. Highly predictive for BKVN, but not practical for routine practice as it requires electron microscopy with interpretation from a pathologist
3-Urinary BK-PCR sensitivity:100; specificity: 78. Measurement variations between laboratories limit its use.
4-Plasma BK-PCR Sen:100 Spe: 88 Broadly available but costly. Has good sensitivity and specificity but a low PPV for BKVN.
Kidney biopsy:allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/mL.
Histology reveals streaky fibrosis of the medulla with circumscribed cortical scars macroscopically, and sclerosed glomeruli, necrotic, atrophic tubules with interstitial fibrosis microscopically. BK virus inclusions within tubular epithelium can be seen via hematoxylin and eosin and PAS staining.
Differential diagnosis
Includes allograft rejection, and any disease associated with early and late allograft dysfunction. Early period would be within 2 weeks post transplant. Late period would be more than 3 months posttransplant. Treatment
Reducing immunosuppression and switching drugs may be the initial therapeutic approach. Consider steroid withdrawal.
If MMF dosages stay the same, switching to cyclosporine may lower MMF levels, but if BK viremia persists, MMF must be stopped. MMF reduces proinflammatory and profibrotic cytokines.
Oral leflunomide inhibits viral replication in vitro and is administered at 100 mg/day for 3–5 days, followed by 20–40 mg/day. Nevertheless, MMF and azathioprine cannot be used with leflunomide.
Cidofovir, generally used for CMV, may induce BKV-induced cell death by reactivating p53 and pRB. but has a nephrotoxicity side effect.
Quinolone, statins, and Rituximab are other treatments. Therefore, regular monitoring of BKV PCR and renal function is crucial to a successful transplant, graft protection, and BKV clearance. Discussion
BK virus is a Polyomavirus, a small non enveloped DNA virus with an isohedral capsid. The virus has different regions – early viral gene region that encodes regulatory nonstructural proteins, and late viral gene region that encodes capsid proteins within the nucleus. BKV comes under 4 major categories or subtypes :
-Genotype I – predominant and most common subtype
-Genotype II and III – rare and infect a small minority of patients
-Genotype IV – second most frequent subtype
There are other subtypes reflecting different geographical and migration patterns. BKV viral replication occurs in a state of immune suppression in the host, such as pregnancy, HIV infection, diabetes, cancer, or following transplant. Replication begins in the early posttransplant period.
Risk factors
Intensive immunosuppression
Male gender
Older recipient
Previous rejection episodes
Degree of HLA mismatch
Prolonged cold ischemia
BK sero status
Lower percentage of lymphocytes
Ureteral stent insertion
Pathogenesis :
Defective immune surveillance by host T lymphocytes
Absent humoral immunity to BKV
Patients with prior immunity to BKV may not show manifestation of disease, irrespective of viral copies.
Alloimmune activation
Viral variation in molecular sequences
CD4+ and CD8+ T cells are the main factors in cell mediated immunity that play a role in clearing BKV.
Recipients who receive graft from a BKV seropositive donor have a higher chance of developing the infection in comparison with those how have a seronegative donor.
BKV goes into the circulatory system through the tonsils, and then infects the mononuclear cells in the peripheral blood. This then gets disseminated into different secondary places in the body, including the kidneys.
BKV can also remain latent in the brain, lymph nodes, and leukocytes.
BKV does not cause infection in people who are immunocompetent.
Clinical manifestations
Virus sheds in the urine. Urine examination can be done to check for infection.
Ureteric stenosis
Late onset hemorrhagic cystitis
Multi Organ involvement
Neurological manifestations include encephalitis, meningoencephalitis, Guillan Barre syndrome, and basculopathy. Signs include headache, dizziness, confusion, paraplegia, ataxia, and seizures.
Bilateral atypical retinitis may occur, although this is rare. Conclusion
BK virus, a diagnostic and therapeutic dilemma, is the focus of the given article. The main issue with this kind of infection is that it can mimic acute rejection, and thus treatment becomes difficult. This infection can be caused by intensive immunosuppression regimen aimed at preventing graft rejection. Early diagnosis through molecular techniques and tissue analysis can achieve a good outcome in terms of the virus clearance as well as good allograft outcome.
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
I like your well-structured detailed summary.
Introduction
The two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients. BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation.
It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma BK virus and renal transplantation: historical perception
In 1971, Gardner et al,were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure.
They named the virus ‘BK’ after the initials of this patient.
Numerous reports on various aspects of BKV in renal transplant recipients have been reported.
This virus was found to have high homology with JCV, the other human polyomavirus, discovered as a cause of progressive multifocal leukoencephalopathy. BKV was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipients. Increased awareness among nephrologists to recognize BKV disease at an earlier stage and the development of better diagnostic laboratory techniques contributed to the ever-increasing incidence of BKV infection. Polyomaviridae variants
Virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40)
It is a family of small, nonenveloped DNA viruses with icosahedral capsid of.
A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017
These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV; HPyV6, HPyV7, HPyV9, and HPyV12; New Jersey polyomavirus (NJPyV, known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14). Epidemiology of BK virus Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
Primary infection predominantly takes place during early childhood, and the virus stays dormant throughout life in immune-competent people.
There is scarcity in data related to BKV prevalence in Middle East countries and Africa, and a single report found was from Iran, with a seroprevalence of 41.8% .
Such variation in percentages can be clarified by the age of the tested population, the sample size, and the antibodies threshold that is viewed as positive BK virus structure BKV-DNA genome can be divided into three parts, BKV genome structure, adapted from De Gascun and Carr.
(1) The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen), which interacts and binds to cellular target proteins to shift the host cell into S phase cycle for efficient viral replication.
(2) The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus
VP1 is highly immunogenic and is the target for neutralizing antibody, cellular immune recognition, and required for virion assembly and hemagglutination of human erythrocytes.
Once it gets inside the cell, the virus travels to the nucleus and establishes a dormant or lytic infection. BK virus variants BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1.
As with subtype I subgroups, each of the subtype IV subgroups may reflect different geographical and migration pattern of the human population.
The subgroup of subtype I (I/b-2) has been noticed mostly in American and European populations, whereas subgroup I/c dominates in Asians.
Apart from the genotypic variations of VP1 region, additional two other forms of BKV present secondary to variations in the NCCR, namely, rearranged and archetype variants.
Continuous duplication of BK genome during activation process can result in deletion and duplication in the NCCR sequences, with subsequent generation of rearranged variant viruses.
The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined.
Immunological response to BK virus
BK viral replication follows a state of immune suppression; it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period. BKV replication and resolution of BK virus nephropathy (BKVN).
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
Progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination.
Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation.
Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss. The role of humoral immunity
Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies.
Bohl and colleagues found the kidney recipients from a seropositive donor were more likely to develop BK viremia compared with others who had a kidney from a seronegative donor.
The role of antibodymediated immunity was validated in BKV infection.
The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated. Role of alloimmune activation
Another possible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity.
The latter concerns with T cells, which cross-react to both BKV and allo-antigens.
Murine kidney allografts were more susceptible to polyomavirus infection, which cause an increase in allo-reactive T cells that lacked crossreactivity to the virus.
CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans.
Showed a reverse association between allograft survival and the level of HLA matches in patients with BKVN, suggesting a lack of HLA matches might predict better outcomes in recipients with The role of other factors
In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role.
Moriyama et al, had demonstrated that a blockage of caveolin-induced endocytosis, either directly or through small interference RNA depletion of caveolin-1, produced substantial reduction in BKV infectivity as measured by immunofluorescence, as BKV particles were found in vitro to colocalize with caveolin-1, and not to a clathrin, in the human renal proximal tubular epithelium.
The pathogenesis of BKV disease is probably related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
It has been proposed that BKV goes into the circulatory system through infected tonsils, and infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
The sophisticated reactions between the BKV and the immune system result in different clinical features of BKV disease. Routes of transmission of primary BK virus
The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
The supportive studies are mainly epidemiological, and none of them had isolated BKV on respiratory samples.
In a study of 99 hospitalized pediatric patients, 45% of the collected stool samples and rectal swabs tested positive for polyomavirus DNA, supporting the fecal-oral transmission of BKV.
A different study had failed to demonstrate BKV in either maternal or fetal tissues.
A negative BK recipient who had a kidney from BKV-infected donor has been noted to have similar genotypes, thereby, supporting donor transmission].
Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes. Clinical manifestations
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals; BKV does not cause disease in immunocompetent people.
In renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC). BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC [78,79], whereas in HIV-.
Infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement and eventually leads to death. BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine, which can progress a few weeks later to blood and eventually to BK-.
The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years. Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% .Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen , and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen, and treatment should involve a percutaneous nephrostomy and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications. Hemorrhagic cystitis BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients.
The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain.
Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy. BKV–HC is extremely rare in renal transplant.
Severe cases of BKV–HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation.
Locally through bladder installation was suggested as a therapeutic option for HC ,the remission varied from 2 to 7 weeks following hematuria BK nephropathy in the native kidney
BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients.
Other less apparent clinical manifestations include the following: Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection.
Such infections are primarily seen in patients with HSCT or HIV infection.
Autopsy showed that BKV infection was present in the brain, kidneys, and peripheral blood smear
As it is a single case, further data are required before labeling BKV to cause an ophthalmological manifestation.
Reported manifestations of BKV in immunocompromised patients, including renal transplant recipients and patients with HSCT and HIV infection. BK virus and hepatic disease
A single report in the literature regarding the association between BKV and hepatitis was reported in a patient with bone marrow transplant who had transient elevations of liver enzymes. BK virus and autoimmune diseases BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immunecompromised individuals.
Taguchi and colleagues were the first to report the isolation of BKV from a urine sample of two patients with lupus.
Several cases were reported since with a prevalence of BKV viruria of 16% in patients with systemic lupus erythematosus.
There is an increase in the prevalence with persistence/or recurrent BK viruria in patients with lupus.
Such a relationship could be explained with a compromised immune system secondary to the systemic illness or the intensified immunosuppression.
There is no article that describes BKV activation in patients with systemic lupus erythematosus at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease. BK virus and malignancy: thoughts on viral oncogenesis
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors .
It has been proposed that BKV has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation.
The LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Inactivation of tumor suppressor p53 and pRb in experimental mice by BKV–LTAg can induce urothelial malignancies.
Tumor cells are likely more vulnerable to BKV than normal urothelium, as the infection happens mainly in proliferating cells, and that positivity is a result instead of being a reason for neoplastic transformation.
Regardless of whether BKV has a causative part in human cancer development or not, it will remain a topic of debate BK virus and urothelial tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, bladder carcinoma as the BKV-DNA was isolated in these tumors.
Alexiev et al, reported a similar experience, where all tumor cells had shown strong expression of BKV–LTAg, p53, p16, and Ki-67, in addition to the intranuclear virions in electron microscopy.
Despite this epidemiological evidence, urothelial malignancies concomitantly with BKV were reported to date in a few and isolated case reports.
Rollison et al, had carried out a tissue-based analysis in a series of bladder tumors (189 samples from 76 transitional cell carcinoma) to determine the potential role of BKV in bladder malignancies.
Roberts et al, reported no evidence of BKV–LTAg in urothelial malignancies from 20 immunocompetent patients Risk factors
Several risk factors were implicated in the pathogenesis of BKVN.
The most consistent risk factor identified in the literature is the overall degree of immunosuppression.
Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; these risk factors have not been uniformly observed in all studies. Screening and diagnostic tools
The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears. Timing of screening
Prospective analyses had revealed that BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year.
In a cohort of Greek postrenal transplant recipients monitored prospectively for 18 months, the incidence of viremia and viruria showed bimodal peaks.
The first and the topmost peak was noticed in the third month, followed by a gradual decline and disappearance in the ninth month, whereas the second peak was noticed at.
12th months after transplant, but with fewer detected cases .
KDIGO guidelines. had recommended BKV screening to start at first month after transplant, monthly for the first 6 months, and every 3 months for up to 2 years Screening tests
Viral replication starts early after transplantation and progresses through noticeable phases: viruria viremia followed by nephropathy.
Viral replication in the urine precedes BK viremia by ∼4 weeks, and there have been confined cases of patients developing viremia without viruria, this is uncommon.
Histological changes of BKVN are observed 12 weeks after BK viruria.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
No single diagnostic pathway has appeared as predominant. Monitoring of the urine
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’.
Aggregates of BKV virions or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA. Urine cytology
Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients.
Such wide variation can be explained by screening strategies that were used in different centers and different immunosuppressive regimens.
Presence of Haufen bodies, which corresponds to upper levels of BK viremia, had a higher sensitivity and specificity for biopsy-proven BKVN
Haufen particles were absent in recipients with a lower BK viremia.
As this method represents singlecenter data, it requires further validation.
Variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis. BK virus mRNA levels in urine
BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication.
This method is considered as highly specific and sensitive.
Though this assay is encouraging as a noninvasive tool and can provide additional diagnostic and prognostic data, yet it requires further validation.
Pros and cons of urinary tests in identifying BKVN: Urinary tests are highly sensitive for detecting active BKV infections.
Decoy cells
Widely available, useful marker in identification of BKV infection, but a poor diagnostic tool in predicting BKVN. BKV-PCR levels may differ substantially between assays, with a magnitude of one to two log-folds in consecutive weekly analyses in commercially available quantitative PCR assays, which may yield significant differences in quantified viral loads and may limit the threshold of assay detection.
Most quantitative PCR primers and probes were designed against BK genotype I (Dunlop) strain as a reference
Using this genotype I strain as a reference might be as much as four-fold less sensitive for different strains, which is risky as uncommon BKV subtypes are often associated with BKVN, and such assays are unable to detect them at low viral levels.
Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels Serum antibodies
Serum antibodies against BKV are commonly present among the general public.
BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain.
It has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients.
The positive donor BKV serostatus and negative recipient serostatus (BK D+/R−).
Have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients. Kidney biopsy
The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks.
Such suggestion came from a prospective analysis of Hirsch et al , who demonstrated that BK viremia of more than or equal to 10 4 is characteristically present in recipients with proven biopsies of BKVN.
An alternative histological detection approach is through the identification of BKV via in-situ hybridization.
Fluorescence in-situ hybridization-based methodology is specific for BKV with a sensitivity of 94.7%.
Rapid viral load reduction has been related to steady or improved allograft function. Treatment of presumptive BK virus nephropathy
The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
Regimens have been attempted upon recognition of viremia
These include withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance.
Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% or converting tacrolimus to cyclosporine or discontinuing CNI.
Withdrawal of the antimetabolite such as MMF is the most usual method; a study by. Treatment of BK virus nephropathy in the setting of allograft dysfunction
Favorable renal allograft outcomes in the context of acute BKV infection were reported when immunosuppression reduction had started early upon detection of BK viremia, permitting early and appropriate therapeutic interference.
If the identification of BKVN is made at an advanced stage when nephropathy ensues, reducing immunosuppression is probably going to be less effective, owing to the advanced disease, with severe histological changes leading to progressive, irreversible renal damage. Allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy .
Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises Drugs with antiviral activities Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug which was developed to be used in rheumatoid arthritis.
Being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages.
It is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage.
Cidofovir showed in-vitro inhibitory action against polyomaviruses, though the mechanism of action is unclear as BKV lacks the viral polymerase gene, the known target of cidofovir.
Tacrolimus and MMF were replaced with sirolimus, which resulted in reduction of the BK viral load with concurrent improvement in estimated glomerular filtration rate. Intravenous immunoglobulin
Has been used for BKVN for its immunomodulatory effects.
IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
In-vitro analysis has shown that IVIG has the most potent antiviral influence, with a selectivity index of more than 1000 as opposed to cidofovir and leflunomide selectivity index of 3.8 and 2.3, respectively.
with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection; the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression. Other therapeutic options for treating BK virus nephropathy LTAg helicase activity and have in-vitro and invivo activity against BKV. It has been found beneficial in combination with leflunomide for treating BKVN,with a significant decrease in BK viremia.
Patients who had received rituximab as an adjuvant therapy with cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN.
In both groups, the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine.
In the late 1990s and early 2000s, BKVN caused permanent allograft damage in 30–60% of cases
This happened as a result of lack of awareness, delayed diagnosis, misdiagnosis, and coincidental utilization of escalated immunosuppression for possible acute rejection episodes. BK nephropathy with concurrent acute rejection
Management of proven allograft biopsies of acute rejection with concomitant BKVN or management of anticipated rejection following a decrease of immunosuppression to treat BKVN remains debatable.
More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in.
Reports have depicted clinical improvement, steady or worse allograft outcomes, following steroid pulses.
Celik et al, found a reduction in immunosuppression is more than capable in reducing IVIG Contain neutralizing antibodies against BKV and are immunomodulatory
MTOR inhibitors Inhibits the proliferation of BKV-specific T-cell and controls the differentiation of memory.
Occurs, such as gastritis, C difficile, hepatoxicity, neurological adverse effects, and altered mental status. Inhibit BK viral proliferation in a primary human renal cell culture
Statins Prevent caveolae-mediated endocytosis Adverse muscle events and hepatic dysfunction.
Viral load than steroid pulses in biopsies with BKVN and tubulitis.
Hirsch et al, suggested a combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection.
An initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.
In the absence of typical features, such as strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage, which could be indicators for acute rejection, the management should be tailored for each patient individually.
The delayed improvement in renal functions following a reduction in immunosuppression is likely to reflect the slow resolution of the cellular infiltrate.
Upon clearance of viremia and BKVN, the advantage of up-titrating immunosuppression to avoid further late acute rejection or chronic rejection remains obscure. Postinfection monitoring
Close observation of BKV-PCR and renal function with any treatment, following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome.
The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
It should be done on a monthly bases until clearance of BK viremia and stabilization of renal function achieved.
Recurring BKV might reflect a previous BK variant or a new infection acquired, because of the long period, in the posttransplantation stage. Findings
Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population.
BK viruria can increase up to 35% during pregnancy, and BKV can cross the placenta and stay dormant in fetal organs, suggesting the possibility of vertical transmission. Conclusion
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment
Please summarise this article.Introduction
o BKV is a significant cause of interstitial nephritis and allograft failure in renal transplant recipients
o Often presents within the first year after transplantation
o It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection
o BKV belongs to the Polyomaviridae (PyV) virions. It is small, nonenveloped DNA viruses with icosahedral capsid of 40–45nmindiameter
Aim of the study: discuss the most recent evidence of virology, pathogenesis, clinical features, diagnostic tools, screening protocols, treatment strategy, and short-term and long-term renal allograft survival concerning BKV infection
Epidemiology of BK virus
o BKV is a ubiquitous virus that infects most humans around the world
o Primary infection predominantly occur during early childhood
o 60–85% of the general population is seropositive for BKV
BK virus structure BKV-DNA genome is divided into three parts:
1. The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen)
2. The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus
3. The capsid protein VP1 in the LVGR: is the main capsid protein present on the surface and is responsible for receptor binding to the host cells, facilitating virus entry into the cell
BK virus variants Four genotypes/subtypes:
1. Genotype I: accounts for > 80% worldwide followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population
2. Genotype 2: rare
3. Genotype 3: rare
4. Genotype 4: the second most common and accounts for 15%
Immunological response to BK virus
o BKV replication begins early in the posttransplant period
o The immune system plays an essential part in controlling BKV replication and resolution of BKVN (cell-mediated immunity, humoral immunity, alloimmune activation, and other factors)
Possible factors that add to the pathogenesis of BKVN:
1. defective immune surveillance by the host Tlymphocytes
2. absence of humoral immunity to BKV
3. alloimmune activation, and
4. viral variation in molecular sequences
Pathogenesis of BK infection
o Primary infection is usually subclinical and rarely manifests as a mild respiratory symptom in childhood
o Infect tonsils first then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys
o Stay dormant in the uroepithelium, renal tubular cells, leukocytes, brain tissues, and lymphnodes
o In thepresence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries
Routes of transmission of primary BK virus
1. Respiratory route
2. Gastrointestinal transmission
3. Vertical transmission
4. Sexual transmission
5. Donor-derived infection
6. Other possible: urine and blood
Clinical manifestations
1. BK virus and renal disease: BKVN
2. BK virus-associated nephropathy: begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure
3. Ureteric stenosis: in 2–6%. Treatment is percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications
4. Hemorrhagic cystitis: in HSCT recipients. The patients present with bladder cramps, painful voiding, hematuria, and/or flank pain. Four degrees of disease severity (I-IV). Management involves vigorous intravenous hydration
5. BK nephropathy in the native kidney: AKI without significant proteinuria
6. BK virus and hepatic disease: hepatitis (one patient with bone marrow transplant)
7. BK virus and autoimmune diseases: SLE, polymyositis, and rheumatoid arthritis
8. Others:
o Neurological manifestations: meningoencephalitis, encephalitis, GBS, and vasculopathy
o Pulmonary diseases: interstitial pneumonitis
o Ophthalmologic manifestations: bilateral atypical retinitis (single case report)
BK virus and malignancy
1. Brain tumors of glial and neural origin (ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas)
2. pancreatic islets cell tumors
3. Kaposi sarcoma
4. Ewing sarcoma
5. osteogenic sarcoma
6. prostatic carcinoma
7. urothelial tumors (particularly bladder carcinoma)
Risk factors
o Overall degree of immunosuppression (the most important risk)
o Other risk factors include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion
Screening and diagnostic tools
The aim is to identify early viruria or viremia before graft dysfunction appears
Timing of screening: at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years (American Society of Transplantation Infectious Diseases Guidelines)
Urine:
1. Urine cytology (Decoy cells)
2. Urine electron microscopy (EM Haufen)
3. Quantitative measurements of urinary BK virus-viral loads
4. BK virus mRNA levels in urine
Serology:
1. Serum BK-PCR
2. Serum antibodies
Virus culture:
o grows slowly in tissue culture
Kidney biopsy:
o the gold standard to diagnose BKVN
o should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction
o biopsy findings can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result; therefore, a minimum of two biopsy cores, preferably including medulla, should be inspected to make the correct diagnosis
o histological grading systems for BK virus nephropathy: Class A: A variable number of virus-infected cells with NO or MINIMAL injury to tubular epithelial cells Class B: Tubular epithelial cell necrosis or lysis with denudation of basement membrane across a length of more than two cells Class C: Any degree of tubular injury with interstitial fibrosis affecting >50% of the cortex
Differential diagnosis
1. Allograft rejection: is challenging.
2. Any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction
BKVN can be distinguished from acute rejection by:
1. Presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40
2. absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful
3. IHC staining of renal tissues or urinary sediments with anti-HLADR (acuterejection)
4. A higher quantity of CD20+ cells in the tissue infiltrates (BKVN)
5. expression of genes related to inflammation and acute rejection (such as CD8, interferon-gamma, CXCR3, and perforin): higher in patients with BKVN
Treatment strategy Treatment of presumptive BK virus nephropathy:
o Reduction/or modifications in immunosuppressive therapy with or without antiviral medications
o Withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance
Treatment of BK virus nephropathy in the setting of allograft dysfunction:
o Acute BKV: immunosuppression reduction
o Advance BKVN: reducing immunosuppression is probably to be less effective
Short-term and long-term allograft survival
o Renal allograft survival for recipients with BKVN had improved considerably in the past years
BK nephropathy with concurrent acute rejection
o Management is debatable
o Initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN
o In the absence of typical features (strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage), the management should be individually
Postinfection monitoring
o Serum creatinine test every 1–2 weeksandplasmaBK-PCRlevelat2–4-weekintervals for 8 weeks then monthly bases until clearance of BK viremia
o BK viremia clears in 7–20 weeks (the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression)
o If viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide
Retransplantation
o Retransplantation following graft loss owing to BKVN is possible and can be done successfully
o Pretransplant clearance of BK viremia is essential after minimizing immunosuppression
o Allograft nephrectomy is not necessary before retransplantation
Conclusions
o Early diagnosis of BKVN (by molecular techniques and tissue analysis) has resulted in substantial improvement in allograft outcomes
What is the level of evidence provided by this article?Level V
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
I like your well-structured detailed summary.
IV. BK virus infection in renal transplant recipients: an overview1.Please summarize this article. Introduction
BKV infection frequently occurs within the 1styear after TX.
It manifests as an asymptomatic steady rise in creatinine with tubulointerstitial nephritis providing a challenge for both diagnosis & treatment since it mimics acute rejection.
Renal allograft failure & consequent allograft loss are caused by untreated BKV infections.
Systematic screening protocols for early detection of asymptomatic BKV infection improve the success of allografts.
Gardner et al. (1971) named the virus ‘BK’ after the initials of a Sudanese KTX recipient presenting with ureteric stenosis & renal failure due to this virus.
The human BKV is a member of the Polyomaviridae (PyV) virions, a family of papovaviruses that also includes the JCV, SV40, & BKV.
BKV is small, nonenveloped DNA virus with icosahedral capsid (40–45nm) that resists heating up to 50°C for 30 min with little effect on infectivity & has a circular dsDNA (5000 bp).
Epidemiology of BK virus
BKV is a common (60–85% of the general population) virus that affects the majority of people worldwide.
Primary infection occurs in early childhood, & then the virus remains latent throughout life in immune-competent adults.
BKV-DNA genome can be divided into 3 parts: 1.The early viral gene region:
It encodes the regulatory nonstructural proteins needed for effective viral replication, cell cycle progression, & transformation.
These proteins interact with & bind to cellular target proteins to shift the host cell into the S phase cycle.
2.The late viral gene region (LVGR):
Inside the nucleus, it encodes the capsid proteins VP-1, VP-2, and VP-3.
During cell lysis, these capsids can release 1000–100 000 virions.
LVGR also encodes agnoprotein that have a variety of regulatory roles (helping to control viral replication & interfering with host cell processes).
3.The capsid protein VP1:
LVGR is the main surface capsid protein & is responsible for receptor binding to the host cells, facilitating virus entry into the cell, & it is highly immunogenic (target for neutralizing antibody, cellular immune recognition).
The virus enters the cell, moves to the nucleus, & creates a latent or lytic infection there.
BK virus variants
Genotype I: the most common one (80%)
Genotype IV: (15%)
Genotypes II & III: relatively rare.
Genotype I has 4 subgroups (I/a, I/b-1, I/b-2, & I/c).
Genotype IV has 6 subgroups (IV/a-1, IV/a-2, IV/b-1, IV/b-2, IV/c-1, & IV/c-2).
The role of cell-mediated immunity
The main elements of cellular-mediated immunity that control the BKV & participate in BK clearance are CD4+ & CD8+ T cells.
T cells can be identified by ELISPOT & tetramer labeling as they react against both nonstructural & BK capsid proteins.
The role of humoral immunity
Humoral immunity may play a part in the pathogenesis of BKVN since persons with a history of immunity to the virus may not display symptoms, regardless of the viral load.
Kidney recipient from a D+ donor is more likely to develop BK viremia than those who received from a D-donor.
The BKV-specific IgG levels increased the most in patients with BKVN, who also had persistently high IgM levels.
Role of alloimmune activation
Allo-HLA-reactivity & heterologous immunity is possibly involved in the development of BKVN.
Heterologous immunity concerns with T cells, which cross-react to both BKV & allo-antigens.
BKV-specific effector memory T cells may not identify the allo-HLA molecules representing BKV-peptides; thus, allowing BKV to evade immunological vigilance.
Pathogenesis
Initial infections in children is asymptomatic or, rarely, present as a mild respiratory symptom.
BKV enters circulation via infected tonsils, & then infect the PBMN cells that spread to secondary sites (kidneys, leukocytes, brain tissues, & lymph nodes).
BKV remains dormant (for life) in the uroepithelium & renal tubular cells after the primary infection has cleared up, occasionally reactivating & causing asymptomatic viruria.
The virus activates & multiply inside the interstitium in the presence of IS treatment, crossing into the peritubular capillaries & causing a series of events that start with tubular cell lysis & viruria.
The degree of injury, inflammation, & fibrosis determines the outcome.Direct viral cytolytic effects & subsequent inflammatory reactions combine to cause tissue destruction.
Clinical aspects of BKV sickness are caused by the interactions between the BKV & the immune system.
Routes of transmission of primary BK virus
Respiratory route: the main one
Gastrointestinal transmission
Vertical transmission
Sexual transmission
Donor-derived infection
Others: urine & blood
Clinical manifestations
7% of healthy immunocompetent persons shed BKV in their urine, yet BKV does not cause disease in them.
Immunocompromised patients, notably KTX recipients, develop illness from BKV:
BK viruria in 30–40%
BK viremia in 10–15%
1.BKVN (2–15%):
Starts with viruria or asymptomatic hematuria & ends with extensive irreversible damage & graft failure.
Might occur as early as 6 days after KTX or as late as 5 years.
2.Ureteric stenosis (2–6%):
Rarely causes graft dysfunction & hydronephrosis.
Treatment: PCN, ureteral dilatation, & reduction of IS medications.
Good sensitivity & specificity but low PPV for BKVN
6.Serum antibodies:
Uncertain role pre-& post-TX
7.Virus culture:
Rare outside research setting.
8.Kidney biopsy:
The gold standard for BKVN diagnosis.
Done when BKV-PCR load is > 10000 copies/ml (4 log10 genome (copies/ml)) +/- graft dysfunction.
Histology:
Streaky fibrosis of the medulla & cortical scars can be seen macroscopically.
Microscopy may show sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis with mononuclear cell infiltrates.
BK viral inclusions within tubular epithelium (H&E & PAS).
BKV can alternatively be identified via in-situ hybridization.
FISH allows BKV identification in KTX tissues via bright nuclear fluorescence technique.
Positive IHC using antibodies against BKV, or the cross-reacting SV40 LTAg has 100% specificity for BKVN but does not differentiate between BKV & JCV.
Suggested screening:
Most centers recommend BK surveillance with plasma BK-PCR.
Screening starting after 1 month, monthly for 3–6months, & then every3months for the initial 1–2 years after TX.
AST guidelines recommended further annual screening till the 5thyear after TX.
Screening beyond 2 years is not recommended in most centers unless allograft dysfunction is present.
Allograft biopsy can be considered in individuals with persistent high viral loads for more than or equal to 3 weeks.
Differential diagnosis
1.Allograft rejection:
It is important to differentiate between AR & BKVN as treating the presumed rejection with increased IS may result in progression of BKVN.
BKVN may exist concurrently with AR.
BKV inclusions & positive IHC for SV40 staining can distinguish BKVN from AR.
Absence of features of AR (endotheliitis & extensive tubulitis & absence of C4d deposits in PTBM are also helpful.
C4d staining occurs in some BKV cases & is linked with more aggressive disease.
2. Any disease associated with early (1–12 weeks after TX) & late (≥3 months after TX) renal allograft dysfunction. Treatment
IS reduction being the only validated therapy to treat BKVN & restore antiviral immune response.
The risk of triggering acute or chronic rejection should always be considered. Rapid viral load reduction is linked to improved allograft function.
No standard strategy for modifying IS therapy.
Approaches include:
Withdrawal of antimetabolites or change from MMF to azathioprine, sirolimus, or leflunomide.
Introduction
BKV can lead to interstitial nephritis and allograft failure in renal transplant recipients.
It occurs within the first year after transplantation. It manifests by gradual creatinine increase with tubulointerstitial nephritis, similar to acute rejection. BK virus and renal transplantation
It was first detected in a Sudanese kidney transplant recipient with ureteric stenosis and renal failure.
Abundant large cells with intranuclear inclusions detected in the urine as ‘decoy cells’. Polyomaviridae variants
It belongs to the Polyomaviridae (PyV)virions, a subgroup of papovaviruses comprising BKV,JCV, and simian virus 40 (SV40). 12 more human polyomaviruses have been isolated BKV Epidemiology
Polyomavirus hominis-1, well known as BKV, is a popular virus that infects most humans.
The infection is caught during childhood and remains dormant in immunocompetent cases BK virus structure
BKV-DNA genome include the noncoding control region (NCCR) ,the early viral gene region,the late viral gene region LVGR , and the capsid protein VP1 in the LVGR is the main capsid protien BK virus variants
BKV can be divided into 4 genotypes according to the DNA sequence variations in the genomic region of VP1 ,genotype I and IV are the most common.
4 more subgroups were detected Immunological response to BK virus
Immunosuppression enhances the virus replication as in diabetes and pregnancy.
It’s replication occur early in the posttransplant period and can occur after antirejection treatment .
BKVN pathogenesis is due to defective immune surveillance ,absence of humoral immunity , alloimmune activation, and viral variation in molecular sequences. Cell mediated immunity role
T cells react against non structural and BK capsid proteins ,Cytotoxic T cells attack BK-infected cells after recognition of damaged segments of viral DNA.
Progressive lytic infection can lead to large nuclear and peri-nuclear viral inclusion in the tubular cells formation then dissemination can lead to cast formation and damage of tubular capillaries causing viral dissemination which can cause allograft dysfunction. Humoral immunity role
BKV seropositive donors are likely to transmit infection to recipients.
Antibody medicated immunity has a role in BKV infection. Alloimmune activation
(HLA)-reactivity and heterologous immunity have a role in BKVN development. BKV can escape the immunological surveillance.
A study showed correlation between HLA mismatch and BKVN, Another study demonstrated that HLA matches absence indicate better outcomes in recipients with BKVN Other factors
BKV tropism to renal tubular epithelial cells. BKV infection pathogenesis
Usually primary infection is subclinical.
Then the virus can be dormant for life in renal tubular epithelial cells also it can be latent in leucocytes ,lymph nodes and brain tissue.
When the patient is immunosuppressed the virus is reactivated and emerge to peritubular capillaries and cause viruria afterwards the conflict between the virus and the immune system leads to BKVN. Primary BKV transmission route
It can be via respiratory, fecal-oral, transplacental, or donor tissues also transmission through urine and blood was a suggested route as well. Clinical presentation
It’s usually asymptomatic in immunocompetent cases .
Present in immunocompromised patients as renal transplant recipients as BKVN,ureteric stenosis, and late-onset hemorrhagic cystitis.
In (HSCT) recipients present with hemorrhagic and non-hemorrhagic cystitis
For HIVinfected patients, it can be disseminated leading to multiorgan affection and mortality.
Less common manifestations include neurological presentations in the forum of meningioencephalitis ,Guillian barre syndrome specially in HIV infection or HSCT. pulmonary manifestations as severe interstitial pneumonitis, Opthalmological manifestations as atypical retinitis Hepatitis was noticed as BKV manifestation
BKV had been implicated in autoimmune diseases as SLE , rheumatoid and polymyositis
BKV has a relation with tumors as brain tumors, islet cell tumor ,Ewing
sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors and Kaposi sarcoma
BKV can have a main role in uroepithelial malignancy Risk factors
Include immunosuppression degree ,male sex, older age, rejection attacks, HLA mismatching, prolonged cold ischemia, BK serostatus, ethnic groups, lower total lymphocyte percentage,and ureteral stent insertion. Screening
It has to be done early post transplant, as infection is common in the first year
KDIGO guidelines recommended BKV screening to start at first month after transplant, then monthly for the first 6 months,and then every 3 months for up to 2 years.
Viral replication in the urine starts before BK viremia by ∼4 weeks, and
BKVN pathological changes are observed 12 weeks after BK viruria.
Active BKV replication screening through identification of viral DNA-PCR in urine and blood.
Urine monitoring by detection of BKV-infected epithelial cells ‘decoy cells,’or aggregates of BKV virions ‘Haufen’ or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA
A study reported 100% sensitivity , 71% specificity for decoy cells
Haufen bodies detection in urine EM indicates upper levels of BK viremia and biopsy-proven BKVN but is an expensive non practical test.
Urinary BKV-PCR has 100% sensitivity and 78% specificity meanwhile lab measurements are variable
BK virus mRNA levels in urine is considered a highly specific and sensitive method for detecting active viral replication and BKVN occurrence but needs more validation due to similarity with acute cellular rejection
BKV-PCR has 100% sensitivity and 88% specificity for BKVN than BK viruria
So it is preferred for screening
A quantitative BKV-PCR > 4logs (1×104) copies/ml can correlate with BKVN on allograft biopsy as suggested by a study.
Serial levels of viremia is the best method to detect BK activity cure after immunosuppression reduction.
Serological testing importance is uncertain.
Virus cultures are non practical.
Kidney biopsy for presumptive BKVN can detect recipients with significant viruria and /or persistent viremia
Allograft biopsy is the main test to diagnose BKVN, it is done when BKV-PCR load >10000 copies/ml in presence or absence of graft dysfunction.
Meanwhile lesions can be focal or isolated to the medulla therefore taking 2 core biopsies with the involvement of the medulla is crucial.
It appears under microscope as sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis with mononuclear cell infiltrates. BK viral inclusions within tubular epithelium can be seen .
Fluorescence in-situ hybridization (FISH) analysis enables BKV detection in renal transplant tissues through bright nuclear fluorescence technique.
Positive Immunohistochemistry using specific antibodies against BKV or the cross-reacting SV40 LTAg has 100% specificity for polyomavirus nephropathy; but it does not differentiate between BKV and JCV.
There are 3 histological grading system as grade A involves viral cytopathic changes of near-normal renal parenchyma, with minimal tubular atrophy, interstitial fibrosis, or inflammation, till stage C, with diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation
A study suggested BKV algorithm including starting with urine cytology for decoy cells every 3 months, and when decoy cells were positive, quantification of viral level in the plasma with the probability of allograft biopsy if kidney function worsened.
Others suggested surveillance biopsies to detect silent BKVN at 3 rd or 4 th month then 12th month post transplantation which improved graft outcomes.
AST guidelines recommend annual screening till the fifth year post transplant; meanwhile screening after 2years is not recommended unless allograft dysfunction occur. Differential diagnosis
Allograft rejection
Differentiation from BKVN is difficult and is done by analysis of blood or urine PCR , and by BKV inclusion bodies detection and immunohistology of positive immunoperoxidase staining for SV40 or urinary sediments with anti-HLA DR, related to acute rejection
Differentiation is important because increased immunosuppression to treat rejection can worsen BKVN meanwhile it can be more challenging as both can occur together.
CD20+ cells in a big quantity infiltrating the tissue has been associated with BKVN
Also other DD include early and late cases of renal allograft dysfunction. Treatment of BKVN
Involves reduction of immunosuppression and returning antiviral response. Treatment of presumptive BK virus nephropathy
By reducing immunosuppression as changing classes in the forum of antimetabolite drugs removal or switch mycophenolate mofetil (MMF) to azathioprine,sirolimus, or leflunomide, lower CNI dose by 25-50% and avoiding steroids with or without antiviral therapy. Treatment of BK virus nephropathy with allograft dysfunction
Immunosuppression reduction have to start early as soon as BK viremia is detected allowing suitable intervention before an advanced stage of BKVN occur with irreversible injury Antiviral drugs Leflunomide can inhibit viral replication and have to be given with removal of antimetabolites as MMF or azathioprine and decreasing CNI dose. Cidofovir has inhibitory action against poliovirus but it is nephrotoxic and has other side effects therefore it’s use have to be with caution.
Brincidofovir(CMX001) is a prodrug of cidofovir, orally administered without nephrotoxicity active against all DNA viruses. mTOR inhibitors
It inhibits BK replication and it improves the immune reaction after BKV infection IVIG
It has immunomodulatory effect, it’s use along side with Immunosuppressives reduction medications in treating BKVN with concurrent acute rejection
Other options include quinolones, artesunate, statins and rituximab. Short and long term allograft survival
Renal allograft survival for recipients with BKVN had improved . BK nephropathy with concurrent acute rejection
It’ s therapy and intervention is controversial , therefore treatment has to be individualised. Post infection monitoring
BKV-PCR and kidney function tracking with treatment is crucial especially after acute rejection treatment or reduction of immunosuppression. Retransplant after BKVN can be done Conclusion
Early detection and diagnosis of BKV can improve the graft outcome
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.Typing whole sentence in bold amounts to shouting. I like your well-structured detailed summary.
Introduction
The two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients. BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation.
It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma BK virus and renal transplantation history
In 1971, Gardner et al were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure.
They named the virus ‘BK’ after the initials of this patient.
Numerous reports on various aspects of BKV in renal transplant recipients have been reported.
This virus was found to have high homology with JCV, the other human polyomavirus, discovered as a cause of progressive multifocal leukoencephalopathy. BKV was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipients.
Polyomaviridae varients
Virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40)
It is a family of small, nonenveloped DNA viruses with icosahedral capsid of.
A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017
These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV; HPyV6, HPyV7, HPyV9, and HPyV12; New Jersey polyomavirus (NJPyV, known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14)
Epidemiology of BK virus Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
Primary infection predominantly takes place during early childhood, and the virus stays dormant throughout life in immune-competent people [2,10,24,25].
60–85% of the general population is seropositive for BKV (Table 1).
There is scarcity in data related to BKV prevalence in Middle East countries and Africa, and a single report found was from Iran, with a seroprevalence of 41.8% [37].
Such variation in percentages can be clarified by the age of the tested population, the sample size, and the antibodies threshold that is viewed as positive
BK virus structure BKV-DNA genome can be divided into three parts, BKV genome structure, adapted from De Gascun and Carr.
(1) The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen), which interacts and binds to cellular target proteins to shift the host cell into S phase cycle for efficient viral replication.
(2) The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus
VP1 is highly immunogenic and is the target for neutralizing antibody, cellular immune recognition, and required for virion assembly and hemagglutination of human erythrocytes.
Once it gets inside the cell, the virus travels to the nucleus and establishes a dormant or lytic infection.
BK virus varients BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1.
As with subtype I subgroups, each of the subtype IV subgroups may reflect different geographical and migration pattern of the human population.
The subgroup of subtype I (I/b-2) has been noticed mostly in American and European populations, whereas subgroup I/c dominates in Asians.
Americans and Europeans, whereas the other subgroups are more common in Asian populations.
Apart from the genotypic variations of VP1 region, additional two other forms of BKV present secondary to variations in the NCCR, namely, rearranged and archetype variants.
Continuous duplication of BK genome during activation process can result in deletion and duplication in the NCCR sequences, with subsequent generation of rearranged variant viruses.
The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined. Immunological response to BK virus
BK viral replication follows a state of immune suppression; it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period. BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression. BKV replication and resolution of BK virus nephropathy (BKVN).
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
Progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination.
Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation.
Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss.
The role of humoral immunity
Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies.
Bohl and colleagues found the kidney recipients from a seropositive donor were more likely to develop BK viremia compared with others who had a kidney from a seronegative donor.
The role of antibodymediated immunity was validated in BKV infection.
The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated Role of alloimmune activation
Another possible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity.
The latter concerns with T cells, which cross-react to both BKV and allo-antigens.
Murine kidney allografts were more susceptible to polyomavirus infection, which cause an increase in allo-reactive T cells that lacked crossreactivity to the virus.
CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans.
Showed a reverse association between allograft survival and the level of HLA matches in patients with BKVN, suggesting a lack of HLA matches might predict better outcomes in recipients with The role of other factors
In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role.
Moriyama et al had demonstrated that a blockage of caveolin-induced endocytosis, either directly or through small interference RNA depletion of caveolin-1, produced substantial reduction in BKV infectivity as measured by immunofluorescence, as BKV particles were found in vitro to colocalize with caveolin-1, and not to a clathrin, in the human renal proximal tubular epithelium.
The pathogenesis of BKV disease is probably related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium
Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
It has been proposed that BKV goes into the circulatory system through infected tonsils, and infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria. BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
The sophisticated reactions between the BKV and the immune system result in different clinical features of BKV disease. Routes of transmission of primary BK virus
The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
The supportive studies are mainly epidemiological, and none of them had isolated BKV on respiratory samples.
In a study of 99 hospitalized pediatric patients, 45% of the collected stool samples and rectal swabs tested positive for polyomavirus DNA, supporting the fecal-oral transmission of BKV.
A different study had failed to demonstrate BKV in either maternal or fetal tissues.
A negative BK recipient who had a kidney from BKV-infected donor has been noted to have similar genotypes, thereby, supporting donor transmission.
(6) Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes. Clinical manifestation
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals; BKV does not cause disease in immunocompetent people.
In renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC) . BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC, whereas in HIV-.
Infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement, and eventually leads to death. BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine, which can progress a few weeks later to blood and eventually to BK-.
The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years. Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% . Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen, and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen, and treatment should involve a percutaneous nephrostomy and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications. Hemorrhagic cystitis BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients.
The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain.
Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy. BKV-HC is extremely rare in renal transplant.
Severe cases of BKV-HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation.
Locally through bladder installation was suggested as a therapeutic option for HC, the remission varied from 2 to 7 weeks following hematuria BK nephropathy in native kidney
BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients.Other less apparent clinical manifestations include the following: Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection.
Such infections are primarily seen in patients with HSCT or HIV infection.
Autopsy showed that BKV infection was present in the brain, kidneys, and peripheral blood smear
As it is a single case, further data are required before labeling BKV to cause an ophthalmological manifestation.
Reported manifestations of BKV in immunocompromised patients, including renal transplant recipients and patients with HSCT and HIV infection. BK virus and autoimmune disease BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immunecompromised individuals.
Taguchi and colleagues were the first to report the isolation of BKV from a urine sample of two patients with lupus.
Several cases were reported since with a prevalence of BKV viruria of 16% in patients with systemic lupus erythematosus.
There is an increase in the prevalence with persistence/or recurrent BK viruria in patients with lupus.
Such a relationship could be explained with a compromised immune system secondary to the systemic illness or the intensified immunosuppression.
There is no article that describes BKV activation in patients with systemic lupus erythematosus at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease.
BK virus and malignancy
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
It has been proposed that BKV has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation.
The LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Inactivation of tumor suppressor p53 and pRb in experimental mice by BKV-LTAg can induce urothelial malignancies.
Tumor cells are likely more vulnerable to BKV than normal urothelium, as the infection happens mainly in proliferating cells, and that positivity is a result instead of being a reason for neoplastic transformation.
Regardless of whether BKV has a causative part in human cancer development or not, it will remain a topic of debate
BK and urethral tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, bladder carcinoma as the BKV-DNA was isolated in these tumors.
Alexiev et al reported a similar experience, where all tumor cells had shown strong expression of BKV-LTAg, p53, p16, and Ki-67, in addition to the intranuclear virions in electron microscopy.
Despite this epidemiological evidence, urothelial malignancies concomitantly with BKV were reported to date in a few and isolated case reports.
Rollison et al, had carried out a tissue-based analysis in a series of bladder tumors (189 samples from 76 transitional cell carcinoma) to determine the potential role of BKV in bladder malignancies.
Roberts et al [139], reported no evidence of BKV-LTAg in urothelial malignancies from 20 immunocompetent patients
Risk factors
Several risk factors were implicated in the pathogenesis of BKVN.
The most consistent risk factor identified in the literature is the overall degree of immunosuppression.
Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; these risk factors have not been uniformly observed in all studies. Timimg of screening
Prospective analyses had revealed that BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year.
In a cohort of Greek postrenal transplant recipients monitored prospectively for 18 months, the incidence of viremia and viruria showed bimodal peaks.
The first and the topmost peak was noticed in the third month, followed by a gradual decline and disappearance in the ninth month, whereas the second peak was noticed at.
12th months after transplant, but with fewer detected cases.
KDIGO guidelines had recommended BKV screening to start at first month after transplant, monthly for the first 6 months, and every 3 months for up to 2 years Screening test
Viral replication starts early after transplantation and progresses through noticeable phases: viruria viremia followed by nephropathy.
Viral replication in the urine precedes BK viremia by ∼4 weeks, and there have been confined cases of patients developing viremia without viruria, this is uncommon.
Histological changes of BKVN are observed 12 weeks after BK viruria.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
No single diagnostic pathway has appeared as predominant. Monitoring of the urine
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’.
Aggregates of BKV virions or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA. Urine cytology
Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients.
Such wide variation can be explained by screening strategies that were used in different centers and different immunosuppressive regimens.
Urine electron microscopy (EM Haufen): in contrast to decoy cells, Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, forming cast-like three-dimensional aggregates, which can be noticed in a urinary smear of kidney recipients using negative-staining electron microscopy.
Presence of Haufen bodies, which corresponds to upper levels of BK viremia, had a higher sensitivity and specificity for biopsy-proven BKVN
Haufen particles were absent in recipients with a lower BK viremia .
As this method represents singlecenter data, it requires further validation.
Variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis. BK virus mRNA levels in urine
BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication.
This method is considered as highly specific and sensitive.
In predicting patients who might develop BKVN, using 6.5×10 5 BKV-VP1 mRNAs/ng RNA in urinary cells as a cutoff value.
Though this assay is encouraging as a noninvasive tool and can provide additional diagnostic and prognostic data, yet it requires further validation.
Pros and cons of urinary tests in identifying BKVN: Urinary tests are highly sensitive for detecting active BKV infections. Decoy cells
Widely available, useful marker in identification of BKV infection, but a poor diagnostic tool in predicting BKVN. BKV-PCR levels may differ substantially between assays, with a magnitude of one to two log-folds in consecutive weekly analyses in commercially available quantitative PCR assays, which may yield significant differences in quantified viral loads and may limit the threshold of assay detection.
Most quantitative PCR primers and probes were designed against BK genotype I (Dunlop) strain as a reference
Using this genotype I strain as a reference might be as much as four-fold less sensitive for different strains, which is risky as uncommon BKV subtypes are often associated with BKVN, and such assays are unable to detect them at low viral levels.
Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels Serum antibodies
Serum antibodies against BKV are commonly present among the general public.
BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain.
It has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients.
The positive donor BKV serostatus and negative recipient serostatus (BK D+/R−).
Have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients. Findings
Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population.
BK viruria can increase up to 35% during pregnancy, and BKV can cross the placenta and stay dormant in fetal organs, suggesting the possibility of vertical transmission. Kidney biopsy
The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks.
Plasma BK-PCR has high sensitivity and specificity in anticipating BKVN, different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without.
Such suggestion came from a prospective analysis of Hirsch et al, who demonstrated that BK viremia of more than or equal to 10 4 is characteristically present in recipients with proven biopsies of BKVN.
An alternative histological detection approach is through the identification of BKV via in-situ hybridization.
Fluorescence in-situ hybridization-based methodology is specific for BKV with a sensitivity of 94.7%.
Drugs with antiviral activities
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug which was developed to be used in rheumatoid arthritis.
Being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages
It is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage.
Notwithstanding, a few factors have limited use of this medication: (a) higher dosage of the drug (≥40 mg/day) is necessary to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity; (b) monitoring of the trough A77 1726 level is not accessible in all laboratories; and (c) the immunosuppressive effectiveness of leflunomide is weak, and the favorable results associated with the use of this drug may primarily reflect reduced immunosuppression. Tacrolimus and MMF were replaced with sirolimus, which resulted in reduction of the BK viral load with concurrent improvement in estimated glomerular filtration rate.
Intravenous immunoglobulin
Has been used for BKVN for its immunomodulatory effects. IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
Other therapeutic options for treating BK virus nephropathy Quinolones have been described to inhibit the LTAg helicase activity and have in-vitro and invivo activity against BKV.
It has been found beneficial in combination with leflunomide for treating BKVN, with a significant decrease in BK viremia.
This happened as a result of lack of awareness, delayed diagnosis, misdiagnosis, and coincidental utilization of escalated immunosuppression for possible acute rejection episodes.
Chen et al [250] reported 1-, 3-, and 5-year allograft survival rates following a diagnosis of BKVN (n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograft survival (P= 0.042)
Postinfection monitoring
Close observation of BKV-PCR and renal function with any treatment, following management of acute rejection or reduction of immunosuppression, is crucial to improve allograftoutcome .
The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
It should be done on a monthly bases until clearance of BK viremia and stabilization of renal function achieved.
Recurring BKV might reflect a previous BK variant or a new infection acquired, because of the long period, in the posttransplantation stage.
Findings
Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening.
(n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograft survival (P= 0.042) conclusion
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment
Introduction
· Polyomavirus (BKV & JC) were discovered in 1971
· BKV belongs to polyomaviridae family
· Small, non-enveloped DNA viruses with icosahedral capsid and it has three parts; early viral gene region (non-structural proteins e.g., small & large T antigens), large viral gene region (capsid proteins VP1-3), and the capsid protein VP1 in the LVGR
· Additional 12 viruses were added to the group over the last two decades Epidemiology
· The primary infection occurs in childhood and around 60 t0 85% of general population is positive for BKV Risk factors
· BKV infection developed in situations of defective immune surveillance, absence of humoral immunity, alloimmune activation, and viral vibration in molecular sequences Transmission
· Respiratory (the primary rout of transmission), feco-oral, vertical transmission, sexual transmission, donor-derived, urine & blood Pathogenesis
· Primary infection is usually asymptomatic or subtle respiratory illness in childhood
· Through the tonsils the virus goes to the circulation infect the mononuclear cells, reaches the kidney and stay dormant in the uroepithelium
· Following immunosuppression, the virus gets activated in the interstitium and crossing into peritubular capillaries causing inflammation, fibrosis, and damage. The interactions between the virus and the immune system will determine the clinical presentation Clinical manifestations A.Immune-competent host
· BKV cause no thing B.Immune compromised host -HIV
· Severe viremia & multi-organ failure leading to death -Kidney transplantation
· BKVN
· Ureteric stenosis
· Late-onset hemorrhagic cystitis (HC) -Hematopoietic stem cell transplant (HSCT)
· Hemorrhagic cystitis
· Non-hemorrhagic cystitis -Other manifestations are rare including CNS, lung, liver and autoimmune diseases BK virus & malignancy: thoughts on viral oncogenes
This was demonstrated in animal studies and may be due to;
· BKV-infected cells (agnoprotein and LTAg) are unable to arrest cell cycle driving cells into a neoplastic transformation
· Inhibition of regulators of cellular apoptosis (LTAg) e.g., Rb and P53 and this have led to urothelial malignancies in experimental mice Screening for BKVN
· First month after transplantation, then monthly for 6 months, and then every 3 months for up to 2 years.
· Screening is carried out by DNA-PCR in urine & blood Monitoring of urine
· Decoy cells (100% sensitivity & 70% specificity)
· Haufen bodies
· DNA-PCR Kidney biopsy
· The gold standard (viral inclusion bodies, SV40 positive, tubulointerstitial inflammation, tubular atrophy & fibrosis)
· May miss the diagnosis in one-third due focal disease or disease isolated to medulla
· Take cores preferably involving medulla for increasing the chance of diagnosis Differential diagnosis
· Allograft rejection
· Other causes of allograft dysfunctions Treatment strategy
Reduction of immune suppression
· Reduction of immune-suppression e.g., change MMF to AZA, sirolimus, or leflunamide, reduce CNIs by 25% to 50% or change tacrolimus to cyclosporin or hold CNIs
· mTORI may be effective and improves immune reaction following BKV infection Antiviral drugs & Antibacterial
Evidence is robust for using these drugs and some are nephrotoxic. Examples are:
· Leflunomide, cidofovir, and Quinolones Monitoring after infection
· SCr every 1 to 2 weeks
· BKV-PCR every 2 to 4 weeks for 8 weeks Re-transplantation
· Pre-transplant clearance of BK viremia following reduction of immune suppression is mandatory before re-transplantation Conclusion
There is no specific treatment for BKV infection but early recognition and diagnosis is associated with improvement in overall allograft function
However, I would not agree with your conclusion and suggestion, as I quote your reply, “Evidence is robust for using these drugs and some are nephrotoxic. Examples are: · Leflunomide, cidofovir, and Quinolones.” Many thanks Dr Ben,
Welcome prof for your comments, sorry i was a typo = I missed to right not robust. It is clearly that we need more studies on these drugs but it is something that can be considered on case by case bases.
Thnxs prof
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.Typing whole sentence in bold amounts to shouting.
BKV infection is a major cause of interstitial nephritis and allograft failure in kidney transplant recipients, presenting a diagnostic and therapeutic treatment dilemma.
BK virus and renal transplantation: historical perception
Gardner et al. and Mackenzie et al. were the first to detect BKpolyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient.
This virus was found to have high homology with JCV, the other human polyomavirus, and was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipients.
Increased awareness among nephrologists and better diagnostic laboratory techniques have contributed to the ever-increasing incidence of BKV infection.
Polyomaviridae variants
Polyomaviridae (PyV)virions are small, nonenveloped DNA viruses with icosahedral capsids that can withstand heating up to 50°C for 30 min and have a circular double-stranded DNA of ∼5000 base pairs.
12 additional human polyomaviruses have been isolated since 2007.
==================================================================== Epidemiology of BK virus
BKV is a widespread virus that infects most humans around the world, with primary infection occurring in early childhood and remaining dormant throughout life.
BK virus structure
The BKV-DNA genome is divided into three parts: the NCCR, the early viral gene region, and the late viral gene region (LVGR).
The NCCR regulates the expression of the early and late genes, while the LVGR encodes the capsid proteins VP-1, VP-2, and VP-3. VP1 is the main capsid protein present on the surface and is responsible for receptor binding to the host cells, facilitating virus entry into the cell.
BK virus variants
BKV can be divided into four genotypes/subtypes based on the DNA sequence variations in the VP1 region.
Genotype I is the predominant subtype, followed by genotype IV which is the second most frequent.
Phylogenetic analysis has identified four more subgroups, subcloned of subtype I (I/b-1, I/b-2, I/c), and six subgroups of subtype IV (IV/a-1, IV/a-2, and IV/c-2).
These subgroups may reflect different geographical and migration patterns of the human population.
Apart from the genotypic variations of VP1, additional two other forms of BKV present secondary to variations in the NCCR.
The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still unknown.
BKV replication and resolution of BKVNephropathy is caused by defective immune surveillance, absence of humoral immunity, alloimmune activation, and viral variation in molecular sequences.
The role of cell-mediated immunity
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
Cytotoxic T cells (CTL) kill BK-infected cells after recognition of damaged segments of viral DNA, leading to progressive lytic infection and viral leakage into the tubular lumen and urine.
Collateral destruction with necrosis and apoptosis of noninfected tubular cells can lead to continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators.
The role of humoral immunity
Humoral immunity may play a role in BKVN pathogenesis, as seropositive donors are more likely to develop BK viremia.
Role of alloimmune activation
Allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity may be involved in the development of BKVN, as T cells cross-react to both BKV and allo-antigens.
The role of other factors
BKV tropism to the renal tubular epithelial cells may play an additional role in the pathogenesis of BKVN.
BKV infection is usually subclinical or manifests as a mild respiratory symptom in childhood, and can remain latent in leukocytes, brain tissues, and lymph nodes for life.
Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
Routes of transmission of primary BK virus
Routes of transmission of primary BK virus have been theorized, such as respiratory, fecal-oral, transplacental, or from donor tissues.
Vertical transmission is also possible, as BK viruria can increase up to 35% during pregnancy and BKV can cross the placenta and stay dormant in fetal organs.
Sexual transmission has been anticipated, but is not popular due to the primary infection occurring before the age of sexual activity.
BKV does not cause disease in immunocompromised people, but is associated with different clinical features, such as BKVN,ureteric stenosis, and late-onset HC.
BK virus and renal disease
BK virus causes renal disease, affecting 30-40% of transplant recipients and 10-15% of kidney allograft recipients.
Different immunosuppressive regimens and screening strategies can detect it.
BK virus-associated nephropathy
BKV-associated nephropathy can occur as early as 6 days after transplant or as late as 5 years.
BKV-associated nephropathy can lead to irreversible injury and allograft failure.
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% . Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen
Treatment should involve nephrostomy and dilatation, with reduction of immunosuppressive medications.
Hemorrhagic cystitis
Hemorrhagic cystitis (BKV-HC) is rare in HSCT recipients, but can occur in renal allograft recipients.
Management involves vigorous intravenous hydration and Cidofovir given locally through bladder installation. Remission varies from 2 to 7 weeks.
BK nephropathy in the native kidney
BK nephropathy in the native kidney has been reported in HSCT recipients, transplant recipients, and immunocompromised HIV-infected patients.
Other less apparent clinical manifestations include the following:
BKV is rarely associated with primary central nervous system disease or reactivated central nervous system infection, but clinical manifestations may include headache, dizziness, confusion, paraplegia, ataxia, and seizures.
Pulmonary diseases linked to BKVhave been reported in HIV-infected patients, with distinctive lung features and positive BK viral DNA.
Ophthalmologic manifestations
Bilateral atypical retinitis was reported in a homosexual white male with AIDS, with BKV-DNA detected in the eye and infection in the brain, kidneys, and peripheral blood smear.
BKV and hepatic disease have been linked in a patient with a bone marrow transplant.
BK virus and autoimmune diseases
BK virus and autoimmune diseases have been studied in nontransplant immune-compromised individuals, with a prevalence of 16% in patients with systemic lupus erythematosus.
BK virus and malignancy: thoughts on viral oncogenesis
BK virus (BKV) has been identified in tissue samples of different neoplasms, including brain tumors of glial and neural origin, pancreatic islets cell tumors, Kaposi sarcoma, Ewingsarcoma, and prostatic carcinoma.
It has been proposed that BKV has an oncogenic property due to expression of early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation.
BKV-LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumorsuppressor gene products, and inactivation of tumor suppressor p53 and pRb can induce urothelial malignancies.
Additionally, tumor cells are more vulnerable to BKV than normalurothelium.
BK virus and urothelial tumors
BK virus has been proposed to play a role in the pathogenesis of urothelial malignancy, particularly bladder carcinoma, but only a few cases have been reported.
Rollison et al. found BKV-DNA by PCR in 5.5% of Urothelial tumors, but Roberts et al. reported no evidence of BKV in 20 immunocompetent patients.
Risk factors for BKVN include overall immunosuppression, male sex, older recipient age, previous rejection episodes, HLA mismatching, cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion.
==================================================================== Screening and diagnostic tools
Screening and diagnostic tools are used to identify with viruria or viremia and treat graft dysfunction.
Screening for active BKV replication involves identifying viral DNA-PCR in urine and blood, but no single diagnostic pathway has been identified.
Monitoring of the urine
Monitoring of the urine may detect BKV-infected epithelial cells, aggregates of BKV virions, or quantification of urinary BKV viral load.
Decoy cells are infected tubular epithelial cells with an enlarged nucleus that contains a single, large intranuclear BK inclusion body and looks similar to those seen frequently in uroepithelial malignancy.
The sensitivity of decoy cells for the diagnosis of BKNephropathy varies in different publications, but Hirsch et al. reported a sensitivity of 100%, and a specificity of 71% when they matched graft-biopsy samples as a diagnostic standard.
Urine electron microscopy (EM Haufen) is a useful diagnostic tool for BKVN.
Quantitative measurements
Molecular analysis of urinary BK virus-viral loads has 100% sensitivity and 78% specificity, but variability in laboratory measurements has made it difficult to standardize.
BK virus mRNA levels in urine
Urinary tests are highly sensitive for detecting active BKVN, but lack specificity due to different laboratory assays. Additionally, raised mRNA levels for granzyme B (>11 mRNA copies/μg total RNA) are usually present in recipients with acute cellular rejection.
Pros and cons of urinary tests in identifying BKVN:
Urinary tests are highly sensitive for detecting active BKV infections. However, they lack specificity for BKVN as the detected viral particles could originate anywhere along the urinary tract.
Different laboratory assays have created difficulty in standardizing the cutoff values for a definite diagnosis.
Although decoy cells are suggestive but not definitive in diagnosing BKVN, their absence does not exclude the disease.
Additionally, it can be confused with other viruses, such as cytomegalovirus (CMV) and adenovirus infection, though CMV can cause cytoplasmic besides the intranuclear inclusions .
BK viral loads are measured with real-time PCR, which has a sensitivity and specificity of 100 and 88%, respectively, for the development of BKVN.
However, not all recipients with BK viremia will develop nephritis.
Nephritis can be seen with plasma BKV-DNA of less than 7000 copies/ml, and quantitative PCR assays may be less sensitive for different strains.
Serial determinations of viremia are required to follow-up patients who lost their allograft due to BKVN.
Pros and cons of the BK-PCR test:
Plasma DNA-PCR has high sensitivity and specificity in anticipating BKVN; however, there is substantial interlaboratory variations in measuring BK viral loads with lack of international standardization.
Moreover, the sensitivity and specificity of PCR seems to be assay dependent and should be interpreted in the light of clinical condition.
Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels.
Serum antibodies
BK antibodies serostatus have no clinical relevance, but are implicated in the development of BK disease in postkidney transplant recipients.
Virus culture is rarely used outside a research setting, and BKV grows slowly in tissue culture.
Kidney biopsy is the gold standard to diagnose BKVN, but different threshold values have been proposed to anticipate the disease.
Hirsch et al. [95] found that BKviremia of more than or equal to 10 4 is characteristically present in recipients with proven biopsies.
FISH analysis is specific for BKV with a sensitivity of 94.7%. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival.
Three different histological grading systems are available, but only the Banff grading system has a moderately good intra-observer agreement.
Preemptive treatment or a repeat biopsy must be considered, and BK-PCR of allograft biopsy tissue is not an applicable investigation to diagnose BKVN.
Pros and cons of kidney biopsy
Renal biopsy is the gold standard for diagnosis of BKVN, but can be inaccurate and requires two biopsy cores, preferably including medulla, to make the correct diagnosis.
Different screening protocols have been developed for BKV screening in renal transplant recipients, with Hirsch et al. recommending a step-wise methodology and Ramos et al. recommending periodic screening of urine cytology for decoy cells.
Buehrig et al. and Khamash et al. recommended routine surveillance biopsies to detect silent BKVN, and American Society of Transplantation guidelines recommend further annual screening till the fifth year after transplant.
Currently, most transplant institutes recommend BK surveillance with plasma BK-PCR.
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies, immunohistology of positive immunoperoxidase staining for SV40, absence of definitive features of acute cellular rejection, and IHC staining of renal tissues or urinary sediments with anti-HLA DR.
BKVN is associated with an increased quantity of CD20+ cells in the tissue infiltrates, higher expression of genes related to inflammation and acute rejection, and increased expression of transcription molecules associated with graft fibrosis.
Other differential diagnosis includes any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction.
The treatment strategy of BK virus nephropathy (BKVN) is to eradicate the virus while saving the kidney function.
There is no standard strategy for modifying immunosuppressant therapy, but different regimens have been attempted.
These include withdrawal of antimetabolite drugs or change from mycophenolate mofetil to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25-50%, converting tacrolimus to cyclosporine or discontinuing CNI, or switching a drug within the same class or to a different class and avoiding steroid avoidance.
Withdrawal of the anti-BKV-specific T-cell response is the most usual method, but a study by Egli et al. showed that both CNI and MMF could inhibit T-cell reaction in vitro and ex vivo.
Drugs with antiviral activities
Leflunomide
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug which was developed to be used in rheumatoid arthritis.
It can inhibit pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects.
However, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage.
Additionally, it has a higher rate of adverse effects such as hemolysis, aplastic anemia, thrombocytopenia, and probably thrombotic microangiopathy.
Cidofovir
Cidofovir is a cytosine analog and viral DNA-polymerase inhibitor that is used to manage other viral infections such as CMV.
It has shown in-vitro inhibitory action against polyoma-viruses, but its mechanism of action is unclear.
When used for treating BKVN, it is given as slow intravenous infusion (over 2 h) at an initial dose of 0.25 mg/kg/dose every 2-3 weeks for 10-15 weeks.
It is a nephrotoxic drug and may cause acute kidney injury, renal tubular acidosis, and proteinuria.
A new promising antiviral drug, CMX001, is being developed.
mTOR inhibitors
mTOR inhibitors (sirolimus and everolimus) have shown effectiveness in inhibiting BK replication and early gene expression, as well as inhibiting proliferation of BKV-specific T cells and controlling the differentiation of memory CD8 T cells.
However, most published reports had fewer patients, generating contradictory results.
Intravenous immunoglobulin
IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain.
Other therapeutic options for treating BK virus
Other therapeutic options for treating BK virus nephropathy include quinolones, artesunate, statins, and rituximab.
Quinolones have been found to inhibit the LTAg helicase activity and have in-vitro and in-vivo activity against BKV.
Artesunate has been found to decrease BKV proliferation in a dose-dependent way, while statins have been shown to reduce the percentage of BKV-infected cells and LTAg expression in human renal proximal tubular epithelial cells, possibly due to inhibiting the formation of caveolin-1.
Rituxamab has been reported to have promising results in nine transplant patients with BKVN, with no graft failure during follow-up of 17 months.
In the late 1990s and early 2000s, BKVN caused permanent allograft damage in 30-60% of cases due to lack of awareness, delayed diagnosis, misdiagnosis, and coincidental utilization of escalated immunosuppression.
Therapeutic approaches have revealed short-term improvements, such as eliminating the circulating viremia, but long-term outcomes such as late acute and chronic rejections need to be further evaluated.
Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening, but 27% had experienced permanent damage.
Buehrig et al. reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis (8/8 patients vs. 3/10, P=0.004).
Dall and Hariharan reported an improvement in allograft survival at 1, 3, and 5 years from 89.8, 68.5, 57.9, and 47.4%, respectively, in 2005 to 94.6%, and Chenet al. reported 1-, 3-, and 5-year improvements.
Management of proven allograft biopsies of acute rejection with concomitant BKVN or management of anticipated rejection following a decrease of immunosuppression is debatable.
Suggested a combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection.
Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.
Treatment should be tailored for each patient individually.
Postinfection monitoring of BKV-PCR and renal function is essential to improve allograft outcome.
The most common approach is to follow transplant recipients with a serum creatinine test every 1-2 weeks and plasma BK-PCR level at 2-4-week intervals for 8 weeks.
Retransplantation following graft loss due to BKVN is possible and can be done successfully, and 126 individuals got retransplant of 823 who lost their graft.
Of the 126 retransplants, BKV was reported in 17.5% of cases, but just a single kidney was lost. 1- and 3-year graft survival was excellent, and pretransplant clearance of BK viremia is essential after minimizing immunosuppression.
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.Typing whole sentence in bold amounts to shouting.
BKV is a significant cause of interstitial nephritis & graft failure in KTR.
It is always one of the differential diagnosis of graft dysfunction.
It is commonly asymptomatic or gradual unexplained rise in serum creatinine with tubulo-interstitial nephritis resembling acute rejection.
BKV & renal transplantation:
BKV noticed for the first time when presented as ureteric stenosis & renal failure(1971).
Decoy cells are large cell with intranuclear inclusion appear in urine
In 1978, histological changes defined extensively with polyomavirus nephritis in kidney biopsy.
Increased incidence of BKV infection mainly due to increased awareness among nephrologist & better diagnostic techniques.
BKV is a DNA virus ,12 human polyoma virus .
Primary infection occur during early childhood & virus stay dormant throughout life in immunocompetent people.
60%-85% of general population are seropositive.
BKV-DNA genome divided into early viral gene region, late viral gene region, & capsid protein(VP1).
4 genotypes present (I-IV), I & IV common inhuman while II & III are rare.
Each genotype had subgroups which reflect different geographical & migration pattern of human population.
Immunological response to BKV:
Viral replication increased during immunosuppression e.g. pregnancy, DM, HIV infection, cancer & post transplant.
Other factors increase viral replication are:
Defective immune surveillance by host T cells: CD4 &CD8 are major component of cellular mediated immunity to control BKV & BV clearance.
Absence of humoral immunity to BKV: patients with BKVN have highest rise in BKV-specific IgG with persistently increased IgM.
Allo-immune activation: host BKV-specific effector memory T cells can’t recognize all-HLA molecule thus it permit BKV to escape immunological surveillance
Viral variation in molecular sequences.
Pathogenesis of BKV infection:
Primary infection usually subclinical or with mild respiratory symptoms in childhood.
The virus dormant in uroepithelium & renal tubular cells for life, also can be dormant in brain tissue & lymph nodes.
Tissue damage result from both direct viral cytolytic effect & secondary inflammatory response.
Route of transmission:
respiratory
GI transmission.
vertical
donor derived
sexual
urine & blood.
Clinical manifestation:
BKVN
ureteric stenosis.
hemorrhagic cystitis
BKV nephropathy in native kidney
Pulmonary disease.
neurological manifestation
ophthalmic manifestation
BKV & hepatic disease.
BKV & autoimmune disease.
BKV & malignancy:
BKV has oncogenic property by expression of LTAg & AST which can drive cells into neoplastic transformation.
Th association between BKV & urological malignancy not documented.
Risk factors of BKVN are:
degree if immunosuppression
male gender
old age recipient
previous rejection episodes
degree of HLA mismatch
prolonged CIT
BKV prostates.
certain ethnic groups.
low total lymphocytes percentage
uretra stent insertion.
Screening & diagnosis of BKVN:
Screening is important in early detection of viremia & viuria to prevent graft dysfunction.
AST & KDIGO guidelines recommend to screen as follow : first month post transplantation, every month for 6 months, then every 3 months for 1-2 years, & yearly for 2-5 years, & any time of unexplained increase in creatinine & after treatment of rejection episodes.
If PCR<10000 monitoring &/ or reduction of immunosuppression , >10000 graft biopsy.
Screening & diagnosis by:
Urine cytology for decoy cells(sensitivity 100%, specificity 71%, PPV29%, NPV100%).
Urine electron microscopy(EM Haufen): sensitivity 100% & specificity 99%.
Urine BKV-PCR sensitivity 100% & specificity 78%.
Urine mRNA level with sensitivity 100% & specificity 97%.
Serum Abs (D+/R-) is a risk factor of BK disease development.
Virus culture: difficult outside research.
Kidney biopsy: gold standard of BKVN diagnosis, should be done if viral load>10000copies/ml with or without graft dysfunction.
Differential diagnosis:
Rejection.
any cause f early or late graft dysfunction.
Treatment:
Immunosuppression reduction(risk of rejection should be balance with immunosuppression reduction).Withdrawal of anti-metabolite, 25-50% reduction of CNI dose.
Antiviral e.g. leflunomide, cidofovir(nephrotoxic)
mTOR-I inhibit BK replication.
Quinolone: conflict result about its efectiveness.
Artesunate: reduce viral proliferation in dose-dependent way.
Pravastatin.
IVIG
Rituximab: singe report show benefit but it need randomized trial to ensure benefit of rituximab in BKVN treatment.
The short term outcome improved.
Long term outcome including late acute & chronic rejection need more evaluation.
Acute rejection after reduction of immunosuppression range between 6%-12%.
BKN with concurrent acute rejection:
Management of proven acute rejection with BKVN is still debatable.
Immunosuppression reduction without steroid pulse should be considered when BKVN detected.
In absence of clear evidence or features of acute rejection, management should be specified for each patient individually.
Close monitoring of BKV-PCR & renal function after treatment of acute rejection or immunosuppression reduction is very important to improve graft outcome.
After reduction of immunosuppression in BKVN, follow-up of serum creatinine every 1-2 weeks & PCR at 2-4 weeks interval for 8 weeks, then monthly until clearance of viremia & stabilization of renal function.
BK viremia clear at 7-20 weeks, but initial decline may take 4-10 weeks after immunosuppression reduction.
Persistent of viremia despite reduction of immunosuppression need further reduction or change to sirolimus or add leflunomide.
Re-transplantation:
Patients with graft loss due to BKVN can be re transplanted successfully.
1&3 year graft survival in re transplanted patients is excellent at 98.5% & 93.6% respectively.
Pre-transplant BKV clearance is essential after immunosuppression reduction & graft nephrectomy may be done if there is active viral replication.
Recurrence of BKV may be due to reactivation of previous variant or new infection (de novo).
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
Introduction:
BKV, one of two human polyomaviruses discovered in 1971, was shown to induce interstitial nephritis and allograft failure in renal transplant patients three decades later. In the first year following kidney transplantation, BKV infection is one of several possible reasons of renal failure. Asymptomatic creatinine increases with tubulointerstitial nephritis may resemble acute rejection, creating a diagnostic and management conundrum.
BK epidemics:
BKV—polyomavirus hominins-1—infects most persons worldwide. In immune-competent humans, the virus remains latent after early childhood infection. 60–85% of the general population is BKV-positive. The only study on BKV prevalence in the Middle East and Africa came from Iran, with a seroprevalence of 41.8%. The age of the studied population, sample size, and antibody threshold explain such percentage variations.
BK virus infection in renal transplant recipients: an overview
Please summarise this article.
*This article to discuss the most recent evidence addressing the virology, pathogenesis, clinical features, diagnostic tools, screening protocols, treatment strategy, and short-term and long-term renal allograft survival concerning BKV infection.
*Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
*Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people.
*BKV infection, an early complication of renal transplant, often presents within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection and poses a diagnostic and therapeutic dilemma
*Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss.
*A routine screening protocol for early recognition of asymptomatic BKV infection has been reported to result in better allograft outcomes.
*BKV-DNA genome can be divided into three parts
-The early viral gene region
-The late viral gene region (LVGR)
-The capsid protein VP1 in the LVGR is the main capsid protein present on the surface and is responsible for receptor binding to the host cells.
*BK viral replication follows a state of immune suppression; it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period.
*BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as aconsequence of intense immunosuppression
*CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
*Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies.
*There is a relationship between BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis.
*The common screening methods for BK virus: Decoy cells, Haufen, Urinary BK-PCR, Urinary BK-mRNA and Plasma BK-PCR.
*Allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction.
*Treatment of presumptive BK virus nephropathy:
-The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
-Leflunomide, Cidofovirm, TOR inhibitors, Intravenous immunoglobulin
-Other therapeutic options for treating BK virus nephropathy
Quinolones, statins, Rituximab
#Conclusion
*Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology.
*There is a bigger ‘known unknown’ that just proves the elusive nature of BKV.
*An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
What is the level of evidence provided by this article?
Level 5
BK virus (BKV) often presents within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection and poses a diagnostic and therapeutic dilemma. Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss. A routine screening protocol for early recognition of asymptomatic BKV infection has been reported to result in better allograft outcomes. In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Routes of transmission of primary BK virus
(1) Respiratory route
(2) Gastrointestinal transmission
(3) Vertical transmission
(4) Sexual transmission
(5) Donor-derived infection
(6) Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK polyomavirus-associated nephropathy (BKVN)/ (PyVAN) .BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia. The estimated incidence of BKVN in different literature ranges between 2 and 15% of kidney allograft recipients.
Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years. The prevalence of ureteric stenosis is 2–6%. BKV-associated Hemorrhagic cystitis or non- Hemorrhagic cystitis is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients. Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy
BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients.
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically, whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BK viral inclusions within tubular epithelium can be identified via the conventional hematoxylin and eosin (H&E) and PAS staining . An alternative histological detection approach is through the identification of BKV via in-situ hybridization.
Treatment is with antiviral drugs which include :
Leflunomide
Cidofovir
brincidofovir
mTOR inhibitors
Intravenous immunoglobulin
Quinolones
artesunate
statins (pravastatin)
Rituximab
BKV post transplantation:
one of the major complications post transplanation is infection with BKV which portend a higher morbidity and mortality.BKV is a DNA virus that is commonly repoted in the first year post transplantation.
its causing tubulo-interstitial allograft nephropathy featuring progressive deterioration of allograft function. Its commonly encountered in the first year post transplantation.
Cell mediated immunity is keeping BKV under scrutiny and CD8 T lymphocytes are dstroying the infected cells. When cell -mediated immunity faltered by immune suppressants, BKV proliferate and produce intra neuclear and paraneuclear inclusion bodies. The explanation for increasing risk for BKV infection is absence of natural surveillance by cell-mediated immune system and lack of targeted humoral immunity against the viral infection.
BKV most portal of entry is respiratory system where it can get into circulation and stay dormant in uroepithelium. However, GIT , vertical and donor related trasfer of BKV is another reported routs.
Clinincal presentation:
1]viruria
2] BK viremia
3]BKVN
4]ureteric stenosis
5] hemorrhagic cystits
Its a narrative review with level of evidence 5
Please summarise this article.BKV, one of two human polyomaviruses discovered in 1971, was shown to induce interstitial nephritis and allograft failure in renal transplant patients three decades later. In the first year following kidney transplantation, BKV infection is one of several possible reasons of renal failure. Asymptomatic creatinine increases with tubulointerstitial nephritis may resemble acute rejection, creating a diagnostic and management conundrum.
BK epidemics:
BKV—polyomavirus hominins-1—infects most persons worldwide. In immune-competent humans, the virus remains latent after early childhood infection. 60–85% of the general population is BKV-positive. The only study on BKV prevalence in the Middle East and Africa came from Iran, with a seroprevalence of 41.8%. The age of the studied population, sample size, and antibody threshold explain such percentage variations.
BK virus immunity:
BK virus replication occurs after immune suppression in pregnancy, diabetes, HIV infection, cancer, and post-transplantation. As a result of strong immunosuppression, BKV replication usually starts early post-transplant. BKV replication and BKVN resolution depend on the immune system [48]. BKVN may be caused by (a) inadequate immunological surveillance by host T lymphocytes, (b) lack of humoral immunity to BKV, (c) alloimmune activation, and (d) viral variation in molecular sequences.
BK pathogenesis:
BKV primary infection seldom causes respiratory symptoms in children. BKV enters the circulatory system by infected tonsils and infects peripheral blood mononuclear cells, which spread to secondary sites, including the kidneys. The virus remains latent in the uroepithelium and renal tubular cells for life, sometimes reactivating as asymptomatic viruria.
BKV may also hide in leukocytes, brain tissues, and lymph nodes. In immunosuppressive treatment, the virus activates and proliferates in the interstitium and enters the peritubular capillaries, causing tubular cell lysis and viruria. Damage, inflammation, and fibrosis determine outcomes. Viral cytolysis and subsequent inflammatory responses harm tissue.
Different BKV illness symptoms originate from complex immune system-BKV interactions.
BK virus renal disease:
This virus proliferates in uroepithelial cells, causing viruria, viremia, and BK polyomavirus-associated nephropathy (BKVN) or PyVAN. 30–40% of renal transplant patients develop BK viruria, whereas 10–15% develop viremia.
BKVN is reported in 2–15% of kidney transplant patients. Different immunosuppressive regimens and screening strategies—including biopsy surveillance in certain centers—can explain these differences.
BK-related nephropathy:
BKV-associated nephropathy starts with viruria or asymptomatic hematuria and progresses to permanent damage and allograft failure. Nephritis might start 6 days or 5 years after a kidney transplant.
Ureteric stenosis the prevalence of ureteric stenosis is 2–6%.
Hemorrhagic cystitis: HSCT patients often develop BKV-associated HC or non-HC, although renal allograft recipients seldom do.
Other rare manifestations: neurological manifestations; pulmonary diseases, Ophthalmologic manifestations, BK virus, urothelial cancers
BKV-DNA was found in urothelial malignancies such as bladder carcinoma, and many believe BKV plays a major role in their development.
Risk factors:
There are many risk factors for BKVN. Immunosuppression is the most consistent risk factor in the research. Male sex, older recipient age, past rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, specific ethnic groups, a lower total lymphocyte percentage, and ureteral stent insertion are further risk factors for BKVN, however, not all investigations have found them.
Screening tests:
1 — Decoy cells: sensitivity: 25, specificity: 84 . Widely available, it is a useful marker in the identification of BKV infection but a poor diagnostic tool in predicting BKVN. Not useful for monitoring the decline in viral load
2-Haufen: sensitivity 100, specificity 99. Highly predictive for BKVN, but not practical for routine practice as it requires electron microscopy with interpretation from a pathologist
3-Urinary BK-PCR sensitivity: 100; specificity: 78. Measurement variations between laboratories limit its use.
4-Plasma BK-PCR Sen: 100 Spe: 88 Broadly available but costly. Has good sensitivity and specificity but a low PPV for BKVN.
Kidney biopsy: allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/mL.
Histology reveals streaky fibrosis of the medulla with circumscribed cortical scars macroscopically, and sclerosed glomeruli, necrotic, atrophic tubules with interstitial fibrosis microscopically.
BK virus inclusions within tubular epithelium can be seen via hematoxylin and eosin and PAS staining.
Differential diagnosis
Includes allograft rejection, and any disease associated with early and late allograft dysfunction. Early period would be within 2 weeks post transplant. Late period would be more than 3 months posttransplant.
Treatment
Reducing immunosuppression and switching drugs may be the initial therapeutic approach. Consider steroid withdrawal.
If MMF dosages stay the same, switching to cyclosporine may lower MMF levels, but if BK viremia persists, MMF must be stopped. MMF reduces proinflammatory and profibrotic cytokines.
Oral leflunomide inhibits viral replication in vitro and is administered at 100 mg/day for 3–5 days, followed by 20–40 mg/day. Nevertheless, MMF and azathioprine cannot be used with leflunomide.
Cidofovir, generally used for CMV, may induce BKV-induced cell death by reactivating p53 and pRB. but has a nephrotoxicity side effect.
Quinolone, statins, and Rituximab are other treatments. Therefore, regular monitoring of BKV PCR and renal function is crucial to a successful transplant, graft protection, and BKV clearance.
Discussion
BK virus is a Polyomavirus, a small non enveloped DNA virus with an isohedral capsid. The virus has different regions – early viral gene region that encodes regulatory nonstructural proteins, and late viral gene region that encodes capsid proteins within the nucleus.
BKV comes under 4 major categories or subtypes :
-Genotype I – predominant and most common subtype
-Genotype II and III – rare and infect a small minority of patients
-Genotype IV – second most frequent subtype
There are other subtypes reflecting different geographical and migration patterns.
BKV viral replication occurs in a state of immune suppression in the host, such as pregnancy, HIV infection, diabetes, cancer, or following transplant. Replication begins in the early posttransplant period.
Risk factors
Intensive immunosuppression
Male gender
Older recipient
Previous rejection episodes
Degree of HLA mismatch
Prolonged cold ischemia
BK sero status
Lower percentage of lymphocytes
Ureteral stent insertion
Pathogenesis :
Defective immune surveillance by host T lymphocytes
Absent humoral immunity to BKV
Patients with prior immunity to BKV may not show manifestation of disease, irrespective of viral copies.
Alloimmune activation
Viral variation in molecular sequences
CD4+ and CD8+ T cells are the main factors in cell mediated immunity that play a role in clearing BKV.
Recipients who receive graft from a BKV seropositive donor have a higher chance of developing the infection in comparison with those how have a seronegative donor.
BKV goes into the circulatory system through the tonsils, and then infects the mononuclear cells in the peripheral blood. This then gets disseminated into different secondary places in the body, including the kidneys.
BKV can also remain latent in the brain, lymph nodes, and leukocytes.
BKV does not cause infection in people who are immunocompetent.
Clinical manifestations
Virus sheds in the urine. Urine examination can be done to check for infection.
Ureteric stenosis
Late onset hemorrhagic cystitis
Multi Organ involvement
Neurological manifestations include encephalitis, meningoencephalitis, Guillan Barre syndrome, and basculopathy. Signs include headache, dizziness, confusion, paraplegia, ataxia, and seizures.
Bilateral atypical retinitis may occur, although this is rare.
Conclusion
BK virus, a diagnostic and therapeutic dilemma, is the focus of the given article. The main issue with this kind of infection is that it can mimic acute rejection, and thus treatment becomes difficult. This infection can be caused by intensive immunosuppression regimen aimed at preventing graft rejection.
Early diagnosis through molecular techniques and tissue analysis can achieve a good outcome in terms of the virus clearance as well as good allograft outcome.
What is the level of evidence provided by this article?Level V
Introduction;
BK virus was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipient.
Epidemiology;
It affects around >80% of population in childhood, and becomes dormant until immunocompromised.
BK virus varients;
There are four genotypes. Type I is 80%, II is around 15%, class II and IV are relatively rare.
Routes of transmission;
It can be transmitted in every fluid.
BKV associated nephropathy;
Usually asymptomatic until immunocompetant, on immunosuppression nephritis can occur as early as six days post-transplantation.
Can present with uretric stenosis,
BKV nephropathy,
Heamurrhagic cystitis,
Very rarly can cause malignancy.
Treatment;
There is no definite treatment yet, main stay of treatment is reduction of dose of immunosuppression.
Level of evidence V
Reduce immunosuppression and give steriod low dose.
Introduction
BK virus (BKV) and JC virus (JCV), 2 human polyomaviruses, were discovered in 1971. Their negative effect was poorly understood untill 3 decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
History of BK virus: In 1971, Gardner et al. first detected BK polyomavirus (BKV) in urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. They named the virus ‘BK’ after the initials of the patient.
Epidemiology of BK virus
BKV, is ubiquitous that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent ghosts. Studies showed as much as 60–85% of the general population is seropositive for BKV.
Immunological response to BK virus
BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and post-transplant patients. BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
BK virus variants
categorized into 4 genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1. Genotype I is the predominant subtype (80%) of all circulating viruses; genotype IV is second most frequent (15%). Genotypes II and III are relatively rare and infect only a minority of patients.
Routes of transmission of primary BK virus
Several routes for the primary BKV virus transmission – might be respiratory, feco-oral, transplacental, or from donor tissues.
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN).
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN).
BK virus-associated nephropathy
BKV-Nephropathy begins with viruria or asymptomatic haematuria; progresses through extensive irreversible injury and allograft failure. Onset of nephritis might occur as early as 6 days after renal transplant, or as late as 5 years
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6%. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppression.
Haemorrhagic cystitis
BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients
BK virus and malignancy: thoughts on viral oncogenesis
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors
BK virus and urothelial tumors
BKV is thought to have fundamental role in pathogenesis of urothelial malignancy, particularly bladder carcinoma as BKV-DNA was isolated in these tumors. Geetha et al. reported a bladder carcinoma with widespread metastases in a simultaneous pancreatic and kidney transplant recipient with concomitant BK interstitial nephritis.
Screening tests and timeline
Viral replication starts early after transplantation and progresses through noticeable phases: viruria then viremia followed by nephropathy. Viral replication in the urine precedes BK viremia by ∼4 weeks, and although there have been confined cases of patients developing viremia without viruria, this is uncommon. Histological changes of BKVN are observed 12 weeks after BK viruria
Kidney biopsy
The term ‘presumptive BKVN;’ has been created to recognize recipients with
(a) significant viruria, suggesting viral proliferation in the urinary tract, and
(b) persistent viremia of > 104 copies/ml for more than 3 weeks.
Although plasma BK-PCR has high sensitivity and specificity in anticipating BKVN, different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN
Treatment of BK virus nephropathy in the setting of allograft dysfunction
Favourable renal allograft outcomes in patients with acute BKV infection were reported after immunosuppression reduction, started early upon detection of BK viremia.
When BKVN is identified at advanced stage, then IS reduction is probably going to be less effective. Advanced disease, with severe histological changes leads to progressive, irreversible renal damage.
Whether reducing or discontinuing one or more of the immunosuppressive regimen can alter the prognosis is not yet clear. However, allograft function may stabilize with modifying immunosuppressants.
Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises BKV-specific IgG-antibodies titre and increases BKV- specific cellular immunity
Level of evidence: level V
Introduction
Although the two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
BK virus and renal transplantation: historical perception
In 1971, Gardner et al.were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. They named the virus ‘BK’ after the initials of this patient.
Epidemiology of BK virus
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people . Studies showed as much as 60–85% of the general population is seropositive for BKV.
Immunological response to BK virus
BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period .BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
BK virus variants
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1 . Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population. Alternatively, genotypes II and III are relatively rare and infect only a minority of patients
Routes of transmission of primary BK virus
Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN).
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN).
BK virus-associated nephropathy
Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% [2]. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications
Hemorrhagic cystitis
BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients
BK virus and malignancy: thoughts on viral oncogenesis
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors
BK virus and urothelial tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors. Geetha et al. reported a bladder carcinoma with widespread metastases in a simultaneous pancreatic and kidney transplant recipient with concomitant BK interstitial nephritis.
Screening tests
Viral replication starts early after transplantation and progresses through noticeable phases: viruria then viremia followed by nephropathy. Viral replication in the urine precedes BK viremia by ∼4 weeks, and although there have been confined cases of patients developing viremia without viruria, this is uncommon. Histological changes of BKVN are observed 12 weeks after BK viruria
Kidney biopsy
The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks . Although plasma BK-PCR has high sensitivity and specificity in anticipating BKVN , different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN
Treatment of BK virus nephropathy in the setting of allograft dysfunction
Favorable renal allograft outcomes in the context of acute BKV infection were reported when immunosuppression reduction had started early upon detection of BK viremia, permitting early and appropriate therapeutic interference
Nevertheless, if the identification of BKVN is made at an advanced stage when nephropathy ensues, then reducing immunosuppression is probably going to be less effective, owing to the advanced disease, with severe histological changes leading to progressive, irreversible renal damage
Whether reducing or discontinuing one or more of the immunosuppressive regimen can alter the prognosis is not yet clear. However, allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy
Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises BKV-specific IgG-antibodies titer and increases BKV- specific cellular immunity
Polyomaviridae variants the human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40). It is a family of small, nonenveloped DNA viruses
12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017. These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery.
Epidemiology of BK virus:
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent.
60–85% of the general population is seropositive for BKV.
BK virus structure:
Noncoding control region (NCCR):
It regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell.
BK virus variants:
4types, type one more common 80percent of cases type 4, 15percent of cases.
Phylogenetic analysis there’s:
Four more subgroups, subcloned of subtype and six subgroups of subtype IV.
Immunological response to BK virus:
BKV replication characteristically begins early in the post transplant period and can follow antirejection therapy as a consequence of intense immunosuppression. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN).
The role of cell-mediated immunity:
Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA.
The lysis of an infected cell can lead to viral leakage into the tubular lumen.
Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation. The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis.
The role of humoral immunity:
May have a role.
Role of alloimmune activation:
(HLA)-reactivity and heterologous immunity. The latter concerns with T cells, which cross-react to both BKV and allo-antigens. Moreover, one can propose that the host BKV-specific effector memory T cells cannot identify the allo-HLA molecules representing BKV-peptides; thus, it allows BKV to escape the immunological surveillance.
The role of other factors:
In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role.
Pathogenesis of BK infection:
Primary infection:
Usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
The virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
Immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitial and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria. Tissue damage is by direct viral cytolytic effects and secondary inflammatory responses.
Routes of transmission of primary BK virus:
Respiratory, fecal-oral, Trans placental, or from donor tissue. Urine and were present in peripheral blood leukocyte
Clinical manifestations:
BK virus and renal disease:
BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia.
BKVN in ranges between 2 and 15%.
BK virus-associated nephropathy:
Begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
Ureteric stenosis:
The prevalence of ureteric stenosis is 2–6%.
Treatment percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Hemorrhagic cystitis:
BKV-associated HC or non-HC.
More common with HSCT recipients. RARE in renal transplant.
Presents with bladder cramps, painful voiding, hematuria, and/or flank pain.
Four degrees of disease severity:
Grade me: microscopic hematuria.
Grade II: macroscopic hematuria.
Grade III: hematuria with clots.
Grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy.
Management:
Vigorous intravenous hydration. Severe cases of BKV-HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation.
Cidofovir, through bladder installation (hence reducing the cumulative drug nephrotoxicity) was suggested as a therapeutic option for HC.
BK nephropathy in the native kidney BKVN:
Has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients. Presented with acute kidney injury without significant proteinuria and had characteristic histological findings on kidney biopsy.
Other less apparent clinical manifestations
Neurological manifestations:
Picture of meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy,
Headache, dizziness, confusion, paraplegia, ataxia, and seizures.
Pulmonary diseases:
Reactivated acute respiratory infection leading to severe interstitial pneumonitis in association with BKV has been reported!
Ophthalmologic manifestations:
To date, there is only a single case report with bilateral atypical retinitis, reported.
BK virus and hepatic disease:
Similarly, a single report in the literature regarding the association between BKV and hepatitis was r
BK virus and autoimmune diseases:
A relationship between BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immunocompromised individuals.
BK virus and malignancy:
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors .
BK virus and urothelial tumors:
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma.
Risk factors:
Degree of immunosuppression.
male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion.
Screening and diagnostic tools:
Most cases arise in the first post-transplant year. Early Peak early 3 month decline by nine month and raise again after 12months.
KDIGO guidelines had recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening test:
Monitoring of the urine:
Urine cytology Decoy cells:
In 13–30%.
A sensitivity of 100%, and a specificity of 71% [positive predictive value (PPV) of 29% and negative predictive value (NPV) of 100%]. In contrast, reported a 25% sensitivity and 84% specificity (5% PPV and 97% NPV) to diagnose BKVN.
Urine electron microscopy (EM Haufen):
A higher sensitivity and specificity for biopsy-proven BKVN (100 and 99% correspondingly).
PPV 97, 100 NPP.
Quantitative measurements of urinary BK virus-viral loads:
Compared with urine cytology, molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity.NPP 40 PPV 100
BK virus mRNA levels in urine:
Has highly specific and sensitive (sensitivity of 100% and specificity 97%) in predicting patients who might develop BKVN, using 6.5×105 BKV-VP1 mRNAs/ng RNA in urinary cells as a cutoff value .
Serology
Serum BK-PCR:
BK viremia is noticed only among immunocompromised patients, with an estimated prevalence of 7–30% in the initial 6 months and 5–10% after that among kidney recipients.
Preferred screening technique at most transplant institution.
BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively, for the development of BKVN than BK viruria.
A definite viral load cutoff associated with nephropathy has not yet been defined. Nonetheless, retrospective analyses had proposed a quantitative BKV-PCR of more than 4 logs (1×104) copies/ml to correlate strongly with findings of BKVN on allograft biopsy.
Treatment strategy of BK virus nephropathy:
The aim is to eradicate the virus while saving the kidney function.
BKVN has limited treatment option.
Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response.
Treatment of presumptive BK virus nephropathy:
Manipulation or reduction of IS:
Reducing the dose of immunosuppressant or withdrawal
Switching a drug within the same class or to a different class and steroid avoidance.
withdrawal of antimetabolite drugs or change MMF to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI .
Withdrawal of the antimetabolite such as MMF is the most usual method.
Switching tacrolimus to cyclosporine might reduce MMF levels if doses of MMF remain the same.
If there’s allograft Dysfunction:
Reducing immunosuppression remained a rational option even in the presence of allograft dysfunction.
Drugs with antiviral activities:
Leflunomide:
Immunomodulatory, prodrug, and ant rheumatic disease-modifying drug.
Inhibit pyrimidine synthesis, resulting in ant proliferative and anti-inflammatory effects.
Dose:
Loading dose of 100 mg daily for 3–5 days followed with a maintenance dose of 20–40 mg/day and recommended target level of 40–100 μg/ml.
Simultaneous withdrawal of ant proliferative medication and reduced CNI dosages.
Limited use of this medication:
(a) Higher dosage of the drug (≥40 mg/day) is necessary to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity;
(b) Monitoring of the trough A77 1726 level is not accessible in all laboratories; and
(c) The immunosuppressive effectiveness of leflunomide is weak.
Adverse effects:
Hemolysis, aplastic anemia, thrombocytopenia, and probably thrombotic microangiopathy, hepatitis, and worsening of hypertension.
Cidofovir:
Cidofovir is a cytosine analog and viral DNA polymerase inhibitor.
When used for treating BKVN, cidofovir has been given as slow intravenous infusion (over 2 h) at an initial dose of 0.25 mg/kg/dose every 2–3 weeks for a period of 10–15 weeks.
Dosage can be increased if the BKV-PCR load does not reduce by one-log fold to a maximum dose of 1 mg/kg/dose.
Its nephrotoxic. Acute kidney injury, renal tubular acidosis, and proteinuria
Vigorous intravenous prehydration.
Dose adjustment if renal dysfunction.
Severe anterior uveitis was reported with cidofovir, which may lead to permanent visual impairment
Used carefully in kidney recipients, with frequent monitoring and informed consent for its potential complication.
Promising antiviral drug brincidofovir is a prodrug of cidofovir, and the oral form of the medicine gets converted to cidofovir when it goes intracellular.
The benefit of CMX001 is its effectiveness against all DNA viruses with no documented nephrotoxicity and ease of oral administration.
MTor inhibitors:
MTor inhibitors have shown effectiveness in in-vitro analysis in inhibiting BK replication and early gene expression.
Intravenous immunoglobulin:
Treatment with IVIG has been used for BKVN for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection.
Other therapeutic options for treating BK virus nephropathy:
(1) Quinolones have been described, no effect.
(2) Artesunate (an antimalarial drug) on BK viral proliferation in a primary human renal cell culture. The investigators found a decrease in BKV proliferation in a dose-dependent way with artesunate.
(3) Similarly, statins (pravastatin) were found experimentally to reduce the percentage of BKV-infected cells and LTAg expression in human renal proximal tubular epithelial cells, possibly owing to inhibiting the formation of caveolin-1, resulting in blocking viral entry into the cells
(4) Rituximab:
As an adjuvant therapy with cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN. In both groups, the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine.
Triple therapy was switched to cyclosporine and azathioprine. The viral load had normalized in most within 18.3±6.8 weeks.
Short-term and long-term allograft survival
There’s improve prognosis now for BKVN.
IS reduction associated with 6-12 % risk of rejection rate graft loss?
Reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified.
27% had experienced permanent allograft dysfunction, 18% ultimately lost their allograft secondary to BKVN.
Reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis.
BK nephropathy with concurrent acute rejection
Combination of antirejection therapy with a subsequent reduction in immunosuppression is suggested.
Postinfection monitoring:
Observation of BKV-PCR and renal function.
Serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
Subsequently, it should be done on a monthly bases until clearance of BK viremia and stabilization of renal function.
BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression. I
Viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide.
Conclusion:
BKV. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
Level of evidence 1V.
Introduction
BKV, JCV, and SV40 are Polyomaviridae, a subfamily discovered in 1971.
BKV was discovered to cause interstitial nephritis and allograft failure in renal transplant recipients three decades later.
BKV infection is one of many possible causes of renal failure in kidney transplant recipients, generally within the first year. Asymptomatic creatinine increases with tubulointerstitial nephritis may mimic acute rejection, creating a diagnostic and management conundrum.
The most common BKV genotype is 1, followed by 4.
Pathogenesis
BKV infection in children typically presents as a mild respiratory symptom and is subclinical in nature.
In the renal tubular cells and urothelium, the virus is still inactive. Moreover, it may remain latent in leukocytes, brain tissue, and lymph nodes.
Immunosuppressive medication causes tubular cell lysis and viruria when the virus replicates and spreads to the peritubular capillaries. BK illness manifests itself in a variety of ways depending on how the immune system and the BKV interact.
Primary BK virus transmission routes
The main modes of transmission for the BKV virus have been identified.
The infection may spread through the airways, orally through feces, transplacentally, or from donor tissues.
Clinical symptoms
7% of immunocompetent adults shed BKV in their urine, but it does not cause disease.
BKV nephropathy, ureteric stenosis, and late-onset hemorrhagic cystitis are diseases.
BKV and renal disease: Uroepithelial cell replication leads to viruria, viremia, and BK-associated nephropathy. BKV-associated nephropathy starts with viruria or asymptomatic hematuria and concludes with significant, irreparable harm and allograft failure.
Uretric stenosis: 2-6% prevalence; rarely causes hydronephrosis or allograft dysfunction. Percutaneous ureteral dilatation, stent insertion, and immunosuppression reduction treat ureteric stenosis.
Hemorrhagic cystitis: painful urination, hematuria, bladder spasms, and flank pains
Neurological manifestations: BKV rarely causes original or reactivated CNS illness.
BKV and cancer: Several neoplasms have BKV DNA. LTAG and STAG proteins may make BKV carcinogenic.
Tests for screening
Viruria comes about 4 weeks before viremia, and BKVN happens 12 weeks after viruria.
1) Urine cytology: Decoy cells are basophilic intranuclear inclusions that are larger tubular cells that are infected.
Decoy cells are thought to be a sign of BKV reactivation and are highly predictive of polyomavirus infection.
It can diagnose BKVN with a sensitivity of 25–100% and a specificity of 71–84.
2) Urine viral loads: PCR has 100% sensitivity and 78% specificity.
Patients at risk for BKVN can be predicted by their persistently elevated viral loads.
3) Serum BK PCR is the screening method of choice in the majority of transplant hospitals due to its 100% sensitivity and 88% specificity.
4) Kidney biopsy: the gold standard for BKVN diagnosis.
Treatment
The only proven therapy to cure BKVN and restore the immune system’s response to viruses is to reduce immunosuppression; however, any reduction in immunosuppression must always be weighed against the danger of inducing acute or chronic rejection. The most common approach is the withdrawal of the antimetabolite, such as MMF.
Medications with antiviral properties
Leflunomide: This immune modulator is taken by mouth at loading doses of 100 mg per day for 3–5 days, then 20–40 mg per day for maintenance.
Cidofovir is an analog of cytosine and an inhibitor of viral DNA polymerase. As BKV lacks the viral polymerase gene, which is cidofovir’s known target, the mechanism of action is uncertain. Due to the fact that urine is the only method of excretion, renal tubular cell concentrations are high.
Inhibitors of mTOR improves the immunological response after BKV infection by controlling memory CD8 T cell development and preventing the growth of BKV-specific T cells.
Strong neutralizing antibodies that can neutralize all main BK virus genotypes are seen in intravenous immunoglobulin. Treatment of BKVN with concomitant acute rejection using IVIG in a dosage of 2-3.5 g/kg spread over 2–5 days with a contemporaneous reduction in immunosuppressive drugs has been successful.
Post-infection surveillance
serum creatinine every one to two weeks.
Plasma BK PCR: 2–4 weeks for an 8/52 sample, then every month until BK viremia disappeared.
Leflunomide addition or sirolimus switch should be explored if viremia continues despite RIS.
Level of evidence: V
Introduction
BKV, JCV, and SV40 are Polyomaviridae, a subfamily discovered in 1971.
BKV was discovered to cause interstitial nephritis and allograft failure in renal transplant recipients three decades later.
BKV infection is one of many possible causes of renal failure in kidney transplant recipients, generally within the first year. Asymptomatic creatinine increases with tubulointerstitial nephritis may mimic acute rejection, creating a diagnostic and management conundrum.
The most common BKV genotype is 1, followed by 4.
Pathogenesis
BKV infection in children typically presents as a mild respiratory symptom and is subclinical in nature.
In the renal tubular cells and urothelium, the virus is still inactive. Moreover, it may remain latent in leukocytes, brain tissue, and lymph nodes.
Immunosuppressive medication causes tubular cell lysis and viruria when the virus replicates and spreads to the peritubular capillaries. BK illness manifests itself in a variety of ways depending on how the immune system and the BKV interact.
Primary BK virus transmission routes
The main modes of transmission for the BKV virus have been identified.
The infection may spread through the airways, orally through feces, transplacentally, or from donor tissues.
Clinical symptoms
7% of immunocompetent adults shed BKV in their urine, but it does not cause disease.
BKV nephropathy, ureteric stenosis, and late-onset hemorrhagic cystitis are diseases.
BKV and renal disease: Uroepithelial cell replication leads to viruria, viremia, and BK-associated nephropathy. BKV-associated nephropathy starts with viruria or asymptomatic hematuria and concludes with significant, irreparable harm and allograft failure.
Uretric stenosis: 2-6% prevalence; rarely causes hydronephrosis or allograft dysfunction. Percutaneous ureteral dilatation, stent insertion, and immunosuppression reduction treat ureteric stenosis.
Hemorrhagic cystitis: painful urination, hematuria, bladder spasms, and flank pains
Neurological manifestations: BKV rarely causes original or reactivated CNS illness.
BKV and cancer: Several neoplasms have BKV DNA. LTAG and STAG proteins may make BKV carcinogenic.
Tests for screening
Viruria comes about 4 weeks before viremia, and BKVN happens 12 weeks after viruria.
1) Urine cytology: Decoy cells are basophilic intranuclear inclusions that are larger tubular cells that are infected.
Decoy cells are thought to be a sign of BKV reactivation and are highly predictive of polyomavirus infection.
It can diagnose BKVN with a sensitivity of 25–100% and a specificity of 71–84.
2) Urine viral loads: PCR has 100% sensitivity and 78% specificity.
Patients at risk for BKVN can be predicted by their persistently elevated viral loads.
3) Serum BK PCR is the screening method of choice in the majority of transplant hospitals due to its 100% sensitivity and 88% specificity.
4) Kidney biopsy: the gold standard for BKVN diagnosis.
Treatment
The only proven therapy to cure BKVN and restore the immune system’s response to viruses is to reduce immunosuppression; however, any reduction in immunosuppression must always be weighed against the danger of inducing acute or chronic rejection. The most common approach is the withdrawal of the antimetabolite, such as MMF.
Medications with antiviral properties
Leflunomide: This immune modulator is taken by mouth at loading doses of 100 mg per day for 3–5 days, then 20–40 mg per day for maintenance.
Cidofovir is an analog of cytosine and an inhibitor of viral DNA polymerase. As BKV lacks the viral polymerase gene, which is cidofovir’s known target, the mechanism of action is uncertain. Due to the fact that urine is the only method of excretion, renal tubular cell concentrations are high.
Inhibitors of mTOR improves the immunological response after BKV infection by controlling memory CD8 T cell development and preventing the growth of BKV-specific T cells.
Strong neutralizing antibodies that can neutralize all main BK virus genotypes are seen in intravenous immunoglobulin. Treatment of BKVN with concomitant acute rejection using IVIG in a dosage of 2-3.5 g/kg spread over 2–5 days with a contemporaneous reduction in immunosuppressive drugs has been successful.
Post-infection surveillance
serum creatinine every one to two weeks.
Plasma BK PCR: 2–4 weeks for an 8/52 sample, then every month until BK viremia disappeared.
Leflunomide addition or sirolimus switch should be explored if viremia continues despite RIS.
Level of evidence: V
Introduction
BKV infection is among many other causes responsible for renal dysfunction in kidney transplant recipients occurring within the first year after transplantation. Negative impacts involve interstitial nephritis and allograft failure in renal transplant recipients resembling acute rejection causing a conflict in the diagnostic as well as the therapeutic approach.
BK virus and renal transplantation: historical perception
1971, Gardner et al. were the first who detected BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. The presence of abundant large cells with intranuclear inclusions were present in the urine known as ‘decoy cells’ as they resemble malignant cells.
Furthermore, Mackenzie et al. in 1978 had established the histological changes consistent with polyomavirus nephritis in renal biopsy.
JCV is the culprit of progressive multifocal leukoencephalopathy.
Polyomaviridae variants
It is a subgroup of papovaviruses BKV, JCV, and simian virus 40 (SV40). They are small, nonenveloped DNA viruses.
Epidemiology of BK virus
Polyomavirus hominis-1 is a ubiquitous virus, causes worldwide infection during early childhood after that the virus remains dormant lifelong in immune-competent population. This can be confirmed according to many studies reporting 60–85% of the general population is seropositive for BKV.
BK virus structure
BKV-DNA genome
The noncoding control region (NCCR) which is responsible for regulation of the expression of viral genes for further differentiation and activation within the host cell.
The early viral gene region encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg). Their role is to bind to cellular target proteins (tumor suppressor proteins Rb, p107, p130, and p53) for efficient viral replication.
The late viral gene region (LVGR) which is responsible for encoding the capsid proteins VP-1, VP-2, and VP-3 within the nucleus.
The capsid protein VP1 in the LVGR present on the surface facilitates the viral entry into the cell.
Among BK virus variants, Genotype I is considered the predominant subtype exceeding 80% worldwide infections while the second common is genotype IV accounts for 15% of the healthy human population.
Immunological response to BK virus
BK viral replication usually occurs in immunocompromised population as clinical states of pregnancy, diabetes, HIV infection, cancer, and post-transplantation.
Regarding the post-transplant early period, it is to be more expected after antirejection therapy administration derived by more intense immunosuppression leading to BK virus nephropathy (BKVN).
Proposed factors explaining to the pathogenesis of BKVN are combination of defective immune surveillance by the host T-lymphocytes, absence of humoral immunity to BKV, alloimmune activation, and viral variation in molecular sequences.
The role of cell-mediated immunity
CD4+ and CD8+ T cells play a role in cellular-mediated immunity to control the BKV and BK clearance. Cytotoxic T cells (CTL) are responsible for killing the BK-infected cells.
Lack of proper immunological regulation in addition to progressive lytic infection results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
Collateral destruction with necrosis and apoptosis of non-infected tubular cells, consequences include continuous intragraft inflammation, tubular injury, up-regulation of profibrotic mediators ending by allograft dysfunction and loss.
Bohl and his colleagues discovered that renal transplant recipients from seropositive donors were more prone to develop BK viremia compared to those from seronegative donors. The role of antibody mediated immunity is significant as patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
Role of alloimmune activation
Allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity are believed to be other contributing factors. As the host BKV-specific effector memory T cells become unable to identify the allo-HLA molecules representing BKV-peptides allowing them to escape the immunological surveillance. Moreover, CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans.
Awadalla et al. also had linked the higher degree of HLA mismatches with an increase in the incidences of BKVN, suggesting the validated role of alloimmune activation.
In contrast, Drachenberg et al. proposed a reverse association between allograft survival and the level of HLA matches in patients with BKVN, suggesting a lack of HLA matches might predict better outcomes in recipients with BKVN.
Another contributing factor is BKV tropism to the renal tubular epithelial cells.
Pathogenesis of BK infection
During primary infection in childhood, BKV affects the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell then get disseminated to secondary places mainly kidneys.
Resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation, manifesting as asymptomatic viruria. It is known BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
Routes of transmission of primary BK virus
Route of infection could be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations
Different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis in renal transplant recipients.
In HIV infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement up to death.
BK virus and renal disease
The virus proliferates within the uroepithelial cells resulting in viruria followed by viremia and finally to BK polyomavirus-associated nephropathy (BKVN). Viruria could be detected in 30–40% of renal transplant recipients, while viremia accounts for 10–15% of recipients. Overall, the estimated incidence of BKVN is variable between 2 and 15% of kidney allograft recipients due to worldwide difference in immunosuppressive regimens, screening strategies and early performance of surveillance biopsies.
BK virus-associated nephropathy onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
Ureteric stenosis occurs in 2–6% while hemorrhagic cystitis is even rarer.
It has been proposed also that BKV has an oncogenic sequel owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA. Agnoprotein and LTAg will make infected cells incapable of arresting the cell cycle and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
However, it was discovered that BKV-DNA by PCR existed in only 5.5% of urothelial tumors.
Risk factors are mainly degree of immunosuppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus.
Screening and diagnostic tools
Most cases arise in the first posttransplant year, Last American Society of Transplantation Infectious Diseases Guidelines and KDIGO guidelines recommended BKV screening to start at first month after transplant, then monthly for the first 6 months and then every 3 months for up to 2 years.
Screening tests
Viral replication in the urine precedes BK viremia by ∼4 weeks, histological changes of BKVN are observed 12 weeks after BK viruria. Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
Monitoring of the urine include detection of BKV-infected epithelial cells ‘decoy cells,’ or aggregates of BKV virions ‘Haufen’ or by quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
BK viremia is prevalent in immunocompromised patients by of 7–30% in the initial 6 months and 5–10% after that among kidney recipients
Retrospective analyses had proposed a quantitative BKV-PCR of more than 4 logs (1×104) copies/ml to correlate strongly with findings of BKVN on allograft biopsy.
Serial determinations of viremia are required to follow-up patients who lost their allograft due to BKVN and considered for retransplantation.
BKV grows slowly in tissue culture, which might extend from weeks to months.
Kidney biopsy
Allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction.
Fluorescence in-situ hybridization (FISH) analysis allows BKV identification in renal transplant tissues through bright nuclear fluorescence technique with a specificity of 100% and sensitivity of 94.7%.
Positive IHC using specific antibodies against BKV or the cross-reacting SV40 LTAg has a specificity of nearly 100% for polyomavirus nephropathy.
Histologically includes viral cytopathic changes of near-normal renal parenchyma, with no or minimal tubular atrophy, interstitial fibrosis, or inflammation, diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation. BK-PCR of allograft biopsy tissue is inapplicable investigation to diagnose BKVN, as it can identify a latent virus, even in asymptomatic recipients.
Suggested algorithm for screening
Recommended a step-wise methodology for BKV screening in renal transplant recipients.
Start by screening patients for BKV, first with urine cytology for decoy cells every 3 months, if positive proceed for quantification of viral level in the plasma with the possibility of performing allograft biopsy only when deterioration of renal functions occur.
Another option is to rely on routine surveillance biopsies to detect patients with silent BKVN. Allograft biopsies were performed at third/fourth month and at 12 months post transplantation, accordingly many patients were detected with a silent disease. Thus, surveillance biopsies had resulted in improved allograft outcomes compared to patients with renal allograft impairment at the time of diagnosis.
Currently, many transplant centres recommend BK surveillance with plasma BK-PCR. It is better to be performed on periodic intervals, starting after 1 month, monthly for 3–6 months and then every 3 months for the initial 1–2 years post renal transplantation.
Annual screening till the fifth year after transplant is suggested by American Society of Transplantation guidelines.
Differential diagnosis
Allograft rejection
Analysis of blood or urine PCR also as BKVN may coexist concurrently with acute rejection. Presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells. Absence of definitive features of acute cellular rejection, such as endotheliitis, extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful in excluding rejection.
Other differential diagnosis includes any disease common in the early (1–12 weeks post renal transplantation) late (≥3 months post renal transplantation) renal allograft dysfunction.
Treatment strategy of BK virus nephropathy
Decreasing immunosuppression is the only validated therapy to treat BKVN. Withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less). Switching tacrolimus to cyclosporine might reduce MMF levels if doses of MMF remain the same. The total withdrawal of MMF in some situations might be essential if BK viremia persists as MMF may limit the proinflammatory and profibrotic cytokines.
Drugs with antiviral activities
Leflunomide is a known immunomodulatory, prodrug, and antirheumatic disease-modifying drug as it acts by inhibiting pyrimidine synthesis having an antiproliferative and anti-inflammatory role.
Leflunomide dosage is orally with a loading dose of 100 mg daily for 3–5 days, then a maintenance dose of 20–40 mg/day with recommended target level of 40–100 μg/ml. highlighting the necessity of frequent liver function monitoring to avoid hepatotoxicity.
Adverse effects are variable as hemolysis, aplastic anemia, thrombocytopenia, thrombotic microangiopathy, hepatitis, and worsening of hypertension.
Cidofovir is a cytosine analog and viral DNA polymerase inhibitor used to manage other viral infections such as CMV. The mechanism of action is thought to be by re-establishing p53 and pRB function (targets of the LTAg) inducing apoptosis of the BKV infected cells.
Recommended dosage is via slow intravenous infusion (over 2 h) at an initial dose of 0.25 mg/kg/dose every 2–3 weeks for 10–15 weeks duration. Dose adjustment is required in cases of renal dysfunction as it is exclusively excreted through urine resulting in high renal tubular cell concentrations.
Side effects are deleterious as acute kidney injury, renal tubular acidosis, proteinuria, severe anterior uveitis up to permanent visual impairment.
New promising antiviral agent is a prodrug of cidofovir is discovered known as brincidofovir (CMX001) which has an advantage of being effective against all DNA viruses without nephrotoxicity and availability of oral administration.
mTOR inhibitors have antiviral effect by inhibiting BK replication and early gene expression. They are thought to produce their inhibitory impact by restoring the down regulation of translation that occurs under cellular stress delaying viral replication.
Moreover, it inhibits the proliferation of BKV specific T cells as well as controlling the differentiation of memory CD8 T cells resulting in improving the immune reaction sequel of BKV infection.
Intravenous immunoglobulin
The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications. It has been effective in cases with BKVN and concurrent acute rejection.
Other therapeutic options are Quinolones, statins (inhibiting the formation of caveolin-1, resulting in blocking viral entry into the cells), Rituximab (an adjuvant therapy with cidofovir)
Finally, close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression is crucial to improve allograft outcome.
The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV. BK viremia clears in 7–20 weeks.
If viremia persists even after reducing the maintenance therapy then further reduction should be considered or trial to shift to sirolimus, or add leflunomide.
Inability to clear BKV can lead to worse allograft outcomes.
Retransplantation is possible and can be done successfully. According to studies the 1- and 3-year graft survival among the retransplanted individuals was excellent at 98.5 and 93.6%, respectively. Provided that pretransplant clearance of BK viremia is crucial after minimizing immunosuppression. Allograft nephrectomy is not necessary prior to retransplantation.
However, Recurrence of BKV after retransplantation suggests another BK variant or even a new infection (de-novo BKV) acquired owing to the long post-transplantation stage duration.
Conclusion
Early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has led to substantial improvement in allograft outcomes.
Level of evidence is V.
reduction of tacrolimus and stopping MMF is first response
BKV
named after initials of first patient
1971
DNA virus
like JCV , it is polyoma virus
most adults are infected
genotype 1 – 80% common
type 4 -15%
T cell immunity has major role to play on BKV infection
caused BKV nephropathy, ureteric stricture , haemorrhagic cystitis
screening
during 1 yr post transplant
urine test is easy and simple , high negative predictive value
VIRUS CULTURE
SEROLOGY
KIDNEY BIOPSY are other options
diff diagnosis
allograft rejection
The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
Withdrawal of the antimetabolite such as MMF is the most usual method;
lefunomide
cidofovir
IV Ig
statin
fluroquinolone
antimalarial artesan
BKV infection, an early complication of renal transplant, often presents within the first year after transplantation.
It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection and poses a diagnostic and therapeutic dilemma.
Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss.
Increased awareness among nephrologists to recognize BKV disease at an earlier stage and the development of better diagnostic laboratory techniques contributed to the ever-increasing incidence of BKV infection
Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population. Alternatively, genotypes II and III are relatively rare and infect only a minority of patients
BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period .BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN) .Possible factors that add to the pathogenesis of BKVN might be a combination of (a) defective immune surveillance by the host Tlymphocytes, (b) absence of humoral immunity to BKV, (c) alloimmune activation, and (d) viral variation in molecular sequences.
Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
In immunocompromised patients, particularly in renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis
BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia.
BK virus-associated nephropathy
Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% [2]. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen ,and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Hemorrhagic cystitis
BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients .
The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain .
Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy .
BKV-HC is extremely rare in renal transplant.
BK virus and malignancy: thoughts on viral oncogenesis
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
BK virus and urothelial tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors.
Risk factors
The most consistent risk factor identified in the literature is the overall degree of immunosuppression. Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; however, these risk factors have not been uniformly observed in all studies.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood. However, no single diagnostic pathway has appeared as predominant.
Monitoring of the urine
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Presence of decoy cells is strongly suggestive of polyomavirus infection and considered a useful marker of BKV reactivation, though it is not a real diagnostic tool for BKVN.
Quantitative measurements of urinary BK virus-viral loads
Compared with urine cytology, molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity .
Persistent DNA-PCR more than 107 /ml instead of episodic identification can recognize patients at risk for BKVN .However, variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis.
Pros and cons of urinary tests in identifying BKVN:
Urinary tests are highly sensitive for detecting active BKV infections. However, they lack specificity for BKVN as the detected viral particles could originate anywhere along the urinary tract.
Different laboratory assays have created difficulty in standardizing the cutoff values for a definite diagnosis. Although decoy cells are suggestive but not definitive in diagnosing BKVN, their absence does not exclude the disease. Additionally, it can be confused with other viruses, such as cytomegalovirus (CMV) and adenovirus infection, though CMV can cause cytoplasmic besides the intranuclear inclusions.
BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively, for the development of BKVN than BK viruria ,hence, it is the preferred screening technique at most transplant institutions.
Nephritis, however, can be seen with plasma BKVDNA of less than 7000 copies/ml
Serum antibodies
Serum antibodies against BKV are commonly present among the general public. The significance of assessing BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain. Additionally, it has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients .
Nevertheless, the positive donor BKV serostatus and negative recipient serostatus (BK D+/R−) have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients.
Although plasma BK-PCR has high sensitivity and specificity in anticipating BKVN ,different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN .
Thus, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction .
Immunosuppression reduction…. May rebuild the immune responses against BKV
Can induce acute rejection
Leflunomide ….Pyrimidine depletion and tyrosine kinase inhibition
Hemolytic anemia thrombocytopenia, and thrombotic microangiopathy
Cidofovir… Inhibits viral replication; mechanism unknown
Potentially nephrotoxic and severe anterior uveitis
IVIG …. Contain neutralizing antibodies against BKV and are immunomodulatory
May lead to paradoxical increase in viral load
mTOR inhibitors ….Inhibits the proliferation of BKV-specific T-cell and controls the differentiation of memory CD8 T cells
Hyperlipidemia, bone marrow toxicity, mucositis and oral ulcerations, and lymphedema
Fluoroquinolones …Inhibit BKV replication in vitro and inhibit the large T antigen helicase activity
Rarely occurs, such as gastritis, C difficile, hepatoxicity, neurological adverse effects, and altered mental status
Artesunate (an antimalarial drug) …Inhibit BK viral proliferation in a primary human renal cell culture
Anorexia, dizziness, nausea, and diarrhea
Statins … Prevent caveolae-mediated endocytosis
Adverse muscle events and hepatic dysfunction
Rituximab
Although therapy with anti-CD20mAb rituximab used for the treatment of antibody-mediated rejection was associated with several adverse effects including BKVN, CMV viremia, herpes zoster, and septic shock.
Conclusion
Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology. There is a bigger ‘known unknown’ that just proves the elusive nature of BKV. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
level of evidence 5
Introduction:
There are two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971.
BKV cause of interstitial nephritis and allograft failure in renal transplant recipients.it causes renal dysfunction in kidney transplant recipients within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma.
causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma
Epidemiology of BK virus:
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people.
BK virus structure:
It is DNA genome the NCCR regulate the expression of the virus and divided into 3 parts:
1) The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen).
2) The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus.
3) The capsid protein VP1 in the LVGR is the main capsid protein present on the surface and is responsible for receptor binding to the host cells, facilitating virus entry into the cell.
BK virus variants:
Divided into 4 subtypes the most common is subtype 1 account for 80% and subtype 4 15%.subtype 2 and 3 are rare.
Immunological response to BK virus:
viral replication follows a state of immune suppression as in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period.
Pathogenesis of BK infection:
Primary infection is subclinical, manifests as a mild respiratory symptom in childhood. After resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria and remain latent in leukocytes, brain tissues, and lymph nodes, and reactivate after immunosuppression.
Routes of transmission of primary BK virus:
1) Respiratory route: it’s the primary route
2) Gastrointestinal transmission: salivary gland
3) Vertical transmission:
4) Sexual transmission
5) Donor-derived infection
6) urine and blood transmission
Clinical presentation:
v In immunocompromised patients, particularly in renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
v Outside renal transplantation, it is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC whereas in HIV infected patients, it may disseminate leading to severe viremia with multiorgan involvement and death.
BK virus and malignancy: thoughts on viral oncogenesis:
It has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation.
BK virus and urothelial tumors:
It may have a role in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors.
Risk factors:
Immunosuppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion.
Screening and diagnostic tools:
The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears.
Timing of screening:
BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year. American Society of Transplantation Infectious Diseases Guidelines and KDIGO guidelines had recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening tests:
DNA-PCR in urine and blood
Monitoring of the urine:
Include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Serology:
Serum BK-PCR of more than 4 logs copies/ml correlates strongly with BKVN, and has sensitivity of 100% with specificity of 88%
Virus culture:
BKV can be isolated from a urine sample before any rise in antibody titers; however, virus culture is hardly used .It grows slowly in tissue culture
Kidney biopsy:
Gold standard to diagnose BKVN, to be performed if BK viral load is more than 10000 copies/ml insistently with or without graft dysfunction.
Macroscopically shows streaky fibrosis of the medulla with circumscribed cortical scars , whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BK viral inclusions within tubular epithelium can be identified via the conventional hematoxylin and eosin (H&E) and PAS staining.
Suggested algorithm for screening:
Hirsch et al. screened patients for BKV, first with urine cytology for decoy cells every 3 months. most transplant centers, recommend BK surveillance with plasma BK-PCR. Screening for BKV should be performed on periodic intervals, starting after 1 month, monthly for 3–6months, and then every 3months for the initial 1–2 years after transplantation.
Differential diagnosis:
1) Allograft rejection:
The distinction of BKVN from acute rejection is challenging as the histological appearance is often similar. Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN.it differentiated by n by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells.
2) Others includes any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction.
Treatment strategy of BK virus nephropathy:
The aim of treating BKV is to eradicate the virus while saving the kidney function
Reduction in immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response
No standard strategy for modifying immunosuppressant’s therapy.
Strategies used include withdrawal of antimetabolites, or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, or reducing the dose of calcineurin inhibitor (CNI) by 25-50%. Even in setting of graft dysfunction, immunosuppression reduction is important treatment option.
Drugs with antiviral activities:
1. Leflunomide: is an immunomodulator, prodrug, and antirheumatic disease-modifying drug with dose of 100 mg daily for 3-5 days followed by 20-40 mg/day has been used as its metabolite A77 1726 inhibits BKV replication but it is associated with hemolysis, thrombocytopenia, hepatitis, and worsening hypertension.
2. Cidofovir: is a cytosine analog and viral DNA polymerase inhibitor that is used to manage other viral infections such as CMV. dose of 0.25 mg/kg every 2-3 week for 10-15 weeks has been used but it may cause acute kidney injury, renal tubular acidosis, proteinuria, and anterior uveitis.
3. mTOR inhibitors: restore downregulation of translation and inhibits BKV-specific T cell proliferation.
4. Intravenous immunoglobulin: has potent neutralizing antibodies and immunomodulatory properties, helping in BKVN management (with concurrent immunosuppression reduction)
5. Other therapeutic options for treating BK virus nephropathy: like quinolones, artesunate, pravastatin and rituximab have also been used.
Short-term and long-term allograft survival:
Short-term improved by reduction in immunosuppression therapy but long-term need to be evaluated.
BK nephropathy with concurrent acute rejection:
A combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection. Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.
Post infection monitoring:
Close observation with serum creatinine every 1-2 weeks and plasma BKV-PCR every 2-4 weeks for 8 weeks should be done, followed by monthly BKV-PCR till viremia gets cleared. If viremia persists despite RIS, then consider changing to sirolimus, or adding leflunomide.
Re transplantation:
Can be done successfully following graft loss owing to BKVN.
Pretransplant clearance of BK viremia is essential after minimizing immunosuppression
BKV viruria, viremia, and BK nephropathy can recur and cause allograft loss which might reflect a previous BK variant or a new infection (de-novo BKV).
Conclusion:
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
What is the level of evidence provided by this article?
It is level V
BKV is identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients in the first year after transplantation. It usually presents with asymptomatic gradual rise in creatinine and tubulointerstitial nephritis.
It may mimic acute rejection therefore making its diagnosis and treatment more difficult.
belongs to the polyomaviridae (PyV) virions, a subgroup of papovavirus. It is a family of small, non-enveloped DNA viruses with icosahedral capsid and a double stranded DNA.
It usually infects humans. Primary infection takes place during early childhood, and then the virus stays dormant throughout life in the immune-competent population.
categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1. The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined. BKV replication occurs during a state of immune suppression, for example in pregnancy, diabetes, HIV infection, cancer, and post-transplantation period. It usually begins early in the posttransplant period and can follow antirejection therapy because of intense immunosuppression.
There are possible factors that contribute to the pathogenesis of BKV nephropathy (BKVN), such as:
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity and aid to clear BKV. T cells react against both nonstructural and BK capsid proteins. Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA. Without appropriate immunological regulation, progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination into the interstitium. Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation. The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis. Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss.
Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, sometimes manifests as a mild respiratory symptom in childhood. It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria. During the use of immune suppressive medications, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria. The outcome relies on the level of damage, inflammation, and fibrosis.
The route of transmission of the infection may be via respiratory, faecal-oral, transplacental, or from donor tissues.
Clinical manifestations
Risk factors
Screening
screening should start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood. However, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml, with or without allograft dysfunction.
Histology
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically, whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BKV affects the kidney allograft in an erratic, multifocal manner; hence, false-negative biopsies may occur, specifically at early stages of the disease, therefore a repeat biopsy may be warranted.
Differential diagnosis
Differential diagnosis include allograft rejection, and any other disease associated with early (1–12 weeks after transplantation) and late ( ≥ 3 months transplantation) renal allograft dysfunction.
Treatment
Drugs with antiviral activities
Leflunamide
Cidofovir
mTOR Inhibitors
IVIG
Allograft survival
Post-infection monitoring
Re-transplantation
Level Of Evidence:
This is a narrative review,level V
IV. BK virus infection in renal transplant recipients: an overview
· BK polyomavirus (BKV) was first detected in both urine and ureteral epithelial cells, in 1971 by Gardner et al.
· BKV was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipients.
· BKV, is a ubiquitous virus that infects most humans around the world.
· Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people.
· BKV-DNA genome can be divided into three parts: 1) The early viral gene region. 2) The late viral gene region (LVGR). 3) The capsid protein VP1 in the LVGR.
· BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and post-transplantation period.
· Primary BKV infection is usually subclinical, it goes into the circulation via tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
· After resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
· In the presence of immunosuppressive therapy, the virus activates and proliferates in the interstitium and crosses into the peritubular capillaries, leading to tubular cell lysis and viruria.
Routes of transmission of primary BK virus
1) Respiratory route: suspected to be the primary route for transmission, but it was not isolated on respiratory samples.
2) Gastrointestinal transmission: BKV detected in saliva and stool.
3) Vertical transmission: via the transplacental passage.
4) Sexual transmission: but primary infection happens before the age of sexual activity
5) Donor-derived infection.
6) transmission through the urine and blood
Clinical manifestations
· in renal allograft recipients, BKV induces BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
· in patients with hematopoietic stem cell transplant (HSCT) recipients, BKV induces hemorrhagic and non- hemorrhagic cystitis.
· in HIV-infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement and death.
BK virus and renal disease
· BK virus-associated nephropathy: begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
· Ureteric stenosis: prevalence 2-6%, but rarely lead to hydronephrosis and Allograft dysfunction
· Hemorrhagic cystitis: Rare in renal allograft recipients
· BK nephropathy in the native kidney: described in HSCT recipients, heart and lung transplant recipients, and HIV-infected patients.
BK virus and autoimmune diseases
· BKV viruria can be seen in patients with systemic lupus erythematosus
BK virus and malignancy: thoughts on viral oncogenesis
· The BKV-DNA has been identified in tissue samples of different neoplasms
BK virus and urothelial tumors
· BKV may have a role in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors.
· But BKV-DNA was discovered by PCR in only 5.5% of urothelial tumors
Timing of screening
· KDIGO guidelines recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening tests
· Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
Monitoring of the urine
· Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients
· Presence of decoy cells is strongly suggestive of polyomavirus infection and considered a useful marker of BKV reactivation
· Presence of Haufen bodies, which corresponds to upper levels of BK viremia, had a higher sensitivity and specificity for biopsy-proven BKVN
· molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity
· BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication
Serology: Serum BK-PCR
· BK viremia is noticed only among immunocompromised patients, with an estimated prevalence of 7–30% in the initial 6 months and 5–10% after that among kidney recipients
· Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis
· not all recipients with BK viremia will develop nephritis (BK-PCR has a PPV for BKVN of 50–60% and an NPV of 100%)
Serum antibodies
· BK D+/R− have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients.
Virus culture
· BKV grows slowly in tissue culture, which may take from weeks to months
Kidney biopsy
· allograft biopsy is the gold standard to diagnose BKVN, which should be performed when BKV-PCR load persistently exceeds more than 10 000 copies/ml with or without allograft dysfunction
· BK viral inclusions within tubular epithelium can be identified via the conventional (H&E) and PAS staining
Suggested algorithm for screening
· Screening for BKV should be performed on periodic intervals, starting after 1 month,monthly for 3–6months, and then every 3months for the initial 1–2 years after transplantation.
· American Society of Transplantation guidelines recommended further annual screening till the fifth year after transplant
Differential diagnosis
· BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells.
· Absence of endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease
Treatment strategy of BK virus nephropathy
Treatment of presumptive BK virus nephropathy
· The first treatment of BKV disease is reduction/or modifications in immunosuppressive therapy with or without antiviral medications. Examples:
1) withdrawal of antimetabolite drugs
2) or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide,
3) reducing the dose of calcineurin inhibitor (CNI) by 25–50% or converting tacrolimus to cyclosporine or discontinuing CNI
Treatment of BK virus nephropathy in the setting of allograft dysfunction
· The best renal allograft outcomes in the acute BKV infection were reported when immunosuppression reduction had started early upon detection of BK viremia
Drugs with antiviral activities
Leflunomide
· Leflunomide (antirheumatic disease-modifying drug) metabolite can inhibit BKV replication in vitro and, to a minor degree, the level of virion assembly and release
· leflunomide cannot be combined with MMF or azathioprine; thus, they should be stopped and reduced CNI dosages during use of leflunomide.
· factors that limited its use: (a) higher dosage of the drug is necessary to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity;
(b) trough level is not accessible in all laboratories
(c) the immunosuppressive effectiveness of leflunomide is weak
Cidofovir
· It had in-vitro inhibitory action against polyomaviruses, and exclusively excreted through urine, resulting in high renal tubular cell concentrations
· It is a nephrotoxic drug; it may cause acute kidney injury, renal tubular acidosis, and proteinuria
mTOR inhibitors
· mTORi inhibits BK replication and early gene expression and inhibits the proliferation of BKVspecific T cells and controls the differentiation of memory CD8 T cells
Intravenous immunoglobulin
· IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes, and it has been used for BKVN
Other therapeutic options for treating BK virus nephropathy
· Quinolones have been found beneficial in combination with leflunomide for treating BKVN, with a significant decrease in BK viremia
· Artesunate has anti-viral influence on BK viral proliferation in a primary human renal cell culture.
· statins (pravastatin) were found to reduce the percentage of BKV-infected cells
· Rituximab
Short-term and long-term allograft survival
· the renal allograft survival for recipients with BKVN had improved considerably in the past years.
· The documented acute rejection rates following a reduction in immunosuppression varied from 6 to 12%
BK nephropathy with concurrent acute rejection
· Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.
Post-infection monitoring
· BKV-PCR and renal function with any treatment, mainly post- treatment of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome
· BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression.
Re-transplantation
· Re-transplantation following graft loss owing to BKVN is possible and can be done successfully
Conclusion
· An early diagnosis of BKVN has resulted in significant improvement in allograft outcomes despite a lack of specific treatment.
1. Please summarise this article.
Introduction: Two human polyoma viruses (BK virus and JC virus) were discovered in 1971, with BK virus causing interstitial nephritis and graft failure, while JC virus being responsible for progressive multifocal leukoencephalopathy (PML). BKV infection may present with asymptomatic gradually increasing creatinine within first year of transplant.
BKV and renal transplantation: historical perception: BKV was first detected in 1971 in a Sudanese renal transplant recipient with ureteric stenosis and renal failure, showing large cells with intranuclear inclusions in the urine (decoy cells). Histological changes of BKV infection were described first in 1978.
Polyomaviridae variants: Polyomaviridae subgroup of papovaviruses comprises of BKV, JCV and simian virus 40 (SV40), which are nonenveloped DNA viruses. 12 additional human polyomaviruses have been identified till now.
Epidemiology of BKV: Polyomavirus hominis-1 or BKV is ubiquitous, affecting primarily during early childhood (seroprevalence 60-85%) and then remaining dormant throughout life.
BKV structure: BKV-DNA genome can be divided into 3 parts: Non coding control region (NCCR) is responsible for regulation of virus early and late gene expression; early viral gene region (EVGR) which encodes small T antigen (STA, causes viral replication cell cycle progression and transformation) and large T antigen (LTAg, drives cell into S phase); and late viral gene region (LVGR) which encodes capsid proteins VP1 (leading to receptor binding to host cell, entering the cell and causing dormant or lytic infection), VP2, VP3, and cytoplasmic protein agnoprotein (having regulatory function).
BKV variants: 4 genotypes of BKV are seen. Genotype I (a, b-1, b-2, and c subgroups) is most common (>80%), with 15% prevalence of genotype IV (a-1, a-2, b-1, b-2, c-1, c-2 subgroups) and genotype II and III being rare. Genotype Ic is prevalent in Asia while IVc and Ib-2 are prevalent in USA and Europe.
Immunological response to BKV: BKV replication occurs in immunosuppressed states (pregnancy, diabetes, HIV, cancer, and post-transplant due to intense immunosuppression). Pathogenesis of BKV nephropathy (BKVN) includes (a) defective immune surveillance by host T-cells: Cytotoxic T cells kill BK-infected cells leading to viral leakage into tubular lumen and urine as well as dissemination into renal interstitium further causing tubular cell necrosis and tubular capillary wall damage leading to basement membrane denudation, cast formation, tubulitis and inflammatory interstitial infiltrates with collateral destruction of non-infected tubular cells responsible for graft dysfunction; (b) absence of humoral immunity to BKV: Patients with prior immunity to BKV do not show manifestations of the disease irrespective of the viral load, while those receiving kidney from seropositive donor have increased likelihood of getting BK viremia; (c) alloimmune activation: allo-HLA reactivity and heterologous immunity has a role with lack of HLA matches showing better outcomes in recipients with BKVN; and (d) viral variation in molecular sequences and BKV tropism to renal tubular epithelial cells colocalizing with caeolin-1.
Pathogenesis of BK infection: BKV infection leads to childhood mild respiratory symptoms infecting tonsils and then spreading to the circulation infecting peripheral blood mononuclear cells, disseminating further to kidneys (uroepithelium and tubular cells), leukocytes, lymph nodes, and brain tissue, remaining latent there. Immunosuppression leads to BKV proliferation in interstitium, peritubular capillaritis, and tubular cell lysis with viruria.
Routes of transmission of primary BK virus: These can be respiratory, feco-oral, transplacental, or donor-tissue derived. Urine and blood have also been proposed as mode of transmission.
Clinical manifestations: Although BK viruria is seen in 7% of immunocompetent individuals, it is not associated with clinical disease. Immnucompromised patients present with BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (in renal transplant recipients), hemorrhagic and non-hemorrhagic cystitis in HSCT recipients, and multiorgan involvement in HIV. BK viruria is seen in 30-40% or renal transplant recipeints, progressing to viremia (seen in 10-15%), eventually leading to BKVN (seen in 2-15%). BKV nephritis onset can occur within 6 days to as late as 5 years. Ureteric stenosis is seen in 2-6%, and is treated with percutaneous nephrostomy followed by ureteral dilatation and reduction in immunosuppression. Hemorrhagic cystitis causes bladder cramps, painful voiding, hemturia, and flank pain. 4 grades include grade I (microscopic hematuria), grade II (macroscopic hematuria), grade III (hematuria with clots), and grade IV (hematuria with clots, clot retention and obstructive nephropathy associated renal failure). Treatment involves suprapubic catheter insertion, continuous bladder irrigation, and local cidofovir instillation. Other clinical manifestations include encephalitis, Guillian-Barre syndrome, interstital pneumonitis, atypical retinitis, retinal necrosis, hepatitis, colitis, associated autoimmune disease like SLE, polymyositis, and rheumatoid arthritis.
BK virus and malignancy: BKV-DNA has been seen in different brain tumors, pancreatic islet cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors. Agnoprotein and LTAg inhibit the cell cycle arrest driving the infected cell into a continuous dividing state. LTAg inhibits Rb and p53 tumor suppressor gene products. BKV is associated with urothelial malignancy, especially bladder carcinoma.
Risk factors for BKVN: These include degree of immunosuppression, male, older recipient age, HLA mismatching, increased cold ischemia time, BK serostatus, lyphopenia, acute rejction, and ureteral stent insertion.
Screening and diagnostic tools: KDIGO recommends BKV screening monthly for first 6 months and then at 9-, 12-, 15-, 18-, 21-, and 24-months post-transplant. BK viruria precedes BK viremia by 4 weeks and BKVN by 12 weeks.
Urine monitoring for BKVN is highly sensitive includes urine cytology showing decoy cells (infected tubular epithelial cells with single enlarged basophilic intranuclear inclusion body in an enlarged nucleus, or Haufen (cast-like 3-dimensional icosahedral aggregate of BKV particles and Tomm-Horsfall protein) can be seen under electron microscope. sensitivity and specificity for BKVN with Haufen is 100% and 99% respectively, while it is 100% and 71% respectively with decoy cells. Urinary BKV-PCR has 100% sensitivity and 78% specificity while urinary BKV mRNA has 100% sensitivity with 97% specificity.
Serology: Serum BK-PCR of more than 4 logs copies/ml correlates strongly with BKVN, and has sensitivity of 100% with specificity of 88%. Serial estimation of BK viral load is better to demonstrate BK resolution after immunosuppression reduction, and in cases under consideration for re-transplantation post BKVN-associated graft loss. These tests have high interlaboratory variations, and most of the tests are designed against genotype I, hence may not give accurate results in infections with other genotypes. There is no clinical relevance in assessing serostatus except BK D+/R- being risk factor for BKV disease development. As BKV grows slowly, viral culture is not useful in routine clinical settings.
Kidney biopsy: It remains the gold standard to diagnose BKVN, to be performed if BK viral load is more than 10000 copies/ml insistently with or without graft dysfunction. Macroscopic appearance of streaky fibrosis of medulla with circumscribed cortical scars, and microscopic appearance of sclerosed glomeruli, atrophied tubules, and interstitial fibrosis can be seen. Histological findings can be focal, hence can be missed leading to false-negative biopsies. Different gradings of histopathological changes have been described by Banff working group, University of Maryland, and American Society of transplantation. BK viral inclusions can be seen with H&E and PAS staining. Positive immunohistochemistry (IHC) using SV40 LTAg has nearly 100% specificity for polyomavirus nephropathy.
Suggested algorithm for screening: Hirsch et al advised to screen with urine cytology for decoy cells every 3 months, and if present, get serum BKV-PCR. Kidney biopsy to be done in presence of graft dysfunction. Most transplant centres perform plasma BKV-PCR monthly for 3-6 months, then 3 monthly for 1-2 years, then annual screening till 5 years post-transplant.
Differential diagnosis: Allograft rejection needs to be ruled out in view of diametrically opposite treatment. Presence of urinary and blood BKV aids in diagnosing BKVN in presence of equivocal biopsy findings. Biopsy positive for BKV inclusion bodies and SV40 stain help in diagnosing BKVN, in addition to absence of endotheliitis, extensive tubulitis and C4d deposits. Other causes of graft dysfunction like pre-renal causes, sepsis, post-renal causes also need to be ruled out.
Treatment strategy of BKVN: Reduction in immunosuppression is the only validated treatment option for BKVN. There is no standard strategy for immunosuppression modification. Reduction in immunosuppression (RIS) can lead to acute rejection in 6-12% patients. Strategies used include withdrawal of antimetabolites, or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, or reducing the dose of calcineurin inhibitor (CNI) by 25-50%. Even in setting of graft dysfunction, immunosuppression reduction is important treatment option. Leflunomide in dose of 100 mg daily for 3-5 days followed by 20-40 mg/day has been used as its metabolite A77 1726 inhibits BKV replication but it is associated with hemolysis, thrombocytopenia, hepatitis, and worsening hypertension. Intravenous cidofovir in dose of 0.25 mg/kg every 2-3 week for 10-15 weeks has been used but it may cause acute kidney injury, renal tubular acidosis, proteinuria, and anterior uveitis. mTOR inhibitors restore downregulation of translation and inhibits BKV-specific T cell proliferation. Intravenous immunoglobulin (IVIG) has potent neutralizing antibodies and immunomodulatory properties, helping in BKVN management (with concurrent immunosuppression reduction). Other therapeutic options like quinolones, artesunate, pravastatin and rituximab have also been used.
Short-term and long-term graft survival: Documented acute rejection following RIS occurs in 6-12% cases. Short-term improvements have taken place with RIS, but long-term effects need to be evaluated.
BKVN with concurrent acute rejection: A combination of antirejection therapy, with subsequent RIS should be done in such cases, with management to be tailored individually for each patient.
Post-infection monitoring: Close observation with serum creatinine every 1-2 weeks and plasma BKV-PCR every 2-4 weeks for 8 weeks should be done, followed by monthly BKV-PCR till viremia gets cleared. If viremia persists despite RIS, then consider changing to sirolimus, or adding leflunomide.
Re-transplantation: It can be done successfully post- graft loss due to BKVN. Pre-transplant BK viremia clearance is essential and allograft nephrectomy is not necessary. BKV might recur post-transplant, which could be either due to the previous BK variant, or due to a de-novo infection. The 1- and 3-year graft survival post-retransplant are excellent.
Conclusion: Screening for BKV infection post-transplant is important part of post-transplant surveillance. An early diagnosis with timely RIS has led to improved graft outcomes in BKVN.
2. What is the level of evidence provided by this article?
Level of evidence: Level V – Narrative review
level of evidence V
BK virus and renal transplantation:
Polyomavirus BK shared a high degree of similarity with JCV, which is responsible for progressive multifocal leukoencephalopathy. In kidney transplant recipients, BKV has been linked to severe interstitial nephritis and allograft failure. Human BKV is a member of the Polyoma viridae (PyV) virions, a subgroup of papovaviruses that includes BKV, JCV, and simian virus 40. (SV40).
Polyoma is derived from the words many (poly) and tumors (oma). Several viruses have been recognized.
Epidemiology of BK virus
Primary infection occurs during childhood, and the virus remains dormant in immune-competent people throughout life.
The BKV-DNA genome is divided into three parts and classified into four genotypes.
The immune response to BK viral replication occurs after a state of immune suppression; thus, it has been reported to occur during pregnancy, diabetes, HIV infection, cancer, and the post-transplantation period.
Possible factors that add to the pathogenesis of BKVN might be a combination of
(a) defective immune surveillance by the host T lymphocytes
(b) absence of humoral immunity to BKV
(c) alloimmune activation
(d) viral variation in molecular sequences .
It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Additionally, BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
In the presence of immunosuppressive therapy, the virus gets activated causing tubular cell lysis and viruria. The outcome relies upon the level of damage, inflammation, and fibrosis .
Routes of transmission of primary BK virus: might be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations
BKV does not cause disease in immunocompetent people
In immunocompromised patients, particularly in renal allograft recipients it can cause BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC) .
The virus can dormant in the uroepithelial cells then it shed in to the urine causing viruria , few weeks later in it disseminate to the blood causing viremia responsible for BKVN
· BK viruria generally affects 30–40% of renal transplant recipients.
· whereas 10–15% of recipients develop BK viremia .
Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
· The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years
· Ureteric stenosis 2–6% , if severe causing hydronephrosis will requires a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications .
· Hemorrhagic cystitis rarely observed among renal allograft recipients. The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain . if severe requires hydration and continuous bladder irrigation
· Other rare manifestations include Neurological , Pulmonary , Ophthalmologic, hepatic disease
· BK virus is associated with certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, in non-transplant immune-compromised individuals .
· BKV-DNA has been identified in tissue samples of different neoplasms such as brain tumors , pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
· There are some reports found association between BK virus and urothelial tumors.
Risk factors implicated in the pathogenesis of BKVN
· Degree of immunosuppression,
· Others include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion;
BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year . the incidence of viremia and viruria showed bimodal peaks. 3rd then 12 month post transplant.
KDIGO recommends screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Diagnosis:
· Cytological analysis of urinary smear may reveal characteristic abnormal BK-infected cells, termed as decoy cells. Decoy cells are infected tubular epithelial cells, with an enlarged nucleus that contains a single, large basophilic intranuclear BK inclusion body and looks similar to those cells seen frequently in uroepithelial malignancy . Presence of decoy cells is strongly suggestive of polyomavirus infection and considered a useful marker of BKV reactivation, though it is not a real diagnostic tool for BKVN.
· Urine electron microscopy (EM Haufen): in contrast to decoy cells, Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, forming cast-like three-dimensional aggregates, which can be noticed in a urinary smear of kidney recipients using negative-staining electron microscopy . it requires further validation.
· Quantitative measurements of urinary BK virus-viral loads using urinary BKV-PCR .
· BK virus mRNA levels in urine viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication
1. BK viral loads (PCR) . Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis is the preferred screening technique at most transplant institutions
2. A serial estimate of viremia is the best technique to date to demonstrate resolution of BK activity following reduction of immunosuppression.
3. Furthermore, serial determinations of viremia are required to follow-up patients who lost their allograft because of BKVN and considered for re-transplantation
Kidney biopsy
allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction .
Positive IHC using specific antibodies against BKV or the cross-reacting SV40 LTAg has a specificity of nearly100% for polyomavirus nephropathy;
AST guidelines recommended further annual screening till the fifth year after transplant; nevertheless, generally screening beyond 2 years is not recommended in most centers unless allograft dysfunction is present.
Differential diagnosis
The distinction of BKVN from acute rejection is challenging as the histological appearance is often similar; therefore, it should be aided by analysis of blood or urine PCR.
Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN. Nevertheless, BKVN may exist concurrently with acute rejection .
BKVN can be distinguished from acute rejection by
1. The presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells.
2. Absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease
3. IHC staining of renal tissues or urinary sediments anti-HLA DR, which has been related to acute rejection
4. Higher quantity of CD20+ cells in the tissue infiltrates has been associated with BKVN as opposed to acute rejection.
The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of concurrent acute rejection
Treatment strategy of BK virus nephropathy
1. Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; There is no standard strategy for modifying immunosuppressant’s therapy; such as withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance .
Such approaches can include withdrawal of antimetabolite drugs(MMF) or change to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI .
Treatment of BK virus nephropathy in the setting of allograft dysfunction Favorable renal allograft However, allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy .
2. Cidofovir, brincidofovir .
3. The mTOR inhibitors (sirolimus and everolimus) are thought to produce their inhibitory effect on BKV replication hence, it improves the immune reaction following BKV infection .
Similar to other therapeutic options, the administration of mTOR inhibitors was concomitantly used with lowering immunosuppression, generating contradictory results.
4. Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN
The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection;
Other therapeutic options for treating BK virus nephropathy
(1) Quinolones
(2) artesunate (an antimalarial drug)
(3) statins (pravastatin)
(4) Rituximab with cidofovir had no graft failure during follow-up of 17 months,
Short-term and long-term allograft survival
The proposed current management have revealed substantial short-term improvements, however it influence on long term outcome such as late acute and chronic rejections need to be further evaluated.
The documented acute rejection rates following a reduction in immunosuppression varied from 6 to 12%.
BK nephropathy with concurrent acute rejection
Most of the biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in 10–30% of the cases .
Though some reported either clinical improvement, steady or worse allograft outcomes, following steroid pulses .
It is recommended once BKVN is diagnosed in concurrence with acute rejection, an initial decrease in immunosuppression without steroid pulses . Upon clearance of viremia and BKVN, the advantage of up-titrating immunosuppression to avoid further late acute rejection or chronic rejection remains obscure
Post-infection monitoring
Close observation of
· BKV-PCR and
· Renal function
The most common approach is to follow serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks after immunosuppressant reduction. Subsequently, it should be done on a monthly bases until clearance of BK viremia and stabilization of renal function achieved.
Reports showed BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression.
If viremia persists despite reducing the maintenance therapy, then switching to sirolimus, or adding leflunomide is advisable.
Retransplantation
Retransplantation post BKVN can be successful. Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression . Allograft nephrectomy is not necessary before retransplantation; however, elimination of infection prior re transplantant is most sensible but there is no evidence to support this.
Recurring BKV might reflect a previous BK variant or a new infection.
Introduction
● BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
● It is often occurring within the first year after transplantation.
● It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection
● Decoy cells are Abundant large cells with intranuclear inclusions present in the urine, resembling malignant cells
● Can bear heating up to 50°C for 30 min
● Double-stranded DNA of ∼5000
● New group members were termed based on the site of discoveey or the diseases they might cause, or an order of discovery
Epidemiology of BK virus
☆ BKV is Polyomavirus hominis-1
☆ Primary infection predominantly takes place during early childhood, then stays dormant throughout life in immune-competent people
☆ 60–85% of the general population is seropositive for BKV
BK virus structure
● The noncoding control region (NCCR) regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell.
(1) The early viral gene region encodes two proteins called small T antigen (STA) and (LTAg, large tumor antigen) which drives the cell into S phase, whereas STA is involved in viral replication, cell cycle progression, and transformation.
(2) The late viral gene region (LVGR): encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus.
* Release around virions through cell lysis.
* Encodes a small cytoplasmic protein called agnoprotein, which assistance in regulating viral replication and interrupt host cell processes.
(3) The capsid protein VP1 in the LVGR is
* Responsible for receptor binding to the host cells, facilitating virus entry into the cell.
* It is highly immunogenic and Once it gets inside the cell, the virus travels to the nucleus and establishes a dormant or lytic infection
BK virus variants
☆ Four genotypes/subtypes
* Genotype I is the predominant > 80% and has 4 subgroups
* Genotype IV found in 15% and has six subgroups
* Genotypes II and III are rare
☆ Variant viruses resulted due to deletion and duplication in the NCCR sequences during activation process
Immunological response to BK virus
● BK viral replication follows a state of immune suppression so it occurs in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period
● BKV begins early in the posttransplant period and can follow antirejection therapy
● The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN)
● Factors that participate pathogenesis of BKVN :
* Defective host T- lymphocytes
* Absence of humoral immunity to BKV
* Alloimmune activation
* Viral variation in molecular sequences
● The role of cell-mediated immunity
☆ CD4+ and CD8+ T cells are the main components that control the BKV and play a role in BK clearance.
☆ LTAg and VP1 gene products contain epitopes responsible for CD4+ and CD8+ cells identification
☆ Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA
☆ Lysis of an infected cell lead to viral leakage into the tubular and interstitium causing necrosis, casts formation, tubulitis and interstitial infiltrate
☆ Continued intragraft inflammation, tubular injury and up-regulation of profibrotic mediators ends with allograft dysfunction and loss
● The role of antibody-mediated immunity was also validated in BKV infection as patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels
● Role of alloimmune activation
☆ Higher degree of HLA mismatches increases incidences of BKVN, which hypothesizes the role of alloimmune activation.
● The role of other factors
☆ BKV tropism to the renal tubular epithelial cells
● The pathogenesis of BKV disease is related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium.
Pathogenesis of BK infection
● Primary infection is usually subclinical or a mild respiratory symptom in childhood
● BKV goes through infected tonsils then infect mononuclear cell that disseminated to secondary places including kidneys then virus stays dormant in the uroepithelium and renal tubular cells with intermittent reactivation
● Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses
Routes of transmission of primary BK virus
☆ Respiratory
☆ Fecal-oral
☆ Transplacental
☆ Donor tissues
☆ Sexual transmission
☆ Other as urine and blood
Clinical manifestations
☆ BKV does not cause disease in immunocompetent people
☆ In immunocompromised patients BKV has been correlated with BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis
☆ In HIV-infected patients, BKV disseminate leading to severe viremia with multiorgan involvement that leads to death
☆ Virus proliferate uroepithelial cells followed viruria which progress to viremia then BKVN
☆ BK viruria affects 30–40% of KTRs but
viremia develop in 10–15% and in 2 -15% progress to BKVN
BK virus-associated nephropathy
☆ Nephritis occurs early (6 days after KTx) or late (5 years after Tx)
☆ Ureteric stenosis secondary to ureteric stricture seen in 2-6% and treatment should involve a percutaneous nephrostomy and percutaneous ureteral dilatation, with concurrent RIs
☆ Hemorrhagic cystitis
* classically noticed in HSCT recipients and rarely in renal allograft recipients
* Four degrees of disease severity:
grade I: microscopic hematuria
grade II: macroscopic hematuria
grade III: hematuria with clots
grade IV: hematuria with clots, clot retention, and obstructive renal failure
* Management involves intravenous hydration. In Severe cases insertion of a supra-pubic catheter with continuous bladder irrigation with locally cidofovir and remission needs 2 to 7 weeks
BK nephropathy in the native kidney
● Occurs in HSCT recipients, heart and lung transplant recipient, and HIV-infected patients.
● Patients present with AKI (characteristic histological findings on kidney biopsy)
without significant proteinuria
● Other manifestations include:
* Neurological manifestations:
meningoencephalitis, encephalitis,Guillain–Barre syndrome, and vasculopathy.
* Pulmonary diseases:
reactivated acute respiratory infection, severe interstitial pneumonitis
* Ophthalmologic manifestations:
bilateral atypical retinitis
* Hepatic disease:
hepatitis, elevations of liver enzymes
BK virus and autoimmune diseases
● There is a relationship between BKV and certain autoimmune diseases, mainly SLE, polymyositis, and RA in nontransplant immunecompromised individuals
● BKV infection can induce antidouble-stranded DNA and histone antibodies
BK virus and malignancy:
● BKV has an oncogenic property owing to expression (LTAg) and Agnoprotein which can drive the cell into a neoplastic state by binding to suppressor gene products
● Tumor cells are likely more vulnerable to BKV than normal urothelium, so positivity of BKV is a result instead of a reason for neoplastic transformation
BK virus and urothelial tumors
● BKV-DNA was isolated in these tumors particularly bladder carcinoma
● High level of BKV-LTAg was noted in the nucleus of almost every tumor cell For both the primary tumor and its metastasis
Risk factors for BKVN:
☆ Degree of immunosuppression.
☆ Male sex
☆ Older recipient age
☆ Previous rejection episodes
☆ Degree of HLA mismatching
☆ Prolonged cold ischemia
☆ BK serostatus
☆ Certain ethnic groups
☆ Lower total lymphocyte percentage
☆ Ureteral stent insertion
Screening and diagnostic tools
● BKV screening to start at first month after transplant, then monthly for 3-6 months, and then every 3 months 12-24 months then annually for 2-5 years
● Viral replication starts by viruria then viremia followed by nephropathy.
● Viuria precedes BK viremia by ∼4 weeks, and Histological changes of BKVN are observed 12 weeks after BK viruria
● Screening for active BKV replication includes:
☆ Decoy cells
* Sensitivity 25% and Specificity 84%
* Widely available, useful marker in identification of BKV infection
* It is a poor diagnostic tool in predicting BKVN.
* Not useful for monitoring decline in viral load
☆ Haufen
* Sensitivity 100% and Specificity 99%
* Highly predictive for BKVN
* Not practical for routine practice as it
requires electron microscopy with interpretation from a pathologist
* It is absent in recipients with a lower BK viremia
☆ Urinary BK-PCR
* Sensitivity 100% and Specificity 78%
* Measurement variations between laboratories limit its use
☆ Urinary BK-mRNA
* Sensitivity 100% and Specificity 97%
* Still under assessment and requires further validation
* Raised mRNA levels >11 mRNA copies/μg total RNA) are usually present in recipients with acute cellular rejections.
☆ Plasma BK-PCR
* Sensitivity 100% and Specificity 88%
* Broadly available but costly.
* Has good sensitivity and specificity but
low PPV for BKVN
● Not all recipients with BK viremia will
develop nephritis that it depend on :
* Viral load > 10^4
* Genotype as sesitivity differs according to genotype
● Virus culture
☆ BKV can be isolated from a urine before antibody titers rise
☆ It needs weeks to months So rarely used
● Kidney biopsy
☆ It is the gold standard to diagnose BKVN
☆ It should be performed when BKV-PCR exceeds >10^4 without allograft dysfunction
☆ Positive of BK viral inclusions within tubular epithelium SV40 LTAg has a specificity of nearly100% for polyomavirus
nephropathy
☆ It can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result
☆ If the initial biopsy did not confirm BKVN, then pre-emptive treatment or a repeat biopsy must be considered.
☆ BK-PCR of allograft biopsy tissue can
identify a latent virus, even in asymptomatic recipients
Differential diagnosis
● Allograft rejection
☆ BKVN has presence of BKV inclusion bodies and immunohistology SV40
☆ Acute cellular rejection : endotheliitis and extensive tubulitis and absence of C4d
☆ Positive C4d stainingreported in some BKV cases and is linked with aggressive disease
☆ IHC staining of renal tissues or urinary sediments with anti-HLA DR
☆ BKVN and acute rejection can present concurrently.
● Any disease associated with early and late renal allograft dysfunction.
Treatment strategy of BK virus nephropathy
● Reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
● Leflunomide
☆ Pyrimidine depletion and tyrosine kinase inhibition
☆ Teriflunomide is a metabolite of leflunomide can inhibit BKV replication
☆ Orally (a loading dose of 100 mg daily for 3–5 days then 20–40 mg/day
☆ MMF or azathioprine should withdrawal and CNi should reduce
☆ Limitaitions :
* Higher dosage is necessary
* Liver toxicity
* Monitoring level is not accessible in all laboratories
* AEs (Hemolysis, aplastic anemia, TMA, hepatitis, thrombocytopenia, HTN)
● Cidofovir
☆ Inhibits viral replication; mechanism unknown
☆ Slow intravenous infusion (over 2 h) at an initial dose of 0.25 mg/kg/dose every
2–3 weeks for a period of 10–15 weeks.
☆ Cidofovir has AEs as:
* Nephrotoxicity: AKI, RTA, and proteinuria.
* Severe anterior uveitis
● mTOR inhibitors :
☆ Inhibits proliferation of BKV-specific T-cell and controls the differentiation of memory CD8 T cells
☆ AEs include: Hyperlipidemia, bone marrow toxicity, mucositis and oral ulcerations, and lymphedema
● Intravenous immunoglobulin
☆ Contain neutralizing antibodies against BKV and are immunomodulatory
☆ Dosage 2–3.5 g/kg over 2–5 days
☆ May lead to paradoxical increase in viral load
● Fluoroquinolones
☆ Inhibit BKV replication in vitro and inhibit the large T antigen helicase activity
☆ AEs: gastritis, C difficile, hepatoxicity, neurological adverse effects, and altered mental status
☆ It has been found beneficial in combination with leflunomide
● Artesunate (an antimalarial drug)
☆ Inhibit BK viral proliferation in a primary
human renal cell culture
☆ AEs:Anorexia, dizziness, nausea,diarrhea
● Statins
☆ Prevent caveolae-mediated endocytosis
☆ AEs: muscle events , hepatic dysfunction
● Rituximab
☆ As an adjuvant therapy with cidofovir to improve graft survival
Short-term and long-term allograft survival
● BKVN caused allograft damage in 30-60% of cases.
● Graft survival had improved recently
● Acute rejection following RI 6 to 12%
● Improvement is due to:
☆ Early therapeutic intervention
☆ Routine surveillance biopsies
BK nephropathy with concurrent acute rejection
● Management should be tailored for each patient individually
● Steroid pulses combind with RI
● Cidofovir combinde with Rituximab
Retransplantation
● It is possible and can be successfully
● The 1- and 3-year graft survival was excellent at 98.5 and 93.6%, respectively
● Allograft nephrectomy is not necessary before retransplantation
● BKV viruria, viremia, and BKVN can recur and cause allograft loss
● Recurring BKV might be a previous BK variant or a (de-novo BKV) acquired
● Level : 5
IV. BK virus infection in renal transplant recipients: an overview
Summarise this article
Introduction
– BK infection is an early complication of kidney transplantation
– mostly occurs within the first year after transplantation
– the increase in BKV incidence is as a consequence of the use of more potent immunosuppressive agents
– untreated BKV infection causes kidney graft dysfunction and subsequent graft loss
– use of screening protocols help in early recognition of asymptomatic BKV infection resulting in better graft outcomes
Pathogenesis
– BKV replication occurs in states of immunosuppression like post-transplantation, HIV, cancer, pregnancy, diabetes
– BKV replication starts early in the post-transplant period and can also occur after antirejection treatment due to the intense immunosuppression
– the immune system plays an important role in controlling BKV replication and resolution of BKVN
– other factors that play a role in the pathogenesis of BKVN include:
·absence of humoral immunity against BKV,
·defective immune surveillance by the host T lymphocytes
·alloimmune activation
·viral variation in molecular sequences
·BKV tropism in the renal tubular epithelial cells
– primary BKV infection is mostly subclinical manifesting as a mild respiratory syndrome in childhood
– BKV gets into circulation through infected tonsils then infects peripheral blood mononuclear cells which get disseminated to secondary places like the kidneys
– following resolution of the primary infection, BKV remains dormant in the uroepithelium and renal tubular cells for life with intermittent reactivation which manifests as asymptomatic viruria
– BKV can also remain latent in lymph nodes, brain tissue, leucocytes
– in the presence of immunosuppressive drugs, BKV gets activated and starts proliferating in within the interstitium then crosses into the peritubular capillaries causing tubular cell lysis and viruria
– the outcome depends on level of damage, inflammation and fibrosis
– tissue damage is a result of direct viral cytolytic effects and secondary inflammatory responses
Routes of transmission of primary BKV
– include respiratory route, GI transmission (fecal-oral route), vertical transmission (transplacental), donor-derived infection, through blood and urine since BKV has been detected in peripheral blood leucocytes and in urine samples
Clinical manifestations
– presents as an asymptomatic gradual increase in serum creatinine with interstitial nephritis which mimics acute rejection posing a diagnostic and therapeutic treatment dilemma
– clinical features that have been described include: BKVN, ureteric stenosis (2-6%), hemorrhagic cystitis
– BKV infection starts as the virus proliferates in the uroepithelial cells followed by viral detachment in the urine (viruria) which progresses in a few weeks to blood (viremia) and eventually to BKVN
– 30-40% of KTRs have BKV viruria while 10-15% develop viremia and another 2-15% develop BKVN
– BKVN:
·begins with asymptomatic hematuria or viruria and culminates in extensive irreversible injury and graft failure
·the nephritis can occur as early as 6 days post- transplant or as late as 5 years
– ureteric stenosis:
·graft dysfunction due to ureteric stricture leading to hydronephrosis is not common
·treatment involves reduction of immunosuppressive medication, percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation
– hemorrhagic cystitis (HC):
·BKV associate HC and non-HC is common in HSCT recipients, rare among KTRs
·patients present with hematuria, dysuria, bladder cramps, flank pains
·4 grades of disease severity have been described: Grade I: microscopic hematuria; Grade II: macroscopic hematuria; Grade III: hematuria with clots; Grade IV: hematuria with clots, clot retention and kidney failure secondary to obstructive nephropathy
– Management: IV hydration, for severe cases, insert a suprapubic catheter for continuous bladder irrigation, cidofovir (given locally through the bladder hence reducing cumulative drug nephrotoxicity)
– other reported manifestations include: nonspecific URTI, interstitial pneumonitis, encephalitis, meningoencephalitis, GBS, atypical retinitis, colitis, hepatitis
– there is a relationship between BKV and autoimmune diseases like SLE, RA, polymyositis
– BKV-DNA has been identified in tissue samples of different neoplasms including brain, pancreatic islet cell tumors, KS, prostate cancer, urothelial tumors
Risk factors in the pathogenesis of BKVN
– overall degree of immunosuppression, previous rejection episodes, degree of HLA mismatch, prolonged CIT, BKV serostatus, ureteral stent insertion, lower total lymphocyte count, male sex, older recipient age, certain ethnic groups
Screening and diagnostic tools
– screening allows for early detection of viruria and viremia enabling the clinician to act before graft dysfunction appears
– BKVN is an early complication of kidney transplantation with most cases occurring in the 1st year posttransplant
– the incidence of viruria na viremia has bimodal peaks, the 1st one being in the 3rd month and the 2nd one in the 12th month
– BKV screening should start in the 1st month posttransplant, then monthly for the first 6 months and then every 3 months for up to 2 years
– BKV replication starts early after transplant and progresses to viruria, viremia and eventually BKVN
– viruria precedes viremia by ~4weeks, histological changes of BKVN are observed 12 weeks after BK viruria
– screening for active BKV replication involves identification of viral DNA-PCR in blood and urine
Monitoring of urine
– this involves: –
– decoy cells (BKV infected tubular epithelial cells with intranuclear BK inclusion bodies): are strongly suggestive of polyomavirus infection, it is a useful indicator of BKV reactivation although it is not a real diagnostic tool for BKVN, sensitivity 100%, specificity 71%, PPV 29% and NPV 100% when matched with graft-biopsy samples as a diagnostic standard
– urine electron microscopy (EM haufen): presence of haufen bodies (BKV virion aggregates) corresponds to high levels of BKV viremia, sensitivity and specificity for BKVN is 100%; however, this method cannot be used routinely due to the expense and inaccessibility to electron microscopy and the need for a pathologist to interpret the findings
Serology: – Serum BK-PCR and serum antibodies
– has a sensitivity 100%, specificity 88%, PPV 50-60%, NPV 88% for the development of BKVN than BK viruria therefore it is the preferred screening tool
– a quantitative BKV-PCR of >10,000 copies/ml correlates strongly with BKVN findings on graft biopsy
– serial BKV-PCR viral load helps monitor resolution of BK activity following immunosuppression reduction as well as in patients considering re-transplantation after graft loss
– serum BK viral load measurements have significant interlaboratory variations and lack international standardization
– the relevance of assessing BK antibodies serostatus pre- and post- transplant on routine basis remains uncertain
– it has no clinical significance in diagnosing acute BKV infection affecting KTRs
– BK D+/ R- serostatus is a risk factor for the development of clinically significant BKV disease in KTRs
Virus culture
– BKV can be isolated from a urine sample even before the antibody titers rise
– BKV grows slowly in tissue culture and may take weeks to months hence viral culture is rarely used outside research settings
Kidney biopsy
– presumptive BKVN refers to patients with significant viruria (indicating viral proliferation in the urinary tract) and persistent viremia of >10,000copies/ml for more than 3 weeks
– graft biopsy is the gold standard diagnostic tool for BKVN
– should be done in KTRs with BKV viremia of >10,000copies/ml with or without graft dysfunction
– immunohistochemistry (IHC) uses specific antibodies against BKV or the cross-reacting SV40 Ag
– positive IHC has a specificity of ~100% for polyomavirus nephropathy but it does not differentiate between BKV and JCV although JCV-related nephropathy is extremely rare
– persistent BKVN results in renal parenchymal scarring with advanced IFTA
– 2 biopsy cores preferably including medulla should be obtained since the biopsy findings can be focal or isolated in the medulla, and this can be missed on 1/3rd of biopsies giving a false negative report
– false negative biopsies can also occur at the early stages of the disease, in such cases consider pre-emptive treatment or a repeat biopsy
– BK-PCR of graft biopsy is not applicable since it can identify latent BKV even in asymptomatic KTRS
Screening algorithm for BKV post-kidney transplantation
– screen for BKV using plasma BKV PCR:
· routinely, monthly for 3-6months then every 3months for 12-24months then annually for 2-5years
· any time there is an unexplained increase in serum creatinine
· following treatment of acute rejection
– in any of the 3 scenarios, if plasma BKV-PCR is <10,000copies/ml consider monthly monitoring as well as reduction in immunosuppression
– however, if plasma BKV-PCR is >10,000copies/ml consider a graft biopsy
Differential diagnosis
· graft rejection:
– histologically similar to BKVN hence the need for blood or urine PCR to differentiate the two, nevertheless BKVN can co-exist with acute rejection
– presence of BKV inclusion bodies and a positive IHV for SV40 favour a diagnosis of BKVAN
– a positive C4d staining is linked with a more aggressive BKV disease
– presence of endarteritis, glomerulitis, fibrinoid vascular necrosis and C4d deposits along peritubular capillaries is conclusive of acute rejection
· any disease associated with early (1-12 weeks post-transplant) and late (>3months post-transplant) graft dysfunction
Treatment strategy for BKVN
– the aim of treatment is to eradicate the virus while preserving graft function
– BKV viremia and BKVN indicate over-immunosuppression hence reduction of immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response
– rapid reduction in BKV viral load is associated with a steady or improved graft function
– however, reduction in immunosuppression ought to be balanced against the risk of triggering an acute or chronic rejection
Treatment of presumptive BKVN
– 1st step is to reduce or modify the immunosuppressive therapy ± antiviral drugs
– there is no standard strategy for this but some approaches have been described e.g.,
· withdrawal of antimetabolite drugs e.g., MMF – this is the most usual strategy
· change from MMF to azathioprine, sirolimus, or leflunomide
· reducing the CNI dose by 25–50% (to achieve a target trough level of tacrolimus 3-4ng/ml and cyclosporine 50-100 ng/ml, or even less) or
· converting tacrolimus to cyclosporine or
· discontinuing CNI
– tacrolimus and cyclosporine have been shown to inhibit anti-BKV-specific T-cell reaction
– MMF may limit the proinflammatory and profibrotic cytokines
Treatment of BKVN in the setting of graft dysfunction
– in advanced disease, reduction of immunosuppression is less effective, and it is not clear if modification of the immunosuppressive medications will alter the prognosis
– graft function may stabilize following modification of immunosuppressive or may still advance to end-stage disease
– reduction of immunosuppression in the setting of graft dysfunction may result in clearance of viremia, raise the BKV-specific IgG AB titers, increase BKV specific cellular immunity with steadiness of the graft function
Drugs with antiviral activities
Leflunomide
– has antiproliferative and anti-inflammatory properties since it inhibits pyrimidine synthesis
– inhibits BKV replication in vitro, level of virion assembly and release
– should not be combined with other antiproliferative agents like MMF, azathioprine
– adverse effects: aplastic anaemia, hemolysis, thrombocytopenia, TMA, hepatitis, worsening hypertension
Cidofovir
– a viral DNA polymerase inhibitor used in management of other viral infections e.g., CMV
– has inhibitory activity against polyomaviruses, given as a slow IV infusion
– nephrotoxic hence requires vigorous IV prehydration and adjust dose depending on kidney function
– can cause AKI, proteinuria, renal tubular acidosis, severe anterior uveitis
Brincidofovir
– a prodrug of cidofovir, given orally, not nephrotoxic but still in the experimental stage
mTOR inhibitors
– inhibit BKV replication and early gene expression, inhibits BKV-specific T-cell proliferation
– requires conversion of CNI to mTORi and concomitant withdrawal of MPA, this results in BKV viral load reduction and improvement in eGFR
– adverse effects: hyperlipidemia, mucositis, oral ulcers, lymphedema, bone marrow toxicity
Intravenous immunoglobulin (IVIG)
– has immunomodulatory effects, has potent neutralizing antibodies hence is able to neutralize all major BKV genotypes
– IVIG plus concurrent reduction in immunosuppression has successfully managed BKVN with concurrent acute rejection
– can cause paradoxical increase in viral load
Other therapeutic options for treating BKVN
Quinolones
– inhibit BKV replication in vitro, thought to be beneficial when combined with leflunomide
Artesunate
– associated with a decrease in BKV replication in a dose-dependent way
Statins (pravastatin)
– reduce the percentage of BKV-infected cells
Rituximab
– prospective RCTs are required to validate the benefit of rituximab in BKVN
Short-term and long-term allograft survival
– previously, lack of awareness, misdiagnosis, delayed diagnosis, use of escalated immunosuppression for possible acute rejection management resulted in permanent graft damage
– this has improved considerably due to early therapeutic intervention
BKVN with concurrent acute rejection
– management remains debatable, reduction in immunosuppression can precipitate rejection
– steroid pulses can result in either clinical improvement, steady or worse graft outcomes
– different studies have used different approaches hence the need to individualise the management
– once BKVN is diagnosed concurrently with acute rejection, a combination of antirejection therapy with a subsequent reduction in immunosuppression should be attempted
– the benefit of up-titrating immunosuppression upon clearance of viremia and BKVN to avoid further late acute rejection or chronic rejection remains largely unknown
Post-infection monitoring
– monitoring of BKV-PCR and kidney function following management of acute rejection of reduction of immunosuppression is crucial to improve graft outcome
– for patients who have had a reduction in immunosuppression due to BKVAN, monitor serum creatinine every 1-2weeks and BK-PCR level every 2-4weeks for 8weeks then thereafter monthly until BK viremia clears (or falls below the threshold values) and the kidney function stabilizes
– BKV viremia clears in 7-20weeks
– if BKV viremia persists despite reduction in immunosuppression consider reducing the immunosuppression further, or switching to sirolimus or adding leflunomide
– failure to clear BKV leads to worse graft outcomes
Re-transplantation
– re-transplantation after graft loss secondary to BKVN is possible and is associated with successful outcomes
– pretransplant clearance of BKV viremia following reduction of immunosuppression is important
– graft nephrectomy is not necessary before re-transplantation unless there is active viral replication in which case it would be prudent to remove the infected graft before re-transplanting, however there is no evidence to support this approach
– recurrent BKV may be due to a previous BK variant or a new infection (de novo BKV) acquired due to the long period post-transplant
Conclusion
– early diagnosis of BKVN via molecular techniques and tissue analysis, has resulted in improvement of the graft outcomes despite the lack of specific treatment
Level of evidence provided by this article
– Level V
Introduction
· BKV and JCV were discovered in 1971, but their negative effect was poorly understood until three decades later when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
· It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection.
BK virus and renal transplantation: historical perception
· Gardner et al. were the first to detect BK polyomavirus (BKV) in 1971, and Mackenzie et al. in 1978 defined histological changes consistent with polyomavirus nephritis.
· Since then, numerous reports have been reported, and BKV has been identified as a cause of severe interstitial nephritis and allograft failure in kidney transplant recipients.
Polyomaviridae variants
· Polyomaviridae (PyV) virions are small, nonenveloped DNA viruses with icosahedral capsids present in the urine, named ‘decoy cells’ for their resemblance to malignant cells.
Epidemiology of BK virus
· BKV is a widespread virus that infects most humans, with up to 60% of the general population being seropositive.
· Variations in prevalence can be explained by age, sample size, and antibody threshold.
BK virus structure
· The BKV-DNA genome is divided into three parts: NCCR, EVGR, and LVGR, with VP1 being the main capsid protein responsible for receptor binding to host cells.
BK virus variants
· Genotype I is the predominant subtype of BKV, with genotype IV being the second most frequent.
· Phylogenetic analysis has identified four subgroups of subtype I (I/a, I/b-1, I/b-2, and I/c) and six subgroups of subtype IV (IV/a-1, IV/a-2, IV/b-1, IV/b-2, IV/c-1, and IV/c-2).
· Subgroup IV/c-2 is predominant among Americans and Europeans, while other subgroups are more common in Asian populations.
Immunological response to BK virus
· BK viral replication follows a state of immunosuppression, and the immune system plays an essential role in controlling BKV replication and resolution of BKVN.
The role of cell-mediated immunity
· CD4+ and CD8+ T cells are key components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
· Epitopes in the viral genome identify CD4+ and CD8+ cells. Cytotoxic T cells (CTL) kill BK-infected cells after the recognition of damaged segments of viral DNA.
· Without appropriate immunological regulation, progressive lytic infection arises and results in large nuclear and peri-nuclear viral inclusion in the tubular cells.
The role of humoral immunity
· Humoral immunity and antibody-mediated immunity play a role in BKV infection, with kidney recipients from a seropositive donor more likely to develop viremia.
Role of alloimmune activation
· Allo-HLA-reactivity and heterologous immunity are important factors in the development of BKVN, allowing BKV to escape immunological surveillance.
· CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been linked to an increase in the incidence of BKVN, suggesting alloimmune activation.
The role of other factors
· The pathogenesis of BKVN is likely related to a combination of cellular and humoral immune deficiencies, alloimmune activation, and BKV’s tropism to the renal tubular epithelium.
Pathogenesis of BK infection
· BKV primary infection is usually subclinical or has mild respiratory symptoms in childhood, and can remain dormant in the uroepithelium and renal tubular cells for life.
· In the presence of immunosuppressive therapy, the virus activates and proliferates, resulting in tissue damage, inflammation, and fibrosis.
Routes of transmission of primary BK virus
· The primary route of transmission of BKV is respiratory, as evidenced by the presence of BKV in the respiratory tract and tonsils of children.
· Gastrointestinal transmission is also proposed, as evidenced by 45% of stool samples and rectal swabs testing positive for polyomavirus DNA.
· Vertical transmission, (crossing the placenta), Sexual transmission, and Donor-derived infection are also possible.
Clinical manifestations
· BKV does not cause disease in immunocompetent people, but in immunocompromised patients, it can cause BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
BK virus and renal disease
· BK polyomavirus-associated nephropathy (BKVN)/PyVAN affects 30-40% of renal transplant recipients, with an estimated incidence of 2-15% due to different immunosuppressive regimens and screening strategies.
BK virus-associated nephropathy
· BKV-associated nephropathy causes viruria, hematuria, and allograft failure.
Ureteric stenosis
· The prevalence of ureteric stenosis is 2–6%.
· Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen
· Treatment of ureteric stenosis involves nephrostomy and dilatation.
Neurological manifestations, Pulmonary diseases, and Ophthalmologic manifestations: are less apparent
Hemorrhagic cystitis
· BKV-associated HC is rare in renal transplant, presenting with bladder cramps, painful voiding, hematuria, and/or flank pain.
· Management involves vigorous intravenous hydration and Cidofovir given locally through bladder installation for remission.
BK nephropathy in the native kidney
· BKVN has been reported in transplant recipients and HIV-infected patients.
BK virus and hepatic disease
· BKV and hepatitis associated with a bone marrow transplant.
BK virus and autoimmune diseases
· BKV has been linked to certain autoimmune diseases, such as systemic lupus erythematosus, polymyositis, and rheumatoid arthritis.
· Taguchi and colleagues reported the isolation of BKV from a urine sample of two patients with lupus, and there is a prevalence of 16% in patients with systemic lupus erythematosus.
BK virus and malignancy: thoughts on viral oncogenesis
· BKV-DNA has been identified in tissue samples of neoplasms, including brain tumors, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
· BKV-LTAg can bind and inhibit cell cycle regulators, leading to urothelial malignancies in experimental mice.
· BKV has variable DNA locations inside cells, but tumor cells are more vulnerable to BKV than normal urothelium.
BK virus and urothelial tumors
· BKV may have a role in the pathogenesis of urothelial malignancy, particularly bladder carcinoma, as evidenced by high levels of BKV-LTAg, p53, p16, and Ki-67 in tumor cells.
Risk factors
· Risk factors for BKVN include immunosuppression, male sex, older recipient age, previous rejection episodes, HLA mismatching, cold ischemia, BK serostatus, ethnic groups, lower lymphocyte percentage, and ureteral stent insertion.
Screening and diagnostic tools
· Early identification of viruria/viremia to prevent graft dysfunction.
Timing of screening
· BKVN is an early complication of a kidney transplant, with bimodal peaks in the third and ninth months.
· BKV screening should start at the first month, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening tests
· Viral replication in the urine precedes BK viremia and histological changes of BKVN are observed 12 weeks after BK viruria.
Monitoring of the urine
· Detection of BKV-infected epithelial cells or viral load.
Urine cytology
· Decoy cells are useful markers of BKV reactivation, but sensitivity varies.
Urine electron microscopy (EM Haufen):
· Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, which has a higher sensitivity and specificity for biopsy-proven BKVN than decoy cells.
· It requires further validation and cannot be applied for routine clinical practice.
Quantitative measurements of urinary BK virus-viral loads
· Urinary BKV-PCR has 100% sensitivity and 78% specificity, but difficulty standardizing for diagnosis.
BK virus mRNA levels in urine
· BKV-VP1 mRNA derivative from urinary cells can be used as a biomarker to detect active viral replication, but further validation is needed.
Serology
Serum BK-PCR
· BK viremia can be detected with real-time PCR and quantitative BKV-DNA in plasma, but not all recipients will develop nephritis.
Serum antibodies
· Positive donor BKV serostatus and negative recipient serostatus (BK D+/R) are risk factors for clinically significant BK disease in kidney allograft recipients.
Virus culture
· BKV can be isolated from urine samples but grows slowly in tissue culture.
Kidney biopsy
· The Banff classification system was shown to correlate with clinical outcomes in 178 patients with biopsy-proven PVN.
· Plasma BK-PCR has high sensitivity and specificity, but allograft biopsy remains the gold standard.
· Histologically, streaky fibrosis of the medulla with cortical scars can be seen.
Suggested algorithm for screening
· BKV screening in renal transplant recipients should be performed at periodic intervals with plasma BK-PCR and allograft biopsy in individuals with persistent high viral loads.
Differential diagnosis
Allograft rejection
· BKVN and acute rejection can be distinguished by BKV inclusion bodies, positive immunoperoxidase staining, anti-HLA DR, CD20+ cells, and increased expression of genes.
Another differential diagnosis
· Early and late renal allograft dysfunction are differential diagnoses.
Treatment strategy of BK virus nephropathy
· Reduced immunosuppression is the only valid therapy to treat BKVN and restore antiviral immune response, but should be balanced against risk of rejection.
Treatment of presumptive BK virus nephropathy
· The first treatment of BKV disease has focused on reduction/modifications in immunosuppressive therapy with or without antiviral medications.
· Different regimens have been attempted, such as withdrawal of antimetabolite drugs, switching a drug class, and steroid avoidance.
· Switching tacrolimus to cyclosporine may reduce MMF levels, but the total withdrawal of MMF may be essential if BK viremia remains.
Treatment of BK virus nephropathy in the setting of allograft dysfunction
· Reducing immunosuppression is a rational option in the context of acute BKV infection, as it can lead to clearance of viremia and increase BKV-specific IgG-antibodies titer and cellular immunity.
· It may also stabilize allograft function or advance to end-stage despite therapy.
Drugs with antiviral activities
Leflunomide
· Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug used in rheumatoid arthritis to inhibit pyrimidine synthesis and reduce CNI dosages.
Cidofovir
· Cidofovir is a cytosine analog and viral DNA-polymerase inhibitor used to manage other viral infections, but it is a nephrotoxic drug and should be used carefully in kidney recipients.
mTOR inhibitors
· mTOR inhibitors inhibit BKV replication and early gene expression, but clinical efficacy is questionable.
Intravenous immunoglobulin
· IVIG has the most potent antiviral influence, with a selectivity index of 1000, and has been successful in treating BKVN with concurrent acute rejection, but its effectiveness is uncertain.
Other therapeutic options for treating BK virus nephropathy
· Quinolones, artesunate, statins, and rituximab have been found to inhibit the LTAg helicase activity and have in-vitro and in-vivo activity against BKV.
· Rituximab has also been found to reduce the percentage of BKV-infected cells and LTAg expression in human renal proximal tubular epithelial cells.
· Further prospective randomized trials are needed to validate the benefit of this
therapy for BKVN.
Short-term and long-term allograft survival
· BKVN caused permanent allograft damage in the late 1990s and
the early 2000s, but renal allograft survival has improved significantly.
· Therapeutic approaches have improved viremia, but long-term
outcomes need further evaluation.
· Management
should be tailored for each patient individually, with delayed improvement in
renal functions likely due to slow resolution of cellular infiltrate.
Postinfection monitoring
· USA-OPTN
registry data showed 126 retransplants lost their graft due to BKVN, with
excellent 1- and 3-year graft survival.
· Pretransplant clearance of BK viremia is essential after
minimizing immunosuppression, and allograft nephrectomy is not necessary before
retransplantation.
· Monitoring BKVN using quantitative plasma BKV-PCR is
important to improve allograft outcomes.
· BK viremia clears in 7-20 weeks, but the initial decline may be
delayed for 4-10 weeks.
Conclusion
· After over three decades of study, we now somewhat’ understand the pathogenesis of BKV.
· A larger “known unknown” just serves to highlight how elusive BKV is.
· Despite the lack of a particular therapy, an early identification of BKVN based on a
combination of genetic
· methods and tissue analysis has significantly improved allograft results.
=================
Level of Evidence 5
Week 9, 10 : BK virus infection in renal transplant recipients: an overview
Summary:
· 3 Human polyomaviruses involved in diseases in kidney transplant recipients (KTRs) include: BK virus (BKV), JC virus (JCV) and simian virus 40 (SV40). The name polyoma represents the viruses’ ability to induce many (poly) tumors (−oma).
· JCV was discovered as a cause of progressive multifocal leukoencephalopathy.
· BK is named after the 1st Sudanese KTR case with viral detection in both urine and ureteral epithelial cells and he was presented with ureteric stenosis and graft failure.
· BK infection early Posttransplant (1st year) is a prominent cause of acute graft dysfunction (found shredded in urine + histopathological evidence of damage in allograft biopsy).
· BKV can be categorized into four genotypes/subtypes, type 1 is the most common (> 80% worldwide), followed by type 4 (15% of the healthy population). While types II and III are relatively rare.
· The incidence of BK infection increased with use of potent IS medications as tacrolimus and MMF in addition to the enhanced microbiological diagnostic techniques.
· Route of infection: respiratory, fecal-oral (viral isolated from saliva and stool), transplacental, or from donor tissues, and may be through the urine and blood (viruses detected in urine and peripheral blood leukocyte).
· BK infection is mostly acquired in early childhood and remains dormant in the urinary tract (60–85% of the general population is seropositive for BKV), till the patient become immunocompromised (pregnancy, DM, HIV infection, cancer, and Posttransplant), it becomes reactivated.
· The main mechanism of immune defense against BK infection is cellular-mediated immunity (CD4+ and CD8+ T cells). Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA. In addition, humoral immunity might have a role in the pathogenesis of BKVN, so BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
· Pathogenesis of BK infection; 1. defective immune surveillance by the host T lymphocytes, (b) absence of humoral immunity to BKV, (c) alloimmune activation (d) viral variation in molecular sequences.
· Pathogenesis of BKVN:
1. Impaired immune response either cell mediated or humoral.
2. Alloimmune activation means cross-reactivity against allo-HLA antigens and BKV in humans. This can be explained by increase in the incidences and severity of BKVN in those with higher degree of HLA mismatches. The higher the degree of HLA mismatch, the worse the prognosis of BKN.
3. BKV tropism to the proximal renal tubular epithelial cells may play an additional role in BKN.
· Clinical presentation of 1ry infection: mild respiratory symptom in childhood (BKV goes into the circulatory system through infected tonsils >> peripheral blood mononuclear cell >> disseminated to the kidneys >> dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
· In case of immunosuppression as KTRs: BKV reactivation >> lysis of infected tubular cells >> viral leakage into the tubular lumen and urine (viruria), as well as dissemination into the interstitium. Then, damage of tubular capillary walls will cause the vascular spread of the virus (viremia), leading to dense inflammatory interstitial infiltrate and tubulitis.>> up-regulation of profibrotic mediators and ends with allograft dysfunction and loss. Mechanism of tissue injury direct viral cytolytic effects and secondary inflammatory responses and the prognosis depends on the degree of tissue damage.
· Time frame:
o Viruria (diagnosis by viral DNA-PCR in urine)
o Then after 4 weeks viremia develop
o Then after 12 weeks of viral shedding in urine >>BKN develops.
· Presentation in transplant patients (immunocompromised host):
o Infection with this virus starts as the virus proliferate in the uroepithelial cells then detached in urine (viruria) >> then in blood (viremia) and eventually to BKVN (2 and 15% of allograft).
o Clinical presentation varies from asymptomatic hematuria up to extensive irreversible injury and allograft failure.
· It usually presents as asymptomatic gradual rise in creatinine with severe tubulointerstitial nephritis that mimics AR presentation.
o BKV has different clinical features, BKVN (ureteric stenosis and late-onset hemorrhagic cystitis).
o Hemorrhagic cystitis is common in patients with hematopoietic stem cell transplant (HSCT) (may be related to pretreatment with cyclophosphamide), but it is rare in KTR.
o HIV infected patients, BKV may disseminate leading to severe multi organ failure (retinitis, encephalitis, GBS, URTI, interstitial pneumonia, hepatitis, pancreatitis, colitis), BKN and death. Most of invasive disease occurs in HSCT.
o Ureteric stenosis is 2–6% allograft dysfunction, treatment by percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent decrease of IS medications.
o Hemorrhagic cystitis is rare in kidney transplantation (mostly in HSCT), grade I: microscopic hematuria; grade II: macroscopic; grade III: hematuria with clots; grade IV: hematuria with clots, clot retention, renal failure secondary to obstructive nephropathy. Treatment by vigorous intravenous hydration. Severe cases might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation + Cidofovir
· The risk of BKV infection is increased in KTRs especially after ttt of AR episodes (aggressive immunosuppression), male gender, older age, degree of HLA mismatching, prolonged cold ischemia, BK serostatus (D+/R-), certain ethnic groups, lower total lymphocyte percentage and ureteral stent insertion.
· Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss. Hence, routine screening protocol for early detection of asymptomatic BKV infection results in better allograft outcomes.
· ‘Decoy cells’ are large cells with intranuclear inclusions present in the urine (resembling malignant cells).
· Oncogenesis properties of BKV:
o It remains a matter of debate.
o BKV-DNA has been identified in tissue samples of different neoplasms, as brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
o However, it is not conclusive that it has a causative role or just coexisting infection in malignant cells.
o It is suggested that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as high level of BKV-LTAg was noted in the nucleus of almost every tumor cell and none of the non-neoplastic urothelium.
· Screening during 1st year posttransplant: first month, then monthly for the first 6 months, and then every 3 months for up to 2 years after transplantation then annually thereafter.
· Screening by viruria/ viremia or decoy cells in urine.
o BK PCR in urine and blood (if viral titer <10,000 just FU viral titer monthly and consider decrease IS while, if plasma PCR > 10,000 copies …do allograft biopsy)
o Decoy cells are identified in 15–30% of KTRs, by Cytological analysis of urinary smear. It indicates active BKV reactivation, but it is not a real diagnostic tool for BKVN. (sensitivity 100%, specificity of 71%, positive predictive value (PPV) 29% and negative predictive value (NPV) 100%), compared to graft biopsy as a diagnostic standard.
o Urine electron microscopy (EM Haufen): Haufen represents cast-like three-dimensional aggregates (BKV particles + Tamm-Horsfall protein), visualized in a urinary smear of kidney recipients using negative-staining electron microscopy, but it is not always available in all health care settings.
· Suggested step wise approach for BKV screening:
o Start with decoy cells in urine (persistence of decoy cells ≥ 3 months).
o Proceed to plasma PCR-for BK (quantitative).
o Consider renal biopsy (some suggest it only if graft dysfunction is present, others suggest it when viral load > 10,000 copies/ml)
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· Serum antibodies have no value (present in healthy population, none confident in such immunocompromised patients), (D+/R-) may be associated with higher risk of infection posttransplant.
· Allograft biopsy is the golden standard to diagnose BKN, is indicated if significant viruria (suggesting viral proliferation in the urinary tract), persistent viremia of more than or equal to 104 copies/ml for > 3 weeks.
o Pros and cons of biopsy:
o Findings can be focal or isolated to the medulla and missed on 1/3 of biopsies (false-negative), a minimum of two biopsy cores involving the renal medulla, to make the correct diagnosis.
· Differential diagnosis:
1. AR (BKVN can be distinguished from AR by presence of BKV inclusion bodies and immunohistology (positive immunoperoxidase staining for SV40).
2. Other causes of graft dysfunction (CMV infection, UTI, sepsis, etc)
· Treatment of BKVN: (No specific therapy for BKN)
1. Reduction of IS (with balance against AR), effective mainly in early stages of BKN, while in advanced disease with graft damage the benefit is debatable.
· No consensus, but many suggestions are considered as:
· Withdrawal of antimetabolites as MMF or shift to azathioprine, sirolimus, or leflunomide.
· Leflunomide is an immunomodulatory used in rheumatoid arthritis, used after stoppage of MMF/aza (cannot be used with antiproliferative drugs). Its use has many limitations (adverse effects as hemolysis, aplastic anemia, thrombocytopenia, TMA, hepatitis, and hypertension worsening).
· Reducing the dose of CNI by 25–50% (to achieve Lower window of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml).
· Converting tacrolimus to cyclosporine (might reduce MMF levels even with same dose of MMF) or discontinuing CNI
2. Cidofovir: antiviral used in CMV, can be useful, adverse effects include severe anterior uveitis and nephrotoxicity that requires adequate prehydartion).
3. Conversion from CNI to mTORi: improves the recovery of BKVN and GFR.
4. IVIG (dose 2–3.5 g/kg divided over 2–5 days) + reduction of IS medications: preferred especially if BKVN is associated with AR, but the effect is still questionable as reduction of IS was done in all patients.
5. Quinolones
6. Artesunate (an antimalarial drug) may have dose dependent anti-viral activity.
7. Rituximab (Although it can increase the risk of viral infection in KTR as BKVN, CMV viremia, herpes zoster, and septic shock, it may be beneficial in ttt of BKVN.
· Treatment of BKVN with concomitant AR (or with anticipated AR with the reduction of IS medications):
o Reduction of IS in BKVN can precipitate AR in 30 % of cases.
o Initial reduction of IS (with or without pulse steroids) can be used.
o The timing of uptitration of IS after clearance of BKV is still debatable.
o Close monitoring of the graft function every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks then monthly thereafter until clearance of BK viremia.
o The initial decline of BKV viral load might be delayed for 4–10 weeks following reduction of IS and virus clears in 7–20 weeks.
o Retransplantation is feasible with excellent graft outcome at 3 years posttransplant. However, recurrent or devo BKVN can occur posttransplant. Consideration of graft nephrectomy to eliminate the source of replicating virus is rationalized, but not standard practice.
· Prognosis of BKVN:
o It is associated with graft loss if diagnosed late after graft dysfunction.
o Early diagnosis through screening protocols and surveillance biopsy is associated with better graft outcome.
Level of evidence: narrative review (level 5).
Introduction:
This paper discusses BK virus infection and how it affects renal transplant recipients. Infection with BKV is a complication that can occur during the first year following a transplant. It presents similarly to acute rejection, making it difficult to distinguish both of them. associated with tubulointerstitial nephritis and asymptomatic creatinine rise. increased overall immunosuppression is the main common risk factor.
Pathogenesis:
BKV primary infection rarely causes lung symptoms in children. BKV enters the circulatory system through diseased tonsils and infects peripheral blood mononuclear cells, which spread to secondary sites like kidneys. The virus remains latent in the uroepithelium and renal tubular cells for life, occasionally reactivating as asymptomatic viruria.
BKV can also hide in leukocytes, brain cells, and lymph nodes. In immunosuppressive therapy, the virus initiates and proliferates in the interstitium and enters the peritubular capillaries, causing tubular cell lysis and viruria. Damage, inflammation, and fibrosis determine outcomes. Viral cytolysis and secondary inflammatory reactions damage tissue.
Different BKV disease symptoms arise from complex immune system-BKV interactions.
Routes of transmission of primary BK virus:
(1) Respiratory route
(2) Gastrointestinal transmission
(3) Vertical transmission: during pregnancy
(4) Sexual transmission
(5) Donor-derived infection
(6) Others:through the urine and blood
c/p:
BK virus renal disease
This virus proliferates in uroepithelial cells, causing viruria, viremia, and BKpolyomavirus-associated nephropathy (BKVN)/PyVAN . 30–40% of renal transplant recipients develop BK viruria, while 10–15% develop viremia.
BKVN is reported in 2–15% of kidney allograft recipients.
BK-related nephropathy
BKV-associated nephropathy starts with viruria or asymptomatic hematuria and progresses to irreversible damage and allograft failure. Nephritis can start 6 days or 5 years after renal transplant.
Uretric stenosis
prevalence 2–6%.
Allograft dysfunction due to ureteric stricture and hydronephrosis is rare. Treatment involves temporary percutaneous nephrostomy and ureteral dilatation, along with immunosuppressive medication reduction.
Hcccccccccc cystitis:
HSCT recipients commonly develop BKV-associated HC or non-HC, but renal allograft recipients rarely do. Bladder cramps, painful voiding, hematuria, and flank pain may occur.
Grade I: microscopic hematuria; grade II: macroscopic; grade III: hematuria with clots; and grade IV: clot retention, renal failure, and obstructive nephropathy. Intense intravenous hydration is required. Supra-pubic catheters with bladder irrigation may be needed for severe BKV-HC. Cidofovir given locally through bladder installation reduced cumulative drug nephrotoxicity and caused HC remission in 2 to 7 weeks after hematuria.
Native BK nephropathy
BKVN has been found in native kidneys of HSCT, heart, and lung transplant recipients and immunocompromised HIV-infected patients. All those patients had acute kidney injury without significant proteinuria and typical kidney biopsy histology.
Neurological manifestations:
BKV rarely causes primary or reactivated CNS disease. Patients with HIV or HSCT usually get such infections. Meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy may present clinically. Headache, dizziness, confusion, paraplegia, ataxia, and seizures may occur .
BKV and neurological symptoms are still debated.
Pulmonary diseases:
reactivated acute respiratory disease leading to severe interstitial pneumonitis in association with BKV has been reported twice in HIV-infected patients, with prominent histopathological lung features with distinctive BK cytopathic changes and a positive BK viral DNA test in the autopsy.
Ophthalmologic manifestations:
reported one case of bilateral atypical retinitis in an AIDS-positive homosexual white male. The eye autopsy showed several retinal necrosis areas. PCR found retinal BKV-DNA. Autopsy revealed BKV infection in the brain, kidneys, and peripheral blood smear. Since it’s a single case, BKV’s ophthalmological effects need more evidence.
Plenty of believe that BKV plays a major role in urothelial carcinoma etiology.
BKVN detection and screening:
Crucial for preventing graft dysfunction is the early diagnosis of viremia and viuria through screening.
The AST and KDIGO guidelines recommend the following screening intervals: the first month after transplantation, every month for six months, every three months for one to two years, annually for two to five years, any presentation with an unexplained rise in creatinine, and following treatment of rejection episodes.
If PCR is 10,000, monitoring and/or immunosuppression reduction should be considered; if PCR is greater than 10,000, graft biopsy should be considered.
Urine cytology for decoy cells is used for screening and diagnosis (sensitivity 100%, specificity 71%, PPV29%, NPV100%).
Sensitivity and specificity are both 100% for urine electron microscopy (EM Haufen).
Urine BKV-PCR has a specificity of 78% and a sensitivity of 100%.
Level of mRNA in the urine with a sensitivity of 100 percent and a specificity of 97%.
100% sensitivity and 88% specificity for BKV-PCR in serum(preferred screening test).
A kidney biopsy should be performed when the viral load exceeds 100,000 copies per milliliter, with or without a transplant dysfunction.
D.D.:
Allograft rejection
BKVN and acute rejection have similar tissue appearances, so blood or urine PCR can help distinguish them. Differentiating these two entities is important because immunosuppression for the assumed rejection may cause BKVN progression. BKVN may coexist with acute rejection.
BKV inclusion bodies and SV40 immunoperoxidase staining separate BKVN from acute rejection. Though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease, absence of definitive features of acute cellular rejection, such as endotheliitis, extensive tubulitis, and C4d deposits in peritubular basement membrane, are valuable. Anti-HLA DR IHC staining of renal tissues or urine sediments can distinguish acute rejection from BKVN. BKVN has more tissue infiltrate CD20+ cells than acute rejection.
BKVN and acute rejection can coexist.
Endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries prove acute rejection.
Additional differential diagnoses include any medical condition linked with early (1-12 weeks post-transplantation) and late (≥3 months post-transplantation) dysfunction of the renal allograft.
management options:
-Reduction of immunosuppression is the main factor (risk of rejection should be balanced with immunosuppression reduction).The recommended action involves the discontinuation of anti-metabolite and a reduction of 25-50% in the dose of calcineurin inhibitor.
-Additionally, mTOR inhibitors have been observed to effectively inhibit BK virus replication.
-Certain antiviral medications, such as leflunomide and cidofovir, have been found to exhibit nephrotoxic effects.
-There is a conflicting body of evidence regarding the effectiveness of quinolone.
-Artesunate (anti malarial) has been observed to exhibit a dose-dependent reduction in viral proliferation.
-ciprofloxacin & leflunamide
-IVIG
-rituximab
Further evaluation is required to assess the long-term outcomes, including instances of late acute and chronic rejection.
-The incidence of acute rejection subsequent to the reduction of immunosuppressive therapy ranges from 6% to 12%.
Acute rejection and BK nephropathy
Proven allograft biopsies of acute rejection with BKVN or expected rejection after immunosuppression reduction to treat BKVN are controversial. Over half of biopsies show tubulitis, and any drop in immunosuppression can cause rejection in 10–30%.
Steroid pulses usually enhance clinical outcomes but worsen allograft outcomes. Celik et al. [215] found that immunosuppression reduction reduces viral load better than steroid pulses in BKVN and tubulitis biopsies.
After BKVN finding, immunosuppression should be reduced without steroid pulses.
However, in the lack of typical features, such as strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage, acute rejection should be managed individually. The cellular infiltrate may slow renal function recovery after immunosuppression reduction. Up-titrating immunosuppression after viremia and BKVN clearing is unclear.
Post-infection monitoring
BKV-PCR and renal function monitoring during and after therapy.
Most centers use quantitative plasma BKV-PCR to assess BKVN.
Most transplant patients who have their immunosuppression reduced for BKVAV are monitored with serum creatinine tests every 1–2 weeks and plasma BK-PCR levels every 2–4 weeks for 8 weeks. It should be repeated monthly until BK viremia is cleared or viral burden falls below threshold levels and renal function stabilizes.
BK viremia clears in 7–20 weeks. Immunosuppression reduction may delay early decline by 4–10 weeks. If viremia remains after reducing maintenance therapy, consider sirolimus, leflunomide, or further reduction.
level of evidence:
narrative review, level 5
Summary:
Introduction:
Pathogenesis:
Primary infection with BKV is usually subclinical, manifests as a mild respiratory symptom in childhood.
In the presence of immunosuppressive therapy, the virus replicates and spreads to the peri-tubular capillaries leading to tubular cell lysis and viruria. Reaction between the BKV and immune system leads to various presentation of BK disease.
Routes of transmission of primary BK virus:
Clinical manifestation
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals but BKV does not cause disease in immunocompetent people.
Diseases include BKV nephropathy, ureteric stenosis, and late onset hemorrhagic cystitis.
Four degrees of disease severity are recognized:
– Asymptomatic hematuria
– Symptomatic hematuria
– Hematuria with clots
– Hematuria with clots, clot retention and renal failure secondary to obstructive uropathy.
Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection.
BKV and malignancy: BKV DNA has been detected in tissue samples of different neoplasms. It has been proposed that BKV has oncogenic properties owing to its LTAG and STAG proteins.
Screening tests
Viruria precedes viremia by approximately 4 weeks while BKVN occurs 12 weeks after viruria.
· 1) Urine cytology: Decoy cells, they are infected tubular cells with with an enlarged nucleus with basophilic intranuclear inclusions.
Presence of decoy cells is strongly suggestive of polyomavirus infection and is considered as a marker of BKV reactivation.
It has sensitivity ranging between 25-100% and specificity 71-84% to diagnose BKVN.
· 2) Urine viral loads: PCR has a sensitivity of 100% and specificity of 78%.
Persistent high viral loads can predicting patients at risk of BKVN.
· 3) Serum BK PCR: sensitivity of 100% and specificity of 88% thus it is the preferred screening tool in most transplant centers.
· 4) Kidney biopsy: Gold standard for diagnosing BKVN..
Treatment:
Decreasing immunosuppression is the only validated therapy to treat BKVN and restore immune response to viruses; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Withdrawal of the antimetabolite such as MMF is the most usual method.
Drugs with antiviral activities:
Post infectious monitoring:
Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome. S. creatinine every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks then monthly until clearance of BK viremia or at viral burden falls below threshold value and stabilization of renal function achieved.
Conclusion:
Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
Level of evidence: level V
Summary
In 1971, Gardner et al were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. They named the virus ‘BK’ after the initials of this patient.
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life .
Studies showed as much as 60–85% of the general population is seropositive for BKV .BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and post transplantation period .
The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN)
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood. It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Routes of transmission of primary BK virus
Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Risk factors
Several risk factors were implicated in the pathogenesis of BKVN. The most consistent risk factor identified in the literature is the overall degree of immunosuppression.
Screening and diagnostic tools
The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears
Treatment strategy of BK virus nephropathy
The aim of treating BKV is to eradicate the virus while saving the kidney function. Unfortunately, BKVN has limited treatment options . As BK viremia and BKVN signify excessive cumulative immunosuppression, hence, decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Therapeutic options
Leflunomide
Cidofovir
IVIG
mTOR inhibitors
Fluoroquinolones
Artesunate (an antimalarial drug)
Postinfection monitoring
There are different protocols in different centers for monitoring BKVN, mostly using quantitative plasma BKV-PCR. The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
Retransplantation
Retransplantation following graft loss owing to BKVN is possible and can be done successfully
BK virus infection in renal transplant recipients: an overview. Please summarise this article.
INTRODUCTION.
Epidemiology and BKV structure.
Immunological response to BKV and Pathogenesis.
Route of transmission of primary BKV.
Clinical Manifestations.
BKV and Malignancy.
Risk factors to BKV infection.
Screening and diagnostic tools.
Ddx;
Tx of BKVN.
–RIS is the only validated approach.
Presumptive BKVN.
TX of BKVN in setting of allograft dysfunction.
Drugs with antiviral activity.
BKVN and Concurrent acute rejection.
Post infection monitoring.
Re-transplantation.
What is the level of evidence provided by this article?
Introduction
The human Polyomavirus (BKV) and JC virus (JCV) were first discovered in 1971 by Gardner et al (1). The human BKV belongs to the Polyomaviridae (PyV)
virions, a subgroup of papova viruses comprising BKV, JCV, and simian virus 40 (SV40), its nonenveloped circular double-stranded DNA virus. The name polyoma stated to the virus’s capacity to create many(poly)tumors(-oma). There are 12 human BKVs have been isolated from 2007-2017 with four genotypes identified. The seroprevalence of BKV in the general population was found in the range of 60-85% as per reports however limited data about the BKV prevalence in the middle east& Africa but one study from Iran shows that BKV prevalence is around 41%.BKV is one of the important causes of early allograft dysfunction, usually in the first year after transplantation and after treatment of acute rejection with intense immunosuppression, and can manifest as an asymptomatic increase in creatinine level that is similar to acute rejection presentation and can lead to diagnostic and management problems.
Structure of the BKV
BKV- DNA genome has three regions. The noncoding control region (NCCR): it regulates the expression of the virus’s early and late genes
regarding differentiation and activation of the host cell.
1. The early viral gene region with it encodes the controlling nonstructural proteins called small T antigen (STA) and large T antigen (LTAg), large tumor antigens which interact and binds to cellular antigens and plays role in viral replication at the S phase cycle.
2 The late viral gene region (LVGR): it converts the capsid proteins VP-1, VP-2, and VP-3 within the nucleus and also encodes a small cytoplasmic protein called agnoprotein, assisting in regulating viral replication and interrupting the host cell processes.
3) The capsid protein VP1 in the LVGR is the chief capsid protein present on the surface and is responsible for receptor binding to the host cells, VP1 is immunogenic as well& it’s the target for the neutralizing antibodies and immune cell recognition. facilitating virus entry into the cell once it gets inside the cell, the virus travels to the nucleus and establishes dormant or lytic infection.
BKV variant
BKV have so far four genotypes based on DNA VP1 genomics sequences, genotype 1 is the predominate type with 80% of BKV infection followed by genotype 1V, and both have further subtypes in each genotype with predominate subtypes to certain populations like USA and Europe have more predominate subtype for genotype 1 I (I/b-2) while 1lc1 in Asian patients.
Immunological response to BK virus
BKV replication can be started early post-kidney transplantation due to immune suppression as in the general population it reported during pregnancy, DM, HIV patients also in cancer patients, and after sold organ transplantation, so the immune system plays a vital role in promoting the viral replication and triggering BKV nephropathy
T cell defect and absence of humoral immune response, alloimmune response, and BKV variation on a molecular level
The role of cell-mediated immunity
CD4 and CD8 play key roles in the eradication or clearance of BKV, T cells react against both nonstructural and BK capsid proteins and can be measured by the enzyme-linked immunosorbent spot
(ELISPOT) and tetramer staining. Cytotoxic T cells (CTL) kill the BK-infected cells after the recognition of damaged segments of viral DNA. The defective cellular immune response resulted in viral replication and the infective lytic stage can infect the tubule epithelial cells with viral shedding in the urine and can progress to tubule interstitial nephritis
The alloimmune activation is an immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity.
The role of humoral immunity
patients with past immunity to BKV may not demonstrate the manifestation of the disease, regardless of the number of viral copies, D+ve /R- ve is at high risk to get BKV Viremia in addition patients with BKVN had the highest
rise in BKV-specific IgG with persistently elevated IgM levels.
Clinical manifestations of BKV in renal transplantation
The clinical manifestation varies from viruria with viral cells (decoy cells ) shedding in the urine is reported in between 30-40% usually asymptomatic or can result in ureteric stenosis, obstruction, late-onset hemorrhagic cystitis (HC), and if progresses to viremia in the blood then BKV nephropathy with viral interstitial inflammation and progressive interstitial inflammation/fibrosis
HC related to BKV is more seen in ALLO-HCT, rare after kidney transplantation with 4 grades of severity from grade one microscopic painful hematuria with abd cramps, grade two hematuria b visible, and grade 3 gross hematuria with clots, and grade 4 hematuria with obstruction and renal impairment, treatment with aggressive hydration with SPC insertion, bladder irrigation, and cidofovir local infusion for 2-7 weeks
BKV in native kidneys
BKV infection of native kidneys with biopsy-proven IB invasion have been reported in recipients of lung and heart transplantation, HIV infections, and also post HCT with clinical manifestations of nonproteinuric AKI
BK virus and malignancy: thoughts on viral oncogenesis
BKV has an oncogenic property owing to the expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation, many reports correlate the BKV association with certain urothelial tumors, Kaposi sarcomas Ewings sarcoma, CNI malignancies like meningioma. Early coding regions in BKV like Agnoprotein and LTAg will make infected cells incapable of arresting the cell cycle and may energy the cell into a continuous dividing status.
Screening for BKV after transplantation
BKV viruria and viremia usually occur early after transplantation with a peak in 3 months then 9 months and another peak after 1 year, many risk factors associated with BKV risk include mainly the intensity of IS therapy, male sex, older age, ethnic background, HLA mismatches, and DGF prolonged cold ischemia time, BKV serostatus and ureteric stenting
As per KDIGO guidelines had recommended BKV screening start in the first month after the transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years
What is the level of evidence provided by this article?
This is a narrative review level 5 of evidence
Introduction
The two human polyomaviruses, BK virus (BKV) and JC virus(JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation.
It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma
In 1971, Gardner et al, were the first to detect BK polyomavirus(BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure.
They named the virus ‘BK’ after the initials of this patient.
The relationship between kidney transplants and shedding of a polyomavirus in the urine was confirmed with subsequent studies by Lecatsas, BK virus (BKV) was discovered in 1971, it took almost three decades for this virus to be routinely considered as a possibility among a plethora of causes of renal dysfunction in a kidney transplant recipient.
Increased awareness among nephrologists to recognize BKVdisease at an earlier stage and the development of better diagnostic laboratory techniques contributed to the ever-increasing incidence of BKV infection.
The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40).
It is a family of small, nonenveloped DNA viruses with icosahedral capsid of.
A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017.
These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV; HPyV6, HPyV7, HPyV9, and HPyV12; New Jersey polyomavirus (NJPyV, known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14).
BKV-DNA genome can be divided into three parts The noncoding control region (NCCR): it regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1.
The subgroup of subtype I (I/b-2) has been noticed mostly in American and European populations, whereas subgroup I/c dominates in Asians.
Among subtype IV isolates, subgroup IV/c-2 is predominant among Americans and Europeans, whereas the other subgroups are more common in Asian populations [16,31].
Apart from the genotypic variations of VP1 region, additional two other forms of BKV present secondary to variations in the NCCR, namely, rearranged and archetype variants.
Continuous duplication of BK genome during activation process can result in deletion and duplication in the NCCR sequences, with subsequent generation of rearranged variant viruses.
The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined.
BK viral replication follows a state of immune suppression; it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period.
BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
The immune system plays an essential part in controlling BKVreplication and resolution of BK virus nephropathy (BKVN).
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
Progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination
Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies.
Bohl and colleagues found the kidney recipients from a seropositive donor were more likely to develop BK viremiacompared with others who had a kidney from a seronegative donor .
The role of antibodymediated immunity was validated in BKVinfection.
The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
Another possible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen(HLA)-reactivity and heterologous immunity.
The latter concerns with T cells, which cross-react to both BKVand allo-antigens.
One can propose that the host BKV-specific effector memory T cells cannot identify the allo-HLA molecules representing BKV-peptides; it allows BKV to escape the immunological surveillance.
Murine kidney allografts were more susceptible to polyomavirusinfection, which cause an increase in allo-reactive T cells that lacked crossreactivity to the virus.
In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role.
Moriyama et al [56] had demonstrated that a blockage of caveolin-induced endocytosis, either directly or through small interference RNA depletion of caveolin-1, produced substantial reduction in BKV infectivity as measured by immunofluorescence, as BKV particles were found in vitro to colocalize with caveolin-1, and not to a clathrin, in the human renal proximal tubular epithelium.
The pathogenesis of BKV disease is probably related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
It has been proposed that BKV goes into the circulatory system through infected tonsils, and infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
The sophisticated reactions between the BKV and the immune system result in different clinical features of BKV disease.
Several routes for the primary BKV virus transmission have been theorized.
The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Respiratory route: several authors had speculated the primary route of transmission to be respiratory, as evident by the presence of BKV in the respiratory tract and tonsils of children.
The supportive studies are mainly epidemiological, and none of them had isolated BKV on respiratory samples.
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals; BKV does not cause disease in immunocompetent people.
In renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC).
BKV is commonly encountered in patients with hematopoietic stem cell tnsplant (HSCT) recipients as hemorrhagic and non-HC. whereas in HIV- infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement and eventually leads to death.
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine, which can progress a few weeks later to blood and eventually to BK- polyomavirus-associated nephropathy (BKVN)/ (PyVAN).
BK viruria generally affects 30–40% of renal transplantrecipients, whereas 10–15% of recipients develop BK viremia.
The estimated incidence of BKVN in different literature ranges between 2 and 15% of kidney allograft recipients.
The variations in these figures can be explained by different immunosuppressive regimens and different screening strategies, including a performance of biopsy surveillance in some centers, which can detect BKVN at earlier stages.
BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
The prevalence of ureteric stenosis is 2–6% . Allograftdysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen , and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen , and treatment should involve a percutaneous nephrostomy and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
BKV-associated HC or non-HC is classically noticed in HSCTrecipients, yet it can be rarely observed among renal allograftrecipients.
The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain.
Severe cases of BKV–HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation.
Reported manifestations of BKV in immunocompromised patients, including renal transplant recipients and patients with HSCT and HIV infection.
Locally through bladder installation was suggested as a therapeutic option for HC, the remission varied from 2 to 7 weeks following hematuria
BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients.
Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection.
Such infections are primarily seen in patients with HSCT or HIV infection.
Autopsy showed that BKV infection was present in the brain, kidneys, and peripheral blood smear.
As it is a single case, further data are required before labeling BKV to cause an ophthalmological manifestation.
A relationship between BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immunecompromised individuals.
Taguchi and colleagues were the first to report the isolation of BKV from a urine sample of two patients with lupus.
This was confirmed with high BK serum antibodies titers; they demonstrated BKV antigen by indirect immunofluorescence.
There is an increase in the prevalence with persistence/or recurrent BK viruria in patients with lupus.
Such a relationship could be explained with a compromised immune system secondary to the systemic illness or the intensified immunosuppression .
There is no article that describes BKV activation in patients with systemic lupus erythematosus at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease.
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
It has been proposed that BKV has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation.
The LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Inactivation of tumor suppressor p53 and pRb in experimental mice by BKV–LTAg can induce urothelial malignancies.
Tumor cells are likely more vulnerable to BKV than normal urothelium, as the infection happens mainly in proliferating cells, and that positivity is a result instead of being a reason for neoplastic transformation.
Regardless of whether BKV has a causative part in human cancer development or not, it will remain a topic of debate
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, bladder carcinoma as the BKV-DNA was isolated in these tumors.
Geetha et al. reported a bladder carcinoma with widespread metastases in a simultaneous pancreatic and kidney transplant recipient with concomitant BK interstitial nephritis.
For both the primary tumor and its metastasis, high level of BKV–LTAg was noted in the nucleus of almost every tumor cell and none in the non-neoplastic urothelium, which supports a possible role of BKV in the development of these tumors.
Alexiev et al [140] reported a similar experience, where all tumor cells had shown strong expression of BKV–LTAg, p53, p16, and Ki-67, in addition to the intranuclear virions in electron microscopy
Several risk factors were implicated in the pathogenesis of BKVN.
The most consistent risk factor identified in the literature is the overall degree of immunosuppression.
Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLAmismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; these risk factors have not been uniformly observed in all studies.
The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears.
Viral replication starts early after transplantation and progresses through noticeable phases: viruria viremia followed by nephropathy.
Viral replication in the urine precedes BK viremia by ∼4 weeks, and there have been confined cases of patients developing viremia without viruria, this is uncommon.
Histological changes of BKVN are observed 12 weeks after BK viruria.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
No single diagnostic pathway has appeared as predominant.
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKVvirions or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients.
Such wide variation can be explained by screening strategies that were used in different centers and different immunosuppressive regimens.
Urine electron microscopy (EM Haufen): in contrast to decoy cells, Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, forming cast-like three-dimensional aggregates, which can be noticed in a urinary smear of kidney recipients using negative-staining electron microscopy.
Presence of Haufen bodies, which corresponds to upper levels of BK viremia, had a higher sensitivity and specificity for biopsy-proven BKVN (100 and 99% correspondingly), in a retrospective, single-center study.
Haufen particles were absent in recipients with a lower BK viremia
Useful marker in identification of BKV infection, but a poor diagnostic tool in predicting BKVN.
Not useful for monitoring decline in viral load.
Predictive for BKVN, but not practical for routine practice as it requires electron microscopy with interpretation from a pathologist Measurement variations between laboratories limit its use
Has good sensitivity and specificity but low PPV for BKVN.
As this method represents singlecenter data, it requires further validation.
This test cannot be applied for routine clinical practice because of the expense and inaccessibility to electron microscopy and the need for interpretation from a pathologist.
Molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity .
Persistent DNA-PCR more than 107/ml instead of episodic identification can recognize patients at risk for BKVN.
Variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis.
BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication.
This method is considered as highly specific and sensitive in predicting patients who might develop BKVN, using 6.5×105 BKV-VP1 mRNAs/ng RNA in urinary cells as a cutoff value.
Though this assay is encouraging as a noninvasive tool and can provide additional diagnostic and prognostic data, yet it requires further validation.
Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels
Serum antibodies against BKV are commonly present among the general public.
The significance of assessing BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain.
It has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients.
The positive donor BKV serostatus and negative recipient serostatus (BK D+/R−) have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients.
The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks.
Such suggestion came from a prospective analysis of Hirsch et al, who demonstrated that BK viremia of more than or equal to 104 is characteristically present in recipients with proven biopsies of BKVN.
BK-PCR of allograft biopsy tissue is not an applicable investigation to diagnose BKVN, as it can identify a latent virus, even in asymptomatic recipients.
Renal biopsy remains the gold standard for diagnosis of BKVN. biopsy findings can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result; a minimum of two biopsy cores, preferably including medulla, should be inspected to make the correct diagnosis.
Different screening protocols are present in the literature, reflecting the experience of several centers where they have been developed.
Hirsch et al,screened patients for BKV, first with urine cytology for decoy cells every 3 months, and whenever decoy cells were detected, additional studies were carried, including quantification of viral level in the plasma with the possibility of doing allograft biopsy only with a deterioration of renal function.
The persistence of decoy cells for more than or equal to 3 months will trigger the performance of quantitative measurement of PCR-viral loads in plasma and renal biopsy in patients with evidence of BK viral reactivation, irrespective of renal function.
Buehrig et al,and Khamash et al, had suggested routine surveillance biopsies to detect patients with silent BKVN.
A variable number of virus-infected cells with any degree of tubular injury and significant inflammation affecting less than 25%, 25–50% or >50% of the core biopsy.
A variable number of infected cells with any degree of tubular injury and tubular atrophy/ fibrosis affecting >50% of core biopsy
Similar to the University of Maryland, except that B1, B2 and B3 are assigned progressively increasing degrees of cytopathic effect, atrophy, and fibrosis.
Same as University of Maryland System time of diagnosis .
Most transplant institutes, including our center, recommend BK surveillance with plasma BK-PCR.
Screening for BKV should be performed on periodic intervals, starting after 1 month, monthly for 3–6 months, and every 3 months for the initial 1–2 years after transplantation.
American Society of Transplantation guidelines recommended further annual screening till the fifth year after transplant; generally screening beyond 2 years is not recommended in most centers unless allograft dysfunction is present .
Allograft biopsy can be considered in individuals with persistent high viral loads for more than or equal to 3 weeks.
Is a suggested algorithm for BKV screening .
The distinction of BKVN from acute rejection is challenging as the histological appearance is often similar; it should be aided by analysis of blood or urine PCR.
Absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease.
Another useful technique to differentiate between acute rejection and BKVN is IHC staining of renal tissues or urinary sediments with.
The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of concurrent acute rejection.
The aim of treating BKV is to eradicate the virus while saving the kidney function.
BKVN has limited treatment options .
As BK viremia and BKVN signify excessive cumulative immunosuppression, decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection .
Rapid viral load reduction has been related to steady or improved allograft function .
The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
There is no standard strategy for modifying immunosuppressant’s therapy; different regimens have been attempted upon recognition of viremia.
These include withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance .
Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% or converting tacrolimus to cyclosporine or discontinuing CNI.
Favorable renal allograft outcomes in the context of acute BKVinfection were reported when immunosuppression reduction had started early upon detection of BK viremia, permitting early and appropriate therapeutic interference.
If the identification of BKVN is made at an advanced stage when nephropathy ensues, reducing immunosuppression is probably going to be less effective, owing to the advanced disease, with severe histological changes leading to progressive, irreversible renal damage.
Allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy.
Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises BKV-specific IgG-antibodies titer and increases BKV– specific cellular immunity.
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug which was developed to be used in rheumatoid arthritis.
Being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages.
It is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppressiondosage.
The mTOR inhibitors are thought to produce their inhibitory effect on BKV replication by restoring the downregulation of translation that occurs under cellular stress, delay the viral replication
It inhibits the proliferation of BKV– specific T cells and controls the differentiation of memory CD8 T cells; it improves the immune reaction following BKV infection .
Tacrolimus and MMF were replaced with sirolimus, which resulted in reduction of the BK viral load with concurrent improvement in estimated glomerular filtration rate.
Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN for its immunomodulatory effects.
The IVIG with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection; the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression.
Other therapeutic options for treating BK virus nephropathy,A latest study examined the anti-viral influence of artesunate on BK viral proliferation in a primary human renal cell culture.
The investigators found a decrease in BKV proliferation in a dose-dependent way with artesunate.
Therapy with anti-CD20mAb rituximab used for the treatment of antibody-mediated rejection was associated with several adverse effects including BKVN, CMV viremia, herpes zoster, and septic shock , yet Babel and colleagues had reported promising results by using rituximab in nine transplant patients with BKVN.
Patients who had received rituximab as an adjuvant therapy with
Cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN.
In both groups, the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine.
In the late 1990s and early 2000s, BKVN caused permanent allograft damage in 30–60% of cases
This happened as a result of lack of awareness, delayed diagnosis, misdiagnosis, and coincidental utilization of escalated immunosuppression for possible acute rejection episodes .
Buehrig et al, reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis (8/8 patients vs 3/10, P=0.004).
Chen et al,reported 1-, 3-, and 5-year allograft survival rates following a diagnosis of BKVN (n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograftsurvival (P= 0.042)
Management of proven allograft biopsies of acute rejection with concomitant BKVN or management of anticipated rejection following a decrease of immunosuppression to treat BKVNremains debatable.
More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in 10–30% of the cases .
Reports have depicted clinical improvement, steady or worse allograft outcomes, following steroid pulses .
Hirsch et al,suggested a combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection.
An initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.
Upon clearance of viremia and BKVN, the advantage of up-titrating immunosuppression to avoid further late acute rejection or chronic rejection remains obscure.
Close observation of BKV-PCR and renal function with any treatment, following management of acute rejection or reduction of immunosuppression, is crucial to improve allograftoutcome.
The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
It should be done on a monthly bases until clearance of BK viremia and stabilization of renal function achieved .
USA-OPTN registry data for the period 2004–2008 showed 126 individuals got retransplant of 823 who lost their graft secondary to BKVN.
Recurring BKV might reflect a previous BK variant or a new infection acquired, because of the long period, in the posttransplantation stage.
Three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology.
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment
Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population.
Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening.
Buehrig et al,reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis (8/8 patients vs 3/10, P=0.004).
Chen et al, reported 1-, 3-, and 5-year allograft survival rates following a diagnosis of BKVN (n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograftsurvival (P= 0.042).
Celik et al,found a reduction in immunosuppression is more than capable in reducing and 18%.
LEVEL OF EVIDENCE IS 5.
Please summarise this article.
BK virus (BKV) was discovered in 1971. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection. Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss. This review is aimed to discuss the most recent evidence addressing the virology, pathogenesis, clinical features, diagnostic tools, screening protocols, treatment strategy, and short-term and long-term renal allograft survival concerning BKV infection.
The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40).
Immunological response to BK virus
BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN).
Pathogenesis of BKV
It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
Routes of transmission of primary BK virus
· Respiratory route
· Gastrointestinal transmission
· Vertical transmission
· Sexual transmission
· Donor-derived infection
· Through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes
Clinical manifestations
BKV does not cause disease in immunocompetent people. In immunocompromised patients, particularly in renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
Risk factor
Risk factors
Immunosuppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion
Screening and diagnostic tools
KDIGO guidelines have recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
DNA-PCR in urine and blood
BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’)
Urine cytology Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients
Urine electron microscopy (EM Haufen)
Quantitative measurements of urinary BK virus-viral loads Compared with urine cytology, molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity
Serum BK-PCR BK viremia is noticed only among immunocompromised patients, with an estimated prevalence of 7–30% in the initial 6 months and 5–10% after that among kidney recipients
Kidney Biopsy
Streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically
BK viral inclusions within tubular epithelium can be identified via the conventional hematoxylin and eosin (H&E) and PAS staining
Fluorescence in-situ hybridization (FISH) analysis allows BKV identification in renal transplant tissues through bright nuclear fluorescence technique
Differential diagnosis
Allograft rejection
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40
Treatment strategy of BK virus nephropathy
The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy
Stop MMF
IVIG
What is the level of evidence provided by this article?
Level 5
Introduction
The human BK virus was first discovered in 1971 belong to Polyomaviridae comprising JC Virus, BK Virus, and Simian virus 40. BKV is one of the common early post-kidney transplant infections that could cause graft loss by BKV nephropathy if not detected timely. There are twelve more polyoma viruses that are named based on the disease they cause, geography, or their epidemiology
Epidemiology of BKV
a) BKV is found worldwide.
b) Affect almost all people during childhood and remained dormant until there is immunosuppression status
c) Studies show upto 60-85% of the population is affected
d) It has three genomic region (NNCR),
e) early viral gene region, late viral region (LVGR), and the capsid protein in VP1 of the late viral region
f) Humoral immunity play vital role in BKVN
Pathogenesis of BKV Infection
Route of transmission of primary BK virus
Clinical Manifestations
Risk factions for BKV
a) Immunosuppression – most common
b) Male sex
c) Older recipient age
d) Previous rejection episode
e) Degree of HLA mismatch
f) Prolong cold ischemic time
g) BK serostatus D+/R-
h) Certain ethnic group
Screening time and diagnostic tool
Treatment of BKVN
Other medications that have been used with varying outcomes
Conclusion
Despite of three decades of research in the field of BKV, there are still remain some gaps, like lack of definitive treatment that could be curative, although some of these searches has helped the understanding of early diagnosis and some early intervention that may help to prevent the progression to BKVN. There is the challenge of difficulty in differentiating acute allograft rejection from BKVN, and sometimes both may coexist. Re-Transplantation is possible after graft loss, and the common reason is to remove the failed graft after period of undetected BKV
Level of evidence is v
Summary:
Introduction:
BK virus (BKV) was discovered in 1971, BKV belongs to the Polyomaviridae a subgroup comprising JCV, BKV and SV40. Their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients. BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma. There are 4 genotypes of BKV, with genotype 1 being the most prevalent followed by genotype 4; genotype 2 and 3 are rare.
Pathogenesis:
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood. The virus remains dormant in the urothelium and renal tubular cells.
It can also remain dormant in the lymph nodes, brain tissue and leukocytes.
In the presence of immunosuppressive therapy the virus replicates and spreads to the peri-tubular capillaries leading tubular cell lysis and viruria.
Reaction between the BKV and immune system leads to varies presentation of BK disease.
Routes of transmission of primary BK virus:
Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestation
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals (but not in plasma); nevertheless, BKV does not cause disease in immunocompetent people. Include BKV nephropathy, ureteric stenosis, and late onset hemorrhagic cystitis.
· BKV and renal disease: Begins with viral replication in the uroepithelial cells, then viruria that progresses to viremia and later BK associated nephropathy.
· BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
· Ureteric stenosis: Prevalence is 2-6%, rarely does it lead to hydronephrosis and allograft dysfunction. Treatment of ureteric stenosis involves placement of a percutaneous stent, percutaneous ureteral dilatation with concurrent reduction of immunosuppression.
· Hemorrhagic cystitis: Presentation include painful voiding, hematuria, painful bladder cramps+/- flank pains.
Four degrees of disease severity are recognised:
– Asymptomatic hematuria
– Symptomatic hematuria
– Hematuria with clots
– Hematuria with clots, clot retention and renal failure secondary to obstructive uropathy.
· Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection.
· BKV and malignancy: BKV DNA has been detected in tissue samples of different neoplasms. It has been proposed that BKV has oncogenic properties owing to its LTAG and STAG proteins.
Screening tests
Viruria precedes viremia by approximately 4 weeks while BKVN occurs 12 weeks after viruria.
· Urine cytology: Decoy cells, they are infected tubular cells with with an enlarged nucleus with basophilic intranuclear inclusions.
Presence of decoy cells is strongly suggestive of polyomavirus infection and is considered as a marker of BKV reactivation.
It has sensitivity ranging between 25-100% and specificity 71-84% to diagnose BKVN.
· Urine viral loads: PCR has a sensitivity of 100% and specificity of 78%.
Persistent high viral loads can predicting patients at risk of BKVN.
· Serum BK PCR: sensitivity of 100% and specificity of 88% thus it is the preferred screening tool in most transplant centers.
· Kidney biopsy: Gold standard for diagnosing BKVN..
Treatment:
Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Withdrawal of the antimetabolite such as MMF is the most usual method.
Drugs with antiviral activities:
Leflunomide:
It’s an immune modulator given orally, loading dose of 100mg daily for 3–5 days followed with a maintenance dose of 20–40mg/day and recommended target level of 40–100 μg/ml.
Cidofovir:
Cytosine analog and viral DNA- polymerase inhibitor
Mechanism of action is unclear as BKV lacks the viral polymerase gene the known target of cidofovir.
It’s exclusively excreted through urine, resulting in high renal tubular cell concentrations.
mTOR inhibitors:
Inhibits the proliferation of BKV- specific T cells and controls the differentiation of memory CD8 T cells; hence, it improves the immune reaction following BKV infection.
Intravenous immunoglobulin:
Potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
IVIG in a dosage of 2–3.5g/kg divided over 2–5 days with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection.
The efficiency is uncertain, as it has been given with concomitant reduction in immunosuppression.
Others:
Quinolones, antimalarial, statin
Post infectious monitoring:
Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome. S. creatinine every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks then monthly until clearance of BK viremia or at viral burden falls below threshold value and stabilization of renal function achieved.
Conclusion:
Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology. There is a bigger ‘known unknown’ that just proves the elusive nature of BKV. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
Level of evidence: level V
Summary of the article
BK virus infection in renal transplant recipients: an overview
1. The two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971.
2. BKV infection is often occurring within the first year after transplantation.
3. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma.
4. Decoy cells are abundant large cells with intranuclear inclusions present in the urine, named as ‘decoy cells’ for their resemblance to malignant cells. Polyomaviridae variants
5. The Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising human BKV, JCV, and simian virus 40 (SV40). The name polyoma represents the viruses’ capability to create many (poly) tumors (−oma).
6. The Polyomaviridae is a family of small, nonenveloped DNA viruses and has a circular double-stranded DNA.
7. A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017. MCPyV (Merkel cell carcinoma) is one of the lately isolated PyV.
Epidemiology of BK virus
1. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people.
2. 60–85% of the general population is seropositive for BKV.
BK virus structure
BKV-DNA genome can be divided into three parts:
1. The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen).
2. The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus.
3. The capsid protein VP1 in the LVGR: is responsible for receptor binding to the host cells, facilitating virus entry into the cell.
BK virus variants
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1:
1. Genotype I: the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide.
2. Genotype IV: is the second most frequent genotype, found approximately in 15% of the healthy human population.
3. Genotypes II and III: are relatively rare and infect only a minority of patients.
Immunological response to BK virus
1. BK viral replication follows a state of immune suppression(in pregnancy, diabetes, HIV infection, cancer, and post-transplantation period).
2. Possible factors that add to the pathogenesis of BKVN might be a combination of:
a) defective immune surveillance by the host T- lymphocytes.
b) absence of humoral immunity to BKV.
c) alloimmune activation.
d) viral variation in molecular sequences.
3. The role of cell-mediated immunity:
a) CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
b) Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA.
c) Progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
d) The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination into the interstitium.
e) Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation.
f) The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis.
g) Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss.
4. The role of humoral immunity:
a) the kidney recipients from a seropositive donor were more likely to develop BK viremia compared with others who had a kidney from a seronegative donor.
b) The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
5. Role of alloimmune activation:
a) CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans.
b) The higher degree of HLA mismatches is linked with an increase in the incidences of BKVN, which hypothesizes the role of alloimmune activation.
c)
6. The role of other factors: BKV tropism to the renal tubular epithelial cells may play an additional role.
Pathogenesis of BK infection
1. Primary infection BKV is usually subclinical.
2. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life. BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
3. Intermittent reactivation may manifests as asymptomatic viruria.
4. When the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
5. Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
6. The outcome relies upon the level of damage, inflammation, and fibrosis.
Routes of transmission of primary BK virus
The route of infection might be respiratory, fecal-oral, transplacental, from donor tissues.
Clinical manifestations
1. BKV does not cause disease in immunocompetent people.
2. In immunocompromised patients(KTRs), BKV has been correlated with BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC).
3. In HSCT recipients, it manifests as hemorrhagic and non-HC.
4. In HIV- infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement and eventually leads to death.
5. BKV is linked to certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis.
BK virus and malignancy: thoughts on viral oncogenesis
1. It has been proposed that BKV has an oncogenic property.
2. The BKV-DNA has been identified in tissue samples of different neoplasms, including:
a) different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas).
b) pancreatic islets cell tumors.
c) Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma.
d) prostatic carcinoma and urothelial tumors.
Screening for active BKV replication
1. Identification of viral DNA-PCR in urine and blood.
2. BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity.
3. BK virus mRNA levels in urine (sensitivity of 100% and specificity 97%.
4. Serum BK-PCR: BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively, for the development of BKVN than BK viruria [95,181]; hence, it is the preferred screening technique at most transplant institutions.
5. Urine cytology for Decoy cells(reported a sensitivity of 100%, and a specificity of 71%).
6. Urine electron microscopy (EM Haufen) for the presence of Haufen bodies, which corresponds to upper levels of BK viremia(had a higher sensitivity and specificity for biopsy-proven BKVN (100 and 99% correspondingly)).
7. Serum antibodies against BKV has no clinical relevance in diagnosing acute BKV infection affecting post-kidney transplant recipients.
8. Virus culture: BKV grows slowly in tissue culture, which might extend from weeks to months.Virus culture is used in the setting of research.
9. Kidney biopsy:
a) to anticipate the disease in presumptive BKVN(patients with significant viruria and persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks.
b) Identification of BK viral inclusions within tubular epithelium via the conventional hematoxylin and eosin (H&E) and PAS staining. H&E is specific for BKV with a sensitivity of 57.9% and specificity of 94.4%.
c) Identification of BKV via in-situ hybridization: fluorescence in-situ hybridization (FISH) analysis is specific for BKV with a sensitivity of 94.7% and a specificity of 100%.
d) Identification of BKV via immunohistochemistry (IHC):IHC is specific for BKV with a sensitivity of 68.4% and specificity of 100%.
e) Positive IHC using specific antibodies against BKV or the cross-reacting SV40 LTAg has a specificity of nearly100% for polyomavirus nephropathy.
Differential diagnosis
· Allograft rejection.
· Any disease associated with early or late renal allograft dysfunction.
Treatment of presumptive BK virus nephropathy:
Reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
Drugs with antiviral activities
· Leflunomide.
· Cidofovir.
· mTOR inhibitors.
· Intravenous immunoglobulin
Other therapeutic options for treating BK virus nephropathy
· Quinolones.
· Artesunate (an antimalarial drug).
· statins (pravastatin).
· Rituximab.
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
SUMMARY
Introduction
Polyomaviruses are small DNA viruses that can infect humans and animals like rabbits.
BK polyomavirus (BKV) is considered one of the highly prevalent forms of polyomaviruses.
BK named after 1st case which was a Sudanese renal transplant patient presented with ureteral obstruction after renal transplant and histological examination showed viral particles in the lining of the ureters.
Pathogenesis of BKV Infection
Clinical Manifestation
Risk factions for BKV
screening time and test
Treatment of BKVN
NO RCT support any of next approachs.
Level of evidence is 5
Introduction :
BKV is a major cause of interstitial nephritis and allograft failure in kidney transplant recipients, presenting as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis.
BK polyomavirus (BKV) was detected for the first time in 1971 in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure .
BK virus structure:
BKV-DNA genome is divided into three parts: NCCR, late viral gene region, and capsid protein VP1. BKV can be divided into four genotypes based on DNA sequence variations in the VP1 region, with genotype I accounting for 80% worldwide and genotype IV being the second most frequent.
Immunological response to BK virus:
The immune system plays an essential role in controlling BKV replication and resolution, with CD4+ and CD8+ T cells being the major components. Humoral immunity, antibody mediated immunity, allo-human leukocyte activation, and polyomavirus infection all play roles in the pathogenesis of BKVN.
Pathogenesis of BK infection:
BKV infection is usually subclinical and manifests as a mild respiratory symptom in childhood. After primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation. Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
Routes of transmission of primary BK virus:
Routes of transmission of primary BK virus have been theorized, such as respiratory, fecal-oral, transplacental, or from donor tissues. Vertical transmission is also proposed, as BK viruria can increase up to 35% during pregnancy and BKV can cross the placenta and stay dormant in fetal organs.
Clinical manifestations:
BK virus (BKV) is a virus that causes urinary shedding in 7% of healthy individuals, but does not cause disease in immunocompromised patients. It is associated with different clinical features, such as BKVN,ureteric stenosis, and late-onset hemorrhagic cystitis (HC). Outside renal transplantation, BKV is commonly encountered in patients with HSCT and HIVinfected patients. BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
BK nephropathy in the native kidney has been reported in HSCT recipients, heart and lung transplant recipients, as well as immunocompromised HIV-infected patients.
Neurological manifestations include meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
Pulmonary diseases include reactivated acute respiratory infection leading to severe interstitial pneumonitis, and ophthalmologic manifestations include bilateral atypical retinitis.
Further data are needed before labeling BKV to cause an ophthalmological manifestation.
BK virus (BKV) has been linked to hepatic disease and autoimmune diseases, including systemic lupus erythematosus, polymyositis, and rheumatoid arthritis. BKV infection can induce antidouble-stranded DNA and histone antibodies, and there is an increase in the prevalence of persistence/or recurrent BK viruria in lupus.
However, there is no article that describes BKV activation in postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease.
BK virus and malignancy:
BKV has an oncogenic property due to expression of early coding region-encoded proteins such as LTAg and STA, which can drive the cell into a neoplastic transformation. BKV-LTAg may have a role in the pathogenesis of urothelial tumors, but evidence is limited.
Risk factors and screening :
Risk factors for BKVN include overall immunosuppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion. Screening and diagnostic tools are used to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears. Viral replication starts early after transplantation and progresses through noticeable phases: viruria then viremia followed by nephropathy.
Monitoring of the urine may detect BKV-infected epithelial cells, aggregates of BKV virions, or quantification of urinary BKV viral load. Cytological analysis of urinary smear may reveal characteristic abnormal BK-infected cells, termed as decoy cells. Decoy cells are infected tubular epithelial cells with an enlarged nucleus that contains a single, large, basophilic intranuclear BK inclusion body and looks similar to those seen frequently in uroepithelial malignancy. Reported a sensitivity of 100%, and a specificity of 71% when they matched graft-biopsy samples as a diagnostic standard.
Quantitative measurements of urinary BK virus-viral loads using urinary BKV-PCR have 100% sensitivity and 78% specificity. However, variability in laboratory measurements has created difficulties in standardizing this technique for definite diagnosis. Recently, BK viral capsid (VP1) protein 1-mRNA derived from urinary cells has been analyzed as a biomarker to detect active viral replication. This assay is highly specific and sensitive, but requires further validation. Additionally, raised mRNA levels for granzyme B (>11 mRNA copies/μg total RNA) are usually present in recipients with acute cellular rejection, which may overestimate the prevalence of BKVN.
Serology serum BK PCR :
BK viremia is mainly seen in immunocompromised patients, with an estimated prevalence of 7-30% in the initial 6 months and 5-10% after that among kidney recipients. Quantitative BKV-DNA in plasma has been successful in identifying early infection before nephritis.
Nephritis can be seen with plasma BKVDNA of less than 7000 copies/ml, The BKV-PCR test has high sensitivity and specificity, but there are interlaboratory variations in measuring BK viral loads. Serum antibodies against BKV are commonly present.
Kidney biopsy:
Kidney biopsy is the gold standard to diagnose BKVN, but different threshold values have been proposed to anticipate the disease. BK viral inclusions within tubular epithelium can be identified via conventional hematoxylin and eosin (H&E) and PAS staining, while in-situ hybridization (FISH) analysis allows for BKV identification in renal transplant tissues through bright nuclear fluorescence technique.
Suggested algorithm for screening:
Different screening protocols have been developed for BKV screening in renal transplant recipients, with Hirsch et al. recommending a step-wise methodology and Ramos et al. recommending periodic screening of urine cytology for decoy cells. Buehrig et al. and Khamash et al. recommended routine surveillance biopsies to detect silent BKVN, and American Society of Transplantation guidelines recommended further annual screening till the fifth year after transplant. Most transplant institutes, including our center, recommend BK surveillance with plasma BK-PCR. Screening should be performed on periodic intervals, starting after 1 month, monthly, and every 3 months for the initial 1-2 years after transplantation.
Differential diagnosis:
Differential diagnosis of BKVN from acute rejection is important as treating the presumed rejection with increased immunosuppression may result in progression, but it can also occur concurrently with acute rejection. Differentiation between these two types of rejection is aided by blood or urine PCR and IHC staining of renal tissues or urinary sediments with anti-HLA DR, as well as a higher quantity of CD20+ cells in the tissue infiltrates and increased expression of genes related to inflammation and acute rejection. The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of coexistence.
Treatment :
Reducing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response, but should be balanced against risk of rejection.
Treatment of BK virus nephropathy in the setting of allograft dysfunction:
Reducing immunosuppression is a rational option for treating BK virus nephropathy in the setting of allograft dysfunction.
Cidofovir :
Cidofovir is a cytosine analog and viral DNApolymerase inhibitor used to manage other viral infections, but its mechanism of action is unclear.
mTOR inhibitors:
MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression, but lack clinical efficacy.
Intravenous immunoglobulin:
IVIG has the most potent antiviral influence, but its efficiency is uncertain.
Other therapeutic options for treating BK virus
nephropathy:
Quinolones and statins have been found to inhibit LTAg helicase activity and have in-vitro and invivo activity against BKV. Artesunate has been found to decrease BKV proliferation in a dose-dependent way, and rituximab has been reported promising results in nine transplant patients with BKVN. The standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine.
Short-term and long-term allograft survival:
BKVN caused permanent allograft damage in 30-60% of cases, but the renal allograft survival for recipients with BKVN had improved considerably in the past years. Therapeutic approaches have revealed substantial short-term improvements, but long-term outcomes such as late acute and chronic rejections need to be further evaluated. Buehrig et al. reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis.
BK nephropathy with concurrent acute rejection:
Management of proven allograft biopsies of acute rejection with concomitant BKVN or anticipated rejection following a decrease of immunosuppression is debatable. Steroid pulses can reduce viral load, but antirejection therapy may be more effective.
Postinfection monitoring:
Postinfection monitoring of BKV-PCR and renal function is essential to improve allograft outcome. Retransplantation is possible and can be done successfully.
Conclusion:
Early diagnosis of BKVN has improved allograft outcomes despite lack of specific treatment.
level of evidence provided by this article?
level V
Please summarise this article.
The term BKVN has been created to recognize recipients with
(a) significant viruria, suggesting viral proliferation in the urinary tract
(b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks
BK-PCR has high sensitivity and specificity in anticipating BKVN different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN
Thus, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction .
. Ultimately, a persistent BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis Three grades of histopathological severity have been identified grade A includes viral cytopathic changes of near-normal renal parenchyma, with no or minimal tubular atrophy, interstitial fibrosis, or inflammation, to stage C, which signifies diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation.
screening protocols had recommended
a step-wise methodology for BKV screening in renal transplant recipients. screened patients for BKV, first with urine cytology for decoy cells every 3 months, and whenever decoy cells were detected, additional studies were carried, including quantification of viral level in the plasma with the possibility of doing allograft biopsy only with a deterioration of renal function.
. Buehrig et al. and Khamash et al. had suggested routine surveillance biopsies to detect patients with silent BKVN. Allograft biopsies were performed at third/fourth month and at 12 months after transplantation, and many patients were detected with a silent disease
Differential diagnosis
Allograft rejection is challenging as the histological appearance is often similar; aided by analysis of blood or urine PCR.
Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN. Nevertheless, BKVN may exist concurrently with acute rejection
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells.
Furthermore, absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported
in someBKV cases and islinked with more aggressive disease
Another useful technique to differentiate between acute rejection and BKVN is IHC staining of renal tissues or urinary sediments with anti-HLA DR, which has been related to acute rejection
Besides, a higher quantity of CD20+ cells in the tissue infiltrates has been associated with BKVN as opposed to acute rejection . Moreover, the expression of genes related to inflammation and acute rejection (such asCD8, interferon-gamma,CXCR3, and perforin) was higher in patients with BKVN compared with acute rejection.
Another differential diagnosis includes any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction.
Treatment strategy of BK virus nephropathy
decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection Rapid viral load reduction has been related to steady or improved allograft function
Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI
Withdrawal of the antimetabolite such as MMF is the most usual method
Treatment of BK virus nephropathy
Drugs with antiviral activities
A metabolite of leflunomide teriflunomide (A77 1726) can inhibit BKV replication in vitro and, to a minor degree, the level of virion assembly and release . Leflunomide is given orally, with a loading dose of 100 mg daily for 3–5 days followed with a maintenance dose of 20–40 mg/day and recommended target level of 40–100 μg/ml. ; thus, treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages .
Cidofovir showed in-vitro inhibitory action against polyomaviruses though the mechanism of action is unclear as BKV lacks the viral polymerase gene, the known target of cidofovir . Cidofovir is exclusively excreted through urine, resulting in high renal tubular cell concentrations. Hence, vigorous intravenous prehydration is needed
Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes
The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection;
Quinolones
It has been found beneficial in combination with leflunomide for treating BKVN
with a significant decrease in BK viremia
Rituximab Although therapy with anti-CD20mAb rituximab used for the treatment of antibody-mediated rejection was associated with several adverse effects including BKVN, CMV viremia, herpes zoster, and septic shock
yet Babel and colleagues had reported promising results by using rituximab in nine transplant patients with BKVN. Patients who had received rituximab as an adjuvant therapy with cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN. In both groups,
the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine. The viral load had normalized in most within 18.3±6.8 weeks . This is a single report, and further prospective randomized trials are required to validate the benefit of this therapy for BKVN
Retransplantation following graft loss owing to BKVN is possible and can be done successfully
Ramos et al. described successful retransplantation in 9/ 10 patients without recurrent BKVN,
An analysis of the USA-OPTN registry data for the period 2004–2008 showed 126 individuals got retransplant of 823 who lost their graft secondary to BKVN
All kinds of induction and maintenance therapy have been used for all recipients as per their center’s protocols. Of the 126 retransplants, BKV was reported in 17.5% of the cases; however, just a single kidney was lost because of repetitive BKVN.
The 1- and 3-year graft survival among the retransplanted individuals was excellent at 98.5 and 93.6%, respectively Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression
Allograft nephrectomy is not necessary before retransplantation; however, in the background of active viral replication, it appears sensible to eliminate the infected graft before getting a new transplant, though there is no evidence to support this approach
What is the level of evidence provided by this article?
the level of evidence is 5
Please summarise this article.
Introduction:
– Two human polyomaviruses, BK virus (BKV), simian virus 40 (SV40) and JC virus (JCV), were discovered in 1971, since that time BKV infection is a major cause of interstitial nephritis and allograft failure in kidney transplant recipients, presenting a diagnostic and therapeutic treatment dilemma.
– Gardner et al. and Mackenzie et al. were the first to detect BKpolyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient. This virus was found to have high homology with JCV, the other human polyomavirus, and was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipient.
Polyomaviridae variants:
The human BKV belongs to the Polyomaviridae (PyV) virions, are small, nonenveloped DNA viruses with icosahedral capsids that can withstand heating up to 50°C for 30 min and have a circular double-stranded DNA of ∼5000 base pairs. 12 additional human polyomaviruses have been isolated since 2007.
Epidemiology of BK virus:
BKV is a widespread virus that infects most humans around the world (60-85% of the general population), with primary infection occurring in early childhood and remaining dormant throughout life.
BK virus structure:
The BKV-DNA genome is divided into three parts:
(1) NCCR – ( The non-coding control region)
(2) Early viral gene region (EVGR)
(3) Late viral gene region (LVGR).
The NCCR regulates the expression of the early and late genes, while the LVGR encodes the capsid proteins VP-1, VP-2, and VP-3.
VP1 is highly immunogenic and is the target for neutralizing antibody, cellular immune recognition, and required for virion assembly and hemagglutination of human-erythrocytes.
BK virus variants:
Based on the differences in the DNA sequence of the VP1 region, BKV can be classified into four genotypes or subtypes. The most common subtype is genotype I, followed by genotype IV, genotypes II and III, and genotype IV. Four more subgroups of subtype I (I/b-2) and six subgroups of subtype IV (IV/a-1, IV/a-2, IV/b-1, and IV/c-1) have been discovered by phylogenetic research. These groupings might represent various migratory and geographic trends in the human population. Other forms of BKV, such as the rearrangement (rr) and archetypal (ww) variants, appear secondary to differences in the NCCR in addition to the genotypic variations of VP1. These genotypes’ clinical and immunological effects on the clinical features and progress of the disease are still unknown.
Immunological response to BK virus:
– Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA, leading to lytic infection and viral leakage. Collateral destruction with necrosis and apoptosis of noninfected tubular cells can lead to intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators.
– Humoral immunity may play a role in the pathogenesis of BKVN, as kidney recipients from asero-positive donors are more likely to develop BK viremia.
– The role of allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity in the development of BKVN is unclear, but CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been found in humans.
– BKV tropism to the renal tubular epithelial cells may play an additional role in the pathogenesis of BKVN, with a blockage of caveolin-induced endocytosis producing a substantial reduction in infectivity.
Pathogenesis:
BKV is usually sub-clinical or manifests as a mild respiratory symptom in childhood, and can remain latent in leukocytes, brain tissues, and lymph nodes for life. In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, leading to tubular cell lysis and viruria.
Routes of transmission:
The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations:
– BK viruria affects 30-40% of renal transplant recipients, while 10-15% develop BK viremia.
– BKV-associated nephropathy can occur as early as 6 days- 5 years post transplant, with incidence range of 2-15%.
– Ureteric stenosis, with prevalence of ureteric stenosis is 2–6%, Treatment should involve apercutaneous nephrostomy and dilatation, with concurrent reduction of immunosuppressive medications.
– Hemorrhagic cystitis, is extremely rare in SOT recipients, with 4 clinical grades from microscopic hematuria grade 1 to gross hamtauira with clots grade 4, treatment is by vigorous intravenous hydration and trans-urethral Cidofovir installation to reduce cumulative drug nephrotoxicity.
– Other rare manifestation: primary central nervous system disease or reactivated central nervous system infection, it has been linked to pulmonary diseases, ophthalmologic manifestations, hepatic disease, and autoimmune diseases. Taguchi and colleagues were the first to report the isolation of BKV (decoy cells) from a urine sample of two patients with SLE.
BK virus and malignancy:
– Brain tumors of glial and neural origins have been found to have BKV-DNA in tissue samples from various neoplasms. Because early coding region-encoded proteins such the large tumor antigen (LTAg) and STA are expressed.
– It has been suggested that BKV possesses an oncogenic characteristic. Agnoprotein and LTAg makes the infected cells incapable of stopping the cell cycle.
– Urothelial cancers can be brought on by the inactivation of the tumor suppressors p53 and pRb. Yet, because tumor cells are more susceptible to BKV than normal urothelium, positive does not cause neoplastic transformation; rather, it is a consequence of it.
BK virus and urothelial tumors:
Only a few cases have been reported. Rollison et al. found BKV-DNA by PCR in 5.5% of Urothelial tumors, but Roberts et al. reported no evidence of BKVLTAg in 20 immunocompetent patients.
Risk factors:
Overall immunosuppression, male sex, recipient age, previous rejection episodes, HLA mismatching, cold ischemia, BK sero-status, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion.
Screening and diagnostic tools:
– BKV screening: starts at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
– Screening for active BKV replication may include detection of viral DNA-PCR in urine and blood.
– Viral replication in the urine precedes BK viremia by ∼4 weeks, and BKVN are observed 12 weeks after BK viruria.
Monitoring of the urine:
– Decoy cells are tubular epithelial cells with an enlarged nucleus that contains a single, large basophilic intra-nuclear BK inclusion body and look similar to those seen in uro-epithelial malignancy. (sensitivity of 100%, and a specificity of 71%)
– EM Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein that can be detected in a urinary smear of kidney recipients. However, it requires further validation and cannot be used in routine clinical practice due to the expense and difficulty of electron microscopy.( senisitivity of 100% and specificity of 99% in BKVN with very high viral load)
– Molecular analysis of urinary BKV-PCR has 100% sensitivity and 78% specificity, but variability in laboratory measurements made it difficult to diagnose.
– BK virus mRNA levels in urine, this assay is highly sensitive and sensitive, but requires further validation and may overestimate the prevalence of BKVN.
Serology:
– Serum BK-PCR is the preferred screening technique for BK viremia, prevalence 6-30% in first 6 months post transplant.
– Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis.
– BK-PCR has high sensitivity and specificity, but there are substantial inter-laboratory variations in measuring BK viral loads.
– Serum antibodies have no clinical relevance, but (BK D+/R−) is a risk factor for the development of clinically significant BK disease in allograft recipients.
– Virus culture can be isolated from a urine sample before any rise in antibody titers, but is hardly used.
Kidney biopsy:
– Allograft biopsy is the gold standard to diagnose BKV, with a sensitivity of 94.7% and specificity of 100% for detecting BKV. Histologically, streaky fibrosis of the medulla with cortical scars can be seen, while microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates
– Three different histological grading systems are available, with the Banff grading system having a moderately good intra-observer agreement.
– Tissue BK PCR is not an applicable investigation to diagnose BKVN.
Suggested algorithm for screening:
Different types of screening are there:
– Stepwise methodology: when decoy cell detected in urnie microscopy then other modalities for diagnosis.
– Routine surveillance biopsies to detect silent BKVN.
– Rourtine surveillance eith plasma BK-PCR.
American Society of Transplantation guidelines recommend further annual screening till the fifth year after transplantation, but screening beyond 2 years is not recommended in most centers unless allograft dysfunction is present.
Allograft biopsy can be considered with persistent high viral loads for more than 3 weeks.
Differential diagnosis:
Allograft rejection.
Other viral infections.
Treatment strategy of BK virus nephropathy:
Treatment is by restoring antiviral immune response/ by reduction of IS, and saving the graft from rejection.
– Treatment of BK virus nephropathy is by reducing or modifying immunosuppressive therapy -/+ antiviral medications. This can include withdrawal of antimetabolite drugs, changing from mycophenolate mofetil (MMF) to azathioprine,sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI), or converting tacrolimus to cyclosporine or discontinuing CNI.
– Frequent graft function monitoring and biopsy when needed.
Drugs with antiviral activities:
Leflunomide: is an immunomodulator, prodrug, and antirheumatic disease-modifying drug developed to treat rheumatoid arthritis, Adverse effects include hemolysis, aplastic anemia, thrombocytopenia, and probablythrombotic microangiopathy, hepatitis, and worsening of hypertension, it is un known is it the drug working on BK viremia or the reduction of immunosppressives.
Cidofovir: is a cytosine analog and viral DNA polymerase inhibitor, given intravenously every 2-3 weeks, it is nephrotoxic (AKI,RTA, and proteinuria).
Brincidofovir: is a new antiviral drug with less toxicity and given orally.
mTOR inhibitors: may be effective in reducing viral replication.
Intravenous immunoglobulin: IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain.
Quinolones: ? have been found to inhibit LTAg helicase activity and have in-vitro and in-vivo uncertain activity against BKV.
Artesunate: ? antimalarial drug, decreases BKV proliferation in a dose-dependent way.
Statins (pravastatin): ? reduce BKV-infected cells and LTAg expression in renal proximal tubular epithelial cells.
Rituximab: ? in nine patient received rituximab – no graft loss were observed.
Short-term and long-term allograft survival:
BKVN caused permanent allograft damage in 30-60% of cases,
Buehrig et al. reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis.
Chenet al. reported 1-, 3-, and 5-year allograftsurvival rates following a diagnosis of BKVN as 99.2, 90.7, and 85.7%, respectively.
BK nephropathy with concurrent acute rejection:
Anti-rejection therapy with subsequent IS reduction, is suggested.
Postinfection monitoring:
– Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is essential to improve allograft outcome.
– The transplant recipients who have their immuneosuppression reduced for BKVAV, with a serum creatinine test every 1-2weeks and plasma BK-PCR level at 2-4-week intervals for 8 weeks. BK viremia clears in 7-20weeks.
– If viremia persists despite reducing the maintenance therapy, further reduction should be considered or changing to sirolimus, or adding leflunomide. Inability to clear BKV can lead to worse allograft outcomes.
Retransplantation following BKV induced graft loss:
An analysis of the USA-OPTN registry data for the period 2004-2008 showed 126 individuals got retransplant of 823 who lost their graft secondary to BKVV, with BKV reported in 17.5% of the cases. The 1- and 3-year graft survival among the retransplanted individuals was excellent at 98.5 and 93.6%, respectively.
Conclusion:
Early diagnosis of BKVN has improved allograft outcomes despite lack of specific treatment.
What is the level of evidence provided by this article?Level of evidence V – erratic review.
Introduction
BK virus (BKV) is identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients in the first year after transplantation. It usually presents with asymptomatic gradual rise in creatinine and tubulointerstitial nephritis.
It may mimic acute rejection therefore making its diagnosis and treatment more difficult.
BKV belongs to the polyomaviridae (PyV) virions, a subgroup of papovavirus. It is a family of small, non-enveloped DNA viruses with icosahedral capsid and a double stranded DNA. It usually infects humans. Primary infection takes place during early childhood, and then the virus stays dormant throughout life in the immune-competent population.
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1. The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined. BKV replication occurs during a state of immune suppression, for example in pregnancy, diabetes, HIV infection, cancer, and post-transplantation period. It usually begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
Immunological response to BK virus
There are possible factors that contribute to the pathogenesis of BKV nephropathy (BKVN), such as:
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity and aid to clear BKV. T cells react against both nonstructural and BK capsid proteins. Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA. Without appropriate immunological regulation, progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination into the interstitium. Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation. The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis. Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss.
Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, sometimes manifests as a mild respiratory symptom in childhood. It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria. During the use of immune suppressive medications, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria. The outcome relies on the level of damage, inflammation and fibrosis.
The route of transmission of the infection may be via respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations
In immunocompromised patients, particularly in renal allograft recipients, BKV usually presents as BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis. Other clinical manifestations include neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome and vasculopathy. Clinical signs may include headache, dizziness, confusion, paraplegia, ataxia, and seizures. Pulmonary disease may be reactivated, and the acute respiratory infection may lead to severe interstitial pneumonitis.
Risk factors
Risk factors for BKVN include degree of immune suppression, male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion.
Screening
It is recommended that BKV screening should start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years. Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood. However, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml, with or without allograft dysfunction.
Histology
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically, whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BKV affects the kidney allograft in an erratic, multifocal manner; hence, false-negative biopsies may occur, specifically at early stages of the disease, therefore a repeat biopsy may be warranted.
Differential diagnosis
Differential diagnosis include allograft rejection, and any other disease associated with early (1–12 weeks after transplantation) and late ( ≥ 3 months transplantation) renal allograft dysfunction.
Treatment
The aim of treating BKV is to eradicate the virus while saving the kidney function. Unfortunately, BKVN has limited treatment options. Decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response. However, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection. Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI.
Drugs with antiviral activities
Leflunamide
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug. It can inhibit pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects. However, being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; thus, treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages. Therefore, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage. Additionally, leflunomide has a higher rate of adverse effects such as hemolysis, aplastic anemia, thrombocytopenia, and probably thrombotic microangiopathy, hepatitis, and worsening of hypertension.
Cidofovir
Cidofovir is a cytosine analog and viral DNApolymerase inhibitor that is used to manage other viral infections such as CMV. It has shown inhibitory action against polyomaviruses in vitro. Cidofovir is excreted through urine, resulting in high renal tubular cell concentrations. Hence, vigorous intravenous prehydration is needed with dose adjustment if renal dysfunction is present. Cidofovir is a nephrotoxic drug, it may cause acute kidney injury, renal tubular acidosis, and proteinuria. It may also cause severe anterior uveitis which may lead to permanent visual impairment.
mTOR Inhibitors
mTOR inhibitors have shown effectiveness in in-vitro analysis in inhibiting BK replication and early gene expression. Similar to other therapeutic options, the administration of mTOR inhibitors was concomitantly used with lowering immunosuppression, questioning its clinical efficacy against BKV.
IVIG
Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes. However, the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression.
Other therapeutic options include quinolones, artesunate, pravastatin and rituximab.
Allograft survival
The renal allograft survival for recipients with BKVN has improved considerably in the past years. The documented acute rejection rates following a reduction in immunosuppression varies from 6 to 12%. Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening. However, 27% had experienced permanent allograft dysfunction and 18% ultimately lost their allograft secondary to BKVN.
BK nephropathy with concurrent acute rejection
Management of acute rejection with concomitant BKVN is debatable. More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection. Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN. In the absence of typical features, such as strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage, which could be indicators for acute rejection, the management should be tailored for each patient individually. The delayed improvement in renal functions following a reduction in immunosuppression is likely to reflect the slow resolution of the cellular infiltrate.
Post-infection monitoring
Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome. Based on different literature, BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression. If viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide. Inability to clear BKV can lead to worse allograft outcomes.
Re-transplantation
Re-transplantation following graft loss owing to BKVN is possible and can be done successfully. Generally, pre-transplant clearance of BK viremia is essential after minimizing immunosuppression. The patient may get infected with BKV after re-transplantation. Recurring BKV might reflect a previous BK variant or a new infection (de-novo BKV) acquired, because of the long period, in the post-transplantation stage.
Level Of Evidence:
This is a narrative review, therefore the LOE is level V
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
Dear All
How would you treat BKV infection in 2 words ONLY
Minimise the immunosuppressive medication
Not good enough
Reduce immunosuppression
Not good enough
May I have a clue professor?
D/C. MMF
Decrease CNI
Finally the two word =>Decrease Immunosuppression
And give a Prednisolone 10 mg
Not good enough
Immunosuppression reduction
Not good enough
Immunosuppression reduction
Not good enough
Thanks; our Prof.
Reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
The main treatment of BKV infection;
RIS
Not good enough
Not good enough
Immunosuppression Reduction
Not good enough
Treatment In kidney transplant recipients with detectable BKPyV viremia or biopsy-proven BKPyVAN, recommended reducing maintenance immunosuppression.
•Several agents have been shown to have in vitro anti-BKPyV activity, including intravenous immune globulin (IVIG), leflunomide, cidofovir, and quinolone antibiotics.
However, not routinely use any of these agents for the treatment of BKPyV infection, given that the efficacy of these agents has not been established and use of these therapies has not been clearly shown to be superior to reduction in immunosuppression alone.
I agree.
Which drug needs to be discontinued?
In patients who are on a triple immunosuppression therapy consisting of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate mofetil/sodium or azathioprine), and prednisone, we initially reduce the dose of the antimetabolite by 50 percent. If the BKPyV viral load does not decrease within two to four weeks, we completely discontinue the antimetabolite. If there is still no decrease in viral load after another two weeks, we decrease the dose of the calcineurin inhibitor by 25 to 50 percent, targeting a whole blood tacrolimus trough level of 4 to 6 ng/mL or a whole blood cyclosporine trough level of 60 to 100 ng/mL.
An alternative approach that is used by others is to first decrease the dose of the calcineurin inhibitor by 25 to 50 percent in one or two steps, followed by reducing the antimetabolite by 50 percent, followed by discontinuing the antimetabolite
●In patients who are on a glucocorticoid-free maintenance regimen with a calcineurin inhibitor and an antimetabolite without prednisone, a similar approach as described above for patients on triple immunosuppression therapy may be used. However, transplant centers may feel less inclined to use monotherapy with either a calcineurin inhibitor or antimetabolite. An alternative approach is to reduce both the calcineurin inhibitor and the mycophenolate, which allows both the targeting of two pathways and lower total immunosuppression.
Thank you Prof. Ahamd.
in two words the treatment is by restoring antiviral immune response/ by reduction of IS, and saving the graft from rejection.
The two words are “Restore immunity.”
This will be achieved by careful reduction of the immune suppression (as explained by my colleagues) to allow the recipient’s immune system to deal with the infection.
Thanks alot for you Prof.Halawa
Decrease maintain immunosuppressive in recipients of kidney transplants who have biopsy-proven BKPyVAN or detectable BKPyV viremia, but avoid using in vitro anti-BKPyV medicines on a regular basis.
Reduction of immunosuppression MMF by 50% or even stop, second CNI by 25% is the first step in treating BKV infection and closely monitoring for risk of rejection, if no response will consider IVIG 0.4mg /kg every 3 weeks ( based on limited evidence)
The two words include reduction/modification of IS
1. Reduction of MMF, CNI
2. Modification of IS to m TOR inhibitors with CNI minimization
this is our practice in local centre , also in few cases used IVIG, we are not using lefuloniamde or cidofovir
Balance modifying /reducing the power of immunosuppression to increase immunity against the virus.
MMF withdrawal is the most common practice.
Many centres do this plus givingLeuflomide
…
We managed a 20-year-old female who was just discharged yesterday. She presented with haemorrhagic cystitis and developed post-renal aKI due to ureter stenosis despite Leflomide and MMF withdrawal. BK was proven by biopsy (bladder and kidney), nephrostomy was applied for 8 days. We gave both iv and intravesical cidofovir. No need to DJ stent, and the nephrostomy was removed. A second dose (cidofovir plus probenecid) is planned for next week
Thnxs prof,
immunosuppression reduction
Balance immunosuppression (rejection vs virus infection)
REDUCE IMMUNOSUPPRESSION
Reverse immunity.
Immunosuppression reduction
MMF can be stopped and Tac dose reduced and mTORI
m-TOR inhibitors (m-TORIs) have been shown to have antiviral properties in vitro
Reference
Jouve T, Rostaing L, Malvezzi P. Place of mTOR inhibitors in management of BKV infection after kidney transplantation. J Nephropathol. 2016;5(1):1-7.
Reduce immunosuppression in 2 words
details : D/C antimetabolites ,optimize the dose of tacrolimus to therapeutic level and continue on prednisolon
Immunosuppression modification.
Stop IS (Stop MMF and reduce CNI25-50%) AND resume when the virus is cleared.
How would you treat BKV infection in 2 words only?
Stop MMF
BKV infection at the level of viruia or viremia or graft invasion??
only 40% kidney transplant patients develop viruria ,20% will develop viremia but only 10% will develop BK nephropathy and less than 5% with develop graft loss because of BKN.
there is no strong evidence in the management of BKV infection in each stage.
immunosuppression reduction (MMF or azathiopurine) is the corner stone for managment but after some consideration like date of transplant, history of graft rejection, immunological risk, stability of CNI level and stability of kidney function because of probability of misdiagnosis of underlying rejection.
individualized management from case to another should be considered with frequent monitoring of kidney functions during slowly withdrawal of immunosuppression with early kidney biopsy if AKI happened at any stage.
immunosuppression modification
Remove mycophenolate
RIS reduction of immunosuppression
Reduce IS; stop MMF, reduce CNI.
reduction in immunosuppression
if not work than stop metabolite
-early detection
-restore immunity as mentioned by colleagues
enhance immunity
RIS and monitor graft function.
Reduce IS (stop MMF, reduce CNI and strat steroids )+ antiviral in severe cases
Reduction immunosupression
Reduce or stop immunosuppression.
Early diagnosis
Immunosuppressive reduction
– immunosuppression reduction
– aim of treatment is to eradicate the virus while preserving graft function (without triggering graft rejection)
– reduce/ modify the immunosuppressive therapy ± antiviral drugs
– options:
– tacrolimus and cyclosporine have been shown to inhibit anti-BKV-specific T-cell reaction
– MMF may limit the proinflammatory and profibrotic cytokines
Immunosuppression reduction
Reconstitute immunity or immunne response
Reduce immunosuppression
SUMMARY
Introduction
The human BK virus named after the initials of the person it was first discovered in 1971 belong to Polyomaviridae comprising JCV, BKV, and Simian virus 40. BKV is one of the common early post-kidney transplant infections that could lead to graft loss by BKV nephropathy if not detected early enough. Moreso, there are twelve more polyomaviruses that are named based on the disease they cause, geography, or their epidemiology
Epidemiology of BKV
Pathogenesis of BKV Infection
Route of transmission of primary BK virus
Clinical Manifestation
Risk factions for BKV
screening time and test
Treatment of BKVN
Other medications that have been used with varying outcomes
Conclusion
In spite of three decades of research in the field of BKV, there still remain some unanswered question like definitive treatment that could bring a cure, although some of these searches has helped the understanding of early diagnosis and some early intervention that may help to prevent the progression to BKVN. There is also challenge of difficulty in differentiating acute allograft rejection from BKVN, and sometimes the two may coexist. Retransplantation is possible after graft loss, and the common reason is to remove the failed graft after period of undetected BKV
Level of evidence is 5
Thank you for your summary.
Prevalence: Primary infection occurs mainly in childhood and account up to 85% of the general population is seropositive for BKV
BK virus structure The BKV-DNA genome is divided into three parts: the noncoding control region NCCR, the early viral gene region, and the late viral gene region (LVGR).
The later encodes the capsid proteins VP-1, VP-2, and VP-3. VP1 is the main capsid protein present on the surface and is responsible for receptor binding to the host cells, facilitating virus entry into the cell.
BK virus variants: (according to VP1) They are four variants, the most common is genotype 1 ( 80%) followed by genotype 4 (15%)
Immunological response to BK virus: BKV replication and resolution of BKV Nephropathy is caused by defective immune surveillance, absence of humoral immunity, alloimmune activation, and viral variation in molecular sequences.
Pathogenesis of BK infection
o Primary infection is usually subclinical and rarely manifests as a mild respiratory symptom in childhood
o Infect tonsils first then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys
o Stay dormant in the uroepithelium, renal tubular cells, leukocytes, brain tissues, and lymph nodes
o In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitial and peritubular capillaries
Routes of transmission of primary BK virus might be respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations
1.BK virus and renal disease
2- Others: hepatitis, interstitial pneumonitis, atypical retinitis, CNS (meningoencephalitis, encephalitis, GBS), AIDs (SLE, RA)
3- malignancy: It associated with urothelial tumours in particular bladder Ca, brain tumors of glial and neural origin, Kaposi sarcoma.
Risk factors
o Overall degree of immunosuppression (the most important risk)
o Other risk factors include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion
Screening and diagnostic tools
Timing of screening: at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years
A) Urine: cytology for Decoy cells and EM for Haufen (PPV 95%)
B) Serology: BK-PCR (100% sensitivity and 88% specificity)
Serum antibodies
C) Kidney biopsy: (the gold standard to diagnose BKVN) – should be performed when BKV-PCR load 4 log with or without allograft dysfunction. Biopsy findings can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result; therefore, a minimum of two biopsy cores, preferably including medulla, should be inspected to make the correct diagnosis.
BANFF histological grading systems for BK virus nephropathy:
Class A: A variable number of virus-infected cells with NO or MINIMAL injury to tubular epithelial cells
Class B: Tubular epithelial cell necrosis or lysis with denudation of basement membrane across a length of more than two cells
Class C: Any degree of tubular injury with interstitial fibrosis affecting >50% of the cortex
Differential diagnosis between rejection and BKVN Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN
1. SV 40 staining: BKV inclusion bodies
2. Absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane, IHC staining of renal tissues or urinary sediments with anti-HLADR (acute rejection)
3. A higher quantity of CD20+ cells in the tissue infiltrates (BKVN)
Treatment strategy
Treatment of presumptive BK virus nephropathy:
o Reduction/or modifications in immunosuppressive therapy with or without antiviral medications
o Withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance
Drugs with antiviral activities:
– Leflunomide: inhibit viral replication and have to be given with removal of antimetabolites as MMF or azathioprine and decreasing CNI dose.
– Cidofovir (nephrotoxic) and Brincidofovir (prodrug)
– mTOR inhibitors: inhibits BK replication and it improves the immune reaction after BKV infection
– IVIG: It has immunomodulatory effect, it’s use alongside with Immunosuppressives reduction medications in treating BKVN with concurrent acute rejection
– Others (quinolones, artesunate, pravastatin, and rituximab)
BK nephropathy with concurrent acute rejection: Management is debatable
Postinfection monitoring: Cr test every 1–2 weeks and plasmaBK-PCR level at 2–4-week intervals for 8 weeks then monthly bases until clearance of BK viremia
= BK viremia clears in 7–20 weeks (the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression). If viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide
Retransplantation can be done successfully
What is the level of evidence provided by this article?
Level 5
Thank you for your summary.
Introduction;
-The two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971,
-The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and Simian virus 40 (SV40).
Epidemiology of BK virus;
-Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
-Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people.
-60–85% of the general population is seropositive for BKV as showed in Studies.
BK virus variants;
-BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1.
-Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population.
-Alternatively, genotypes II and III are relatively rare and infect only a minority of patients.
The role of cell-mediated immunity;
-CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
-From immunological factors involved in the development of BKVN are Humoral immunity and another possible is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity.
Pathogenesis of BK infection;
-Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
-It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
-Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
Risk factors;
–The most consistent risk factor is the overall degree of immunosuppression.
-Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion.
Routes of transmission of primary BK virus;
-Several routes for The primary BKV virus transmission have been theorized.
-The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
-Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes.
Clinical manifestations;
-Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals (but not in plasma); nevertheless, BKV does not cause disease in immunocompetent people.
-BK virus-associated nephropathy; Clinically, it begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
-The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
–Ureteric stenosis;The prevalence of ureteric stenosis is 2–6% .
-Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
–Hemorrhagic cystitis; BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients.
-Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy.
Screening and diagnostic tools;
–The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears.
-KDIGO guidelines had recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Monitoring of the urine:
-Including detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
-Urinary tests are highly sensitive for detecting active BKV infections. However, they lack specificity for BKVN as the detected viral particles could originate anywhere along the urinary tract.
-Different laboratory assays have created difficulty in standardizing the cutoff values for a definite diagnosis.
-Although decoy cells are suggestive but not definitive in diagnosing BKVN, their absence does not exclude the disease.
-Additionally, it can be confused with other viruses, such as cytomegalovirus (CMV) and adenovirus infection, though CMV can cause cytoplasmic besides the intranuclear inclusions
Serology;
–Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis.
-Plasma DNA-PCR has high sensitivity and specificity in anticipating BKVN; however, there is substantial interlaboratory variations in measuring BK viral loads with lack of international standardization.
-Moreover, the sensitivity and specificity of PCR seems to be assay dependent and should be interpreted in the light of clinical condition.
-Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels.
Serum antibodies , Virus culture
-Kidney biopsy;
–Allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log 10 genome (copies/ml)) with or without allograft dysfunction.
-However, biopsy findings can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result; therefore, a minimum of two biopsy cores, preferably including medulla, should be inspected to make the correct diagnosis.
Treatment strategy of BK virus nephropathy;
–The aim of treating BKV is to eradicate the virus while saving the kidney function.
-The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
-There is no standard strategy for modifying immunosuppressant’s therapy; however, different regimens have been attempted ;
-Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI.
Drugs with antiviral activities;
-Leflunomide , Cidofovir , brincidofovir (CMX001).
Other therapeutic options for treating BK virus nephropathy;
-Quinolones , Artesunate (an antimalarial drug) , statins (pravastatin) , Rituximab
BK nephropathy with concurrent acute rejection;
-Management of proven allograft biopsies of acute rejection with concomitant BKVN or management of anticipated rejection following a decrease of immunosuppression to treat BKVN remains debatable.
-There was study suggested; combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection.
-Follow the transplant recipients who have their immunosuppression reduced for BKVAV, by
monitoring BKVN, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
-Subsequently, it should be done on a monthly bases until clearance of BK viremia (or at least viral burden falls below threshold values) and stabilization of renal function achieved.
Retransplantation;
-Retransplantation following graft loss owing to BKVN is possible and can be done successfully.
-pre-transplant clearance of BK viremia is essential after minimizing immunosuppression.
-There is no evidence to support such as allograft nephrectomy is not necessary before retransplantation; however, in the background of active viral replication, it appears sensible to eliminate the infected graft before getting a new transplant.
-Although. BKV viruria, viremia, and BK nephropathy can recur and cause allograft loss.
-Recurring BKV might reflect a previous BK variant or a new infection (de-novo BKV) acquired, because of the long period, in the post-transplantation stage.
Level of evidence;
-This article is a narrative review, and this (LOE V)
Thank you, I appreciate your effort.
Summary
Introduction
BKV belongs to the Polyomaviridae a subgroup comprising JCV, BKV and SV40.
Additional 12 viruses have been identified.
BKV primary infections usually occurs in childhood after the virus remains dormant in immunocompetent individuals.
Seropositivity rates in the general population range between 60-85%, however there is scarcity of data in Africa and Middle East.
There are 4 genotypes of BKV, with genotype 1 being the most prevalent followed by genotype 4; genotype 2 and 3 are rare.
Immunological response
BKV replication follows a state of immunosuppression, hence occurs in pregnancy, HIV, DM, cancer and post-transplant period.
Possible mechanisms for the pathogenesis of BKVN are:
Pathogenesis of BKV infection
Primary infection is usually sub-clinical or presents as a mild respiratory infection.
BKV reaches the circulatory system through infected tonsils then disseminates to other organs.
The virus remains dormant in the uroepithelium and renal tubular cells.
It can also remain dormant in the lymph nodes, brain tissue and leukocytes.
In the presence of immunosuppressive therapy the virus replicates and spreads to the peri-tubular capillaries leading tubular cell lysis and viruria.
Reaction between the BKV and immune system leads to varies presentation of BK disease.
Clinical manifestation
Include BKVN, ureteric stenosis, and late onset hemorrhagic cystitis.
BKV and renal disease
Begins with viral replication in the uroepithelial cells, then viruria that progresses to viremia and later BK associated nephropathy.
BK viruria affects 30-40% of renal transplant recipients, while 10-15% of them get viremia and 2-15% have BKVAN.
BKVAN ends with irreversible kidney injury and allograft failure.
Ureteric stenosis
Prevalence is 2-6%, rarely does it lead to hydronephrosis and allograft dysfunction.
Treatment of ureteric stenosis involves placement of a percutaneous stent, percutaneous ureteral dilatation with concurrent reduction of immunosuppression.
Hemorrhagic cystitis
Commonly in the HSCT recipients and rare in renal allograft recipients.
Presentation include painful voiding, hematuria, painful bladder cramps+/- flank pains.
Four degrees of disease severity are recognised:
Management involve vigorous hydration.
Cidofovir given locally has been suggested as a treatment option.
Other clinical manifestations include:
BKV and malignancy
BKV DNA has been detected in tissue samples of different neoplasms.
It has been proposed that BKV has oncogenic properties owing to its LTAG and STAG proteins.
BKV Agnoprotein and LTAG are able to to arrest the cell cycle of an infected cell and keep it in a continuous diving state.
LTAG can also bind and inhibit cell regulators eg p53, Rb.
Risk factors
The most consistent risk factors is the degree of immunosuppression, other risk factors identified have been variable among studies and the include male gender, older age of recipient, some ethnic groups, degree of HLA mismatch, cold ischaemia time etc.
Timing of screening
Most BKVN have been reported in the first year post-transplant.
Incidence of BK viruria and viremia have a bimodal peak with the first peak in the third month post-transplant then gradual decline and the second peak in the 12 month but with few detected cases.
Screening tests
Viruria precedes viremia by approximately 4 weeks while BKVN occurs 12 weeks after viruria.
Urine cytology
Decoy cells
They are infected tubular cells with with an enlarged nucleus with basophilic intranuclear inclusions.
Presence of decoy cells is strongly suggestive of polyomavirus infection and is considered as a marker of BKV reactivation.
It has sensitivity ranging between 25-100% and specificity 71-84% to diagnose BKVN.
Thus it is a poor diagnostic tool for BKVN and can’t be used to monitor declining viral loads.
Haufen
Icosahedral aggregates of BKV particles and Tomm-Horsfall proteins that can be detected in the urine smear using negative staining EM.
They are highly predictive in diagnosing BKVN however they are not routinely done in routine clinical practise.
Urine viral loads
Urine PCR has a sensitivity of 100% and specificity of 78%.
Persistent high viral loads can predicting patients at risk of BKVN.
However variability between laboratories makes it difficult to standardise it.
Serum BK PCR
Has a sensitivity of 100% and specificity of 88% thus it is the preferred screening tool in most transplant centers.
However not all patients with viremia will develop BKVN, PPV 50-60% ,NPV 100%.
Additionally the primers were designed against genotype 1 hence may not detect other different strains.
Kidney biopsy
Gold standard for diagnosing BKVN.
BKV affects the kidney erratically hence false negative biopsy may occur thus a repeat biopsy or pre-emptive treatment may be considered.
Viral inclusions can be identified by H&E and PAS staining.
IHC using specific antibodies against SV40 has a specificity of nearly 100%,does not differentiate between BKV and JCV.
FISH has sensitivity of 94.7% compared with 57.9% for H&E and 68.4% for IHC f; and a specificity of 100% comparable to 94.4% for H&E and 100% for IHC. However its use is limited.
Suggested algorithm for screening
Persistence of decoy cells for more than or equal to 3 months will trigger the performance of quantitative measurement of PCR-viral loads in plasma and renal biopsy in patients with evidence of BK viral reactivation, irrespective of renal function.
Screening for BKV should be performed on periodic intervals, starting after 1 month, monthly for 3–6 months, and then every 3 months for the initial 1–2 years after transplantation.
Differential diagnosis
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and IHC staining for SV40, highlighting the virally infected cells.
Can also be differentiated by IHC staining of renal tissues or urinary sediments with anti-HLA DR, which has been related to acute rejection.
Treatment
BK viremia and BKVN signify excessive cumulative immunosuppression, hence, decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Withdrawal of the antimetabolite such as MMF is the most usual method; however, a study by Egli et al showed that both cyclosporine and tacrolimus could inhibit anti-BKV-specific T-cell reaction, and not so much with MMF or prednisone challenging this practice.
Leflunomide
It’s an immune modulator given orally, loading dose of 100mg daily for 3–5 days followed with a maintenance dose of 20–40mg/day and recommended target level of 40–100 μg/ml.
Being a pyrimidine synthesis inhibitor, it cannot be combined with other anti-proliferative drugs like MMF or azathioprine; thus, treatment with this drug should involve simultaneous withdrawal of anti-proliferative medication and reduced CNI dosages.
Therefore, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage.
It requires higher dosage of the drug (≥40 mg/day) to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity.
It higher rate of adverse effects such as hemolysis, aplastic anemia, thrombocytopenia, and probably thrombotic microangiopathy, hepatitis, and worsening of hypertension
Cidofovir
Cytosine analog and viral DNA- polymerase inhibitor
Mechanism of action is unclear as BKV lacks the viral polymerase gene the known target of cidofovir.
It’s exclusively excreted through urine, resulting in high renal tubular cell concentrations.
Its nephrotoxic may cause acute kidney injury, renal tubular acidosis, and proteinuria hence caution in kidney transplant recipients.
Brincidofovir prodrug of cidofovir that gets converted to cidofovir when it goes intracellular. It’s effectiveness against all DNA viruses with no documented nephrotoxicity and ease of oral administration.
M-tor inhibitors
Inhibits the proliferation of BKV- specific T cells and controls the differentiation of memory CD8 T cells; hence, it improves the immune reaction following BKV infection.
Intravenous immunoglobulin
Potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
Selectivity index of more than 1000 as opposed to cidofovir and leflunomide selectivity index of 3.8 and 2.3, respectively.
IVIG in a dosage of 2–3.5g/kg divided over 2–5 days with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection.
The efficiency is uncertain, as it has been given with concomitant reduction in immunosuppression.
Quinolones
Beneficial in combination with leflunomide for treating BKVN with a significant decrease in BK viremia.
Though some studies have shown no benefit.
Post infectious monitoring
Scr every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks then monthly until clearance of BK viremia or at viral burden falls below threshold value and stabilisation of renal function achieved.
If viremia persists despite reducing the maintenance therapy, further reduction should be considered or to consider changing to sirolimus, or adding leflunomide.
Re-transplantation following graft loss owing to BKVN is possible and can be done successfully.
Clearance of BK viremia is essential before re-transplantation.
Allograft nephrectomy is not necessary before, however, in the background of active viral replication, it is sensible to eliminate the infected graft before getting a new transplant, though there is no evidence to support this approach.
Level of evidence:V
Thank you, I appreciate your effort.
BK virus in Renal Transplant Recipients
Summary of the article
a) The early viral gene region.
b) The late viral gene region.
c) The capsid protein VP1 in the LVGR is the main capsid protein.
a) DM.
b) Pregnancy.
c) HIV.
d) Cancer.
e) Post transplantation.
Immunological response
T-cell immunity
Humoral immunity
Alloimmune activation
Other factors
Pathogenesis
Routes of transmission of primary BK virus
Clinical manifestation (In immunocompromised patients)
a)Viruria, in 30-40 % in KTR.
b) Asymptomatic hematuria.
c) Allograft failure.
Risk factors
Screening and diagnosis
a) cytological finding in urine examination, and it is an infected tubular epithelial cell, with an enlarged nucleus with viral inclusion.
b) Useful marker of BKV reactivation.
c) sensitivity varies with different centers (100% sensitivity and 71% specificity by Hirch et al), while (25% sensitivity and 84% specificity by Viscount et al).
Differential diagnosis
Treatment
Treat BKN with concomitant acute rejection
Post-infection monitoring
Conclusion
Level of evidence
Level ((V))
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
I like your well-structured detailed summary.
Thank you, I appreciate your effort.
Introduction
-BKV infection can affect KTR and lead to significant impact of kidney function. It has variable presentation producing a diagnostic and therapeutic treatment dilemma.
-It was first described in 1971, in KTR presented with ureteric stenosis and virus named from patient initial.
-The virus became more recognized and its effect on the kidney is established as a cause for interstitial nephritis and renal failure.
Polyomaviridae variants
-It belong to Polyomaviridae (PyV), a subgroup of papovaviruses comprising BKV,JCV& SV40. With 12 additional new virus identified from the same group.
– It is a family of small, nonenveloped DNA viruses with icosahedral capsid of
Epidemiology of BK virus
-Primary infection occurs mainly during childhood, and the virus remain dormant in immunocompetent
– Around 60–85% of the general population is seropositive
BK virus structure
BKV-DNA genome can be divided into three parts:
The noncoding control region (NCCR): it regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell.
(1) The early viral gene region: it encodes for small T antigen (STA) and large T antigen.
(2) The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3.
(3) The capsid protein VP1 in the LVGR
BK virus variants
– Variation in VP1 DNA sequence or in the NCCR resulted in 4 genotypes/subtypes and different subgroup in each subtype, may reflect geographic variation.
– The clinical and immunological consequences of these genotypes are still undefined
Immunological response to BK virus
The immune system plays an essential part in controlling BKV replication, virus will replicates in immunocompromised state with combination of:
– Defective immune surveillance by the host T lymphocytes:
– Absence of humoral immunity to BKV;
– Allo-immune activation;
– Viral variation in molecular sequences.
Pathogenesis of BK infection
– Primary infection is usually subclinical in childhood.
– After that, it styed dormant in the uroepithelium and renal tubular cells for life.
– Intermittent reactivation manifests as asymptomatic viruria.
– In immunosuppressed state, the virus activates and proliferate inside the interstitium and crosses into the peritubular capillaries, producing cell lysis and viruria.
– Combination of direct viral cytolytic effects and secondary inflammatory result in tissue damage and fibrosis.
Routes of transmission of primary BK virus
– Respiratory route (1ry route).
– Gastrointestinal transmission: fecal-oral transmission
– Vertical transmission: transplacental
– Sexual transmission
– Donor-derived infection; similar
– Other proposed mode for BKV transmission is through the urine and blood.
Clinical manifestations
– BK virus and renal disease: start with shedding of infected cells in the urine (viruria 30–40%), which can progress a few weeks later to blood (viremia 10–15%) and then BK nephropathy (BKVN)/ (PyVAN) 2-15%
–BK virus-associated nephropathy: Nephritis occurs as early as 6 days after KT or as late as 5 years, may ends with extensive irreversible injury and allograft failure.
– Ureteric stenosis; in 2–6%, lead to hydronephrosis and may result in allograft dysfunction.
Treated with percutaneous nephrostomy and ureteral dilatation, with concurrent reduction of IS.
– Hemorrhagic cystitis: is extremely rare in KTR, noted frequently in HSCT recipients, present with bladder cramps, painful voiding, hematuria, and/or flank pain. Four grade of severity.
Treated with IV hydration, sometime needs bladder irrigation. Local bladder Cidofovir can be tried.
–BK nephropathy in the native kidney of HSCT, HIV and non-kidney SOTR; present with AKI without significant proteinuria.
–Neurological manifestations: can cause 1ry or 2ry CNS disease in HSCT/ HIV present with meningoencephalitis, encephalitis,
Guillain–Barre syndrome, and vasculopathy.
–Pulmonary diseases: severe interstitial pneumonitis
–Ophthalmologic manifestations: bilateral atypical retinitis,
– BK virus and hepatic disease; hepatitis in BMT
– BK virus and autoimmune diseases in nontransplant immunecompromised individuals; SLE, polymyositis, and RA.
BK virus and malignancy: virus DNA found in different malignancy;
– Brain tumors of glial and neural origin.
– Pancreatic islets cell tumors
– Kaposi sarcoma.
– Ewing sarcoma.
– Osteogenic sarcoma.
– Prostatic carcinoma.
– Urothelial tumors.
Conversely, tumor cells are likely more vulnerable to BKV than normal cells, as the infection happens mainly in
proliferating cells, causation is not certain.
Risk factors
-The overall degree of immunosuppression (the main factor).
-Others; male sex, older age, previous rejection episodes, HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion
Presumptive BKVN; patient with significant viruria and persistent viremia of more than or equal to 104 copies/ml for > 3 weeks.
Screening and diagnostic tools
Aim: early detection before significant damage occurs.
Timing of screening:
AST and KDIGO guidelines recommended; start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.
Screening tests
However, no single diagnostic pathway has appeared as predominant
Monitoring of the urine
– Urine cytology Decoy cells; (occurs in 13–30%); infected epithelial cells
– Urine electron microscopy (EM Haufen); aggregates of BKV virions.
– Urinary BKV viral load PCR.
– BK virus mRNA levels in urine
Urinary tests are highly sensitive for detecting active BKV infections. However, they lack specificity for BKVN as the detected viral particles could originate anywhere along the urinary tract.
Serum
– Serum BK-PCR; it is the preferred screening, there is substantial interlaboratory variations in measuring BK viral loads with lack of international standardization.
– Serum antibodies; routine bases is uncertain, it has no clinical relevance in diagnosing acute BKV infection
Virus culture BKV grows slowly in tissue culture, hardly used outside research setting.
Kidney biopsy the gold standard to diagnose BKVN, should be performed when BKV-PCR load insistently > 10000 copies/ml with or without allograft dysfunction
– Histologically, interstitial fibrosis might present with mononuclear cell infiltrates. BK viral inclusions& positive IHC using specific antibodies against SV40.
– Histopathological grading of the severity of BKAN; Banff grading has shown good intra-observer agreement.
-It affects the allograft in multifocal manner; hence, false-negative biopsies may occur (minimum of two biopsy cores including medulla).
Differential diagnosis
-Allograft rejection; differentiation is challenging for similar histological appearance, and they can present concurrently, features might help to differentiate;
* Presence of BKV inclusion bodies and IHC for SV40.
* Absence of definitive features of ACR; endotheliitis, extensive tubulitis & C4d deposition.
– Any disease associated with early (1–12 weeks post-Tx) and late (≥3 months post-Tx) renal allograft dysfunction.
Treatment strategy of BK virus nephropathy
– The only validated therapy to treat BKVN is decreasing immunosuppression should be balanced against the risk of rejection.
Treatment of presumptive BK virus nephropathy
– Reduction/or modifications in IS with or without antiviral medications.
-There is no standard strategy for modifying IS.
-Withdrawal of antimetabolite drugs or change from MMF to azathioprine, sirolimus, or leflunomide.
– Reducing the dose of CNI by 25–50%
-Converting tacrolimus to cyclosporine or discontinuing CNI
Treatment in the setting of allograft dysfunction
– Reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia in acute BKV with a steadiness of allograft functions in advanced stage BKVN
Drugs with antiviral activities
– Leflunomide; immunomodulator, can inhibit BKV replication, cannot be combined with other antiproliferative drugs
– Cidofovir; nephrotoxic drug
– Brincidofovir; new promising antiviral drug, prodrug of cidofovir, no documented nephrotoxicity
– mTOR inhibitors
-Intravenous immunoglobulin; immunomodulatory effects, has potent neutralizing antibodies
-Other therapeutic options: Quinolones, artesunate (an antimalarial drug), statins (pravastatin), Rituximab
Short-term and long-term allograft survival
-Renal allograft survival for recipients with BKVN had improved considerably.
-Substantial short-term improvements, such as eliminating the circulating viremia,
-long term outcomes such as late acute and chronic rejections need to be further evaluated
BK nephropathy with concurrent acute rejection
Management remains debatable.
Suggested; combination of antirejection therapy with a subsequent reduction in immunosuppression.
Generally, an initial decrease in IS without steroid pulses should be considered upon detection of BKVN.
Postinfection monitoring
Close observation of BKV-PCR and renal function with any treatment, especially after AR or reduction of IS is crucial to improve allograft outcome
-Serum creatinine test every 1–2 weeks & plasma BK-PCR level at 2–4-week intervals for 8 weeks. Then, done on a monthly bases until clearance of BK viremia (or at least viral burden falls below threshold values) and stabilization of renal function achieved
Re-transplantation
– Re-transplantation following graft loss owing to BKVN is possible and can be done successfully [10,13]. Ramos
– The graft survival among the retransplanted individuals was excellent
– Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression
– Allograft nephrectomy is not necessary before re-transplantation
– It can recur and cause allograft loss .
Conclusion
early diagnosis of BKVN has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.
Level of evidence: 5 narrative review.
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant. Typing whole sentence in bold amounts to shouting.
I like your well-structured detailed summary.
BK virus infection in renal transplant recipients: an overview
Please summarise this article:
Introduction
BKV, one of two human polyomaviruses discovered in 1971, was shown to induce interstitial nephritis and allograft failure in renal transplant patients three decades later. In the first year following kidney transplantation, BKV infection is one of several possible reasons of renal failure. Asymptomatic creatinine increases with tubulointerstitial nephritis may resemble acute rejection, creating a diagnostic and management conundrum.
BK epidemics:
BKV—polyomavirus hominins-1—infects most persons worldwide. In immune-competent humans, the virus remains latent after early childhood infection. 60–85% of the general population is BKV-positive. The only study on BKV prevalence in the Middle East and Africa came from Iran, with a seroprevalence of 41.8%. The age of the studied population, sample size, and antibody threshold explain such percentage variations.
BK virus immunity:
BK virus replication occurs after immune suppression in pregnancy, diabetes, HIV infection, cancer, and post-transplantation. As a result of strong immunosuppression, BKV replication usually starts early post-transplant. BKV replication and BKVN resolution depend on the immune system [48]. BKVN may be caused by (a) inadequate immunological surveillance by host T lymphocytes, (b) lack of humoral immunity to BKV, (c) alloimmune activation, and (d) viral variation in molecular sequences.
BK pathogenesis:
BKV primary infection seldom causes respiratory symptoms in children. BKV enters the circulatory system by infected tonsils and infects peripheral blood mononuclear cells, which spread to secondary sites, including the kidneys. The virus remains latent in the uroepithelium and renal tubular cells for life, sometimes reactivating as asymptomatic viruria.
BKV may also hide in leukocytes, brain tissues, and lymph nodes. In immunosuppressive treatment, the virus activates and proliferates in the interstitium and enters the peritubular capillaries, causing tubular cell lysis and viruria. Damage, inflammation, and fibrosis determine outcomes. Viral cytolysis and subsequent inflammatory responses harm tissue.
Different BKV illness symptoms originate from complex immune system-BKV interactions.
BK virus renal disease:
This virus proliferates in uroepithelial cells, causing viruria, viremia, and BK polyomavirus-associated nephropathy (BKVN) or PyVAN. 30–40% of renal transplant patients develop BK viruria, whereas 10–15% develop viremia.
BKVN is reported in 2–15% of kidney transplant patients. Different immunosuppressive regimens and screening strategies—including biopsy surveillance in certain centers—can explain these differences.
BK-related nephropathy:
BKV-associated nephropathy starts with viruria or asymptomatic hematuria and progresses to permanent damage and allograft failure. Nephritis might start 6 days or 5 years after a kidney transplant.
Ureteric stenosis the prevalence of ureteric stenosis is 2–6%.
Hemorrhagic cystitis: HSCT patients often develop BKV-associated HC or non-HC, although renal allograft recipients seldom do.
Other rare manifestations: neurological manifestations; pulmonary diseases, Ophthalmologic manifestations, BK virus, urothelial cancers
BKV-DNA was found in urothelial malignancies such as bladder carcinoma, and many believe BKV plays a major role in their development.
Risk factors:
There are many risk factors for BKVN. Immunosuppression is the most consistent risk factor in the research. Male sex, older recipient age, past rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, specific ethnic groups, a lower total lymphocyte percentage, and ureteral stent insertion are further risk factors for BKVN, however, not all investigations have found them.
Screening tests:
1 — Decoy cells: sensitivity: 25, specificity: 84 . Widely available, it is a useful marker in the identification of BKV infection but a poor diagnostic tool in predicting BKVN. Not useful for monitoring the decline in viral load
2-Haufen: sensitivity 100, specificity 99. Highly predictive for BKVN, but not practical for routine practice as it requires electron microscopy with interpretation from a pathologist
3-Urinary BK-PCR sensitivity: 100; specificity: 78. Measurement variations between laboratories limit its use.
4-Plasma BK-PCR Sen: 100 Spe: 88 Broadly available but costly. Has good sensitivity and specificity but a low PPV for BKVN.
Kidney biopsy: allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/mL.
Histology reveals streaky fibrosis of the medulla with circumscribed cortical scars macroscopically, and sclerosed glomeruli, necrotic, atrophic tubules with interstitial fibrosis microscopically.
BK virus inclusions within tubular epithelium can be seen via hematoxylin and eosin and PAS staining.
Differential diagnosis
Includes allograft rejection, and any disease associated with early and late allograft dysfunction. Early period would be within 2 weeks post transplant. Late period would be more than 3 months posttransplant.
Treatment
Reducing immunosuppression and switching drugs may be the initial therapeutic approach. Consider steroid withdrawal.
If MMF dosages stay the same, switching to cyclosporine may lower MMF levels, but if BK viremia persists, MMF must be stopped. MMF reduces proinflammatory and profibrotic cytokines.
Oral leflunomide inhibits viral replication in vitro and is administered at 100 mg/day for 3–5 days, followed by 20–40 mg/day. Nevertheless, MMF and azathioprine cannot be used with leflunomide.
Cidofovir, generally used for CMV, may induce BKV-induced cell death by reactivating p53 and pRB. but has a nephrotoxicity side effect.
Quinolone, statins, and Rituximab are other treatments. Therefore, regular monitoring of BKV PCR and renal function is crucial to a successful transplant, graft protection, and BKV clearance.
Discussion
BK virus is a Polyomavirus, a small non enveloped DNA virus with an isohedral capsid. The virus has different regions – early viral gene region that encodes regulatory nonstructural proteins, and late viral gene region that encodes capsid proteins within the nucleus.
BKV comes under 4 major categories or subtypes :
-Genotype I – predominant and most common subtype
-Genotype II and III – rare and infect a small minority of patients
-Genotype IV – second most frequent subtype
There are other subtypes reflecting different geographical and migration patterns.
BKV viral replication occurs in a state of immune suppression in the host, such as pregnancy, HIV infection, diabetes, cancer, or following transplant. Replication begins in the early posttransplant period.
Risk factors
Intensive immunosuppression
Male gender
Older recipient
Previous rejection episodes
Degree of HLA mismatch
Prolonged cold ischemia
BK sero status
Lower percentage of lymphocytes
Ureteral stent insertion
Pathogenesis :
Defective immune surveillance by host T lymphocytes
Absent humoral immunity to BKV
Patients with prior immunity to BKV may not show manifestation of disease, irrespective of viral copies.
Alloimmune activation
Viral variation in molecular sequences
CD4+ and CD8+ T cells are the main factors in cell mediated immunity that play a role in clearing BKV.
Recipients who receive graft from a BKV seropositive donor have a higher chance of developing the infection in comparison with those how have a seronegative donor.
BKV goes into the circulatory system through the tonsils, and then infects the mononuclear cells in the peripheral blood. This then gets disseminated into different secondary places in the body, including the kidneys.
BKV can also remain latent in the brain, lymph nodes, and leukocytes.
BKV does not cause infection in people who are immunocompetent.
Clinical manifestations
Virus sheds in the urine. Urine examination can be done to check for infection.
Ureteric stenosis
Late onset hemorrhagic cystitis
Multi Organ involvement
Neurological manifestations include encephalitis, meningoencephalitis, Guillan Barre syndrome, and basculopathy. Signs include headache, dizziness, confusion, paraplegia, ataxia, and seizures.
Bilateral atypical retinitis may occur, although this is rare.
Conclusion
BK virus, a diagnostic and therapeutic dilemma, is the focus of the given article. The main issue with this kind of infection is that it can mimic acute rejection, and thus treatment becomes difficult. This infection can be caused by intensive immunosuppression regimen aimed at preventing graft rejection.
Early diagnosis through molecular techniques and tissue analysis can achieve a good outcome in terms of the virus clearance as well as good allograft outcome.
Level of evidence
A narrative review=> level of evidence is V
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
I like your well-structured detailed summary.
Introduction
The two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation.
It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma
BK virus and renal transplantation: historical perception
In 1971, Gardner et al,were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure.
They named the virus ‘BK’ after the initials of this patient.
Numerous reports on various aspects of BKV in renal transplant recipients have been reported.
This virus was found to have high homology with JCV, the other human polyomavirus, discovered as a cause of progressive multifocal leukoencephalopathy.
BKV was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipients.
Increased awareness among nephrologists to recognize
BKV disease at an earlier stage and the development of better diagnostic laboratory techniques contributed to the ever-increasing incidence of BKV infection.
Polyomaviridae variants
Virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40)
It is a family of small, nonenveloped DNA viruses with icosahedral capsid of.
A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017
These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV; HPyV6, HPyV7, HPyV9, and HPyV12; New Jersey polyomavirus (NJPyV, known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14).
Epidemiology of BK virus
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
Primary infection predominantly takes place during early childhood, and the virus stays dormant throughout life in immune-competent people.
There is scarcity in data related to BKV prevalence in Middle East countries and Africa, and a single report found was from Iran, with a seroprevalence of 41.8% .
Such variation in percentages can be clarified by the age of the tested population, the sample size, and the antibodies threshold that is viewed as positive
BK virus structure
BKV-DNA genome can be divided into three parts, BKV genome structure, adapted from De Gascun and Carr.
(1) The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen), which interacts and binds to cellular target proteins to shift the host cell into S phase cycle for efficient viral replication.
(2) The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus
VP1 is highly immunogenic and is the target for neutralizing antibody, cellular immune recognition, and required for virion assembly and hemagglutination of human erythrocytes.
Once it gets inside the cell, the virus travels to the nucleus and establishes a dormant or lytic infection.
BK virus variants
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1.
As with subtype I subgroups, each of the subtype IV subgroups may reflect different geographical and migration pattern of the human population.
The subgroup of subtype I (I/b-2) has been noticed mostly in American and European populations, whereas subgroup I/c dominates in Asians.
Apart from the genotypic variations of VP1 region, additional two other forms of BKV present secondary to variations in the NCCR, namely, rearranged and archetype variants.
BK viral replication follows a state of immune suppression; it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period.
BKV replication and resolution of BK virus nephropathy (BKVN).
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
Progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination.
Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation.
Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss.
The role of humoral immunity
Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies.
Bohl and colleagues found the kidney recipients from a seropositive donor were more likely to develop BK viremia compared with others who had a kidney from a seronegative donor.
The role of antibodymediated immunity was validated in BKV infection.
The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated.
Role of alloimmune activation
Another possible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity.
The latter concerns with T cells, which cross-react to both BKV and allo-antigens.
Murine kidney allografts were more susceptible to polyomavirus infection, which cause an increase in allo-reactive T cells that lacked crossreactivity to the virus.
CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans.
Showed a reverse association between allograft survival and the level of HLA matches in patients with BKVN, suggesting a lack of HLA matches might predict better outcomes in recipients with
The role of other factors
In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role.
The pathogenesis of BKV disease is probably related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium
Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
It has been proposed that BKV goes into the circulatory system through infected tonsils, and infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
The sophisticated reactions between the BKV and the immune system result in different clinical features of BKV disease.
Routes of transmission of primary BK virus
The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
The supportive studies are mainly epidemiological, and none of them had isolated BKV on respiratory samples.
In a study of 99 hospitalized pediatric patients, 45% of the collected stool samples and rectal swabs tested positive for polyomavirus DNA, supporting the fecal-oral transmission of BKV.
A different study had failed to demonstrate BKV in either maternal or fetal tissues.
A negative BK recipient who had a kidney from BKV-infected donor has been noted to have similar genotypes, thereby, supporting donor transmission].
Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes.
Clinical manifestations
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals; BKV does not cause disease in immunocompetent people.
In renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC).
BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC [78,79], whereas in HIV-.
Infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement and eventually leads to death.
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine, which can progress a few weeks later to blood and eventually to BK-.
The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% .Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen , and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen, and treatment should involve a percutaneous nephrostomy and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Hemorrhagic cystitis
BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients.
The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain.
Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy.
BKV–HC is extremely rare in renal transplant.
Severe cases of BKV–HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation.
Locally through bladder installation was suggested as a therapeutic option for HC ,the remission varied from 2 to 7 weeks following hematuria
BK nephropathy in the native kidney
BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients.
Autopsy showed that BKV infection was present in the brain, kidneys, and peripheral blood smear
As it is a single case, further data are required before labeling BKV to cause an ophthalmological manifestation.
Reported manifestations of BKV in immunocompromised patients, including renal transplant recipients and patients with HSCT and HIV infection.
BK virus and hepatic disease
A single report in the literature regarding the association between BKV and hepatitis was reported in a patient with bone marrow transplant who had transient elevations of liver enzymes.
BK virus and autoimmune diseases
BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immunecompromised individuals.
Taguchi and colleagues were the first to report the isolation of BKV from a urine sample of two patients with lupus.
Several cases were reported since with a prevalence of BKV viruria of 16% in patients with systemic lupus erythematosus.
There is an increase in the prevalence with persistence/or recurrent BK viruria in patients with lupus.
Such a relationship could be explained with a compromised immune system secondary to the systemic illness or the intensified immunosuppression.
There is no article that describes BKV activation in patients with systemic lupus erythematosus at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease.
BK virus and malignancy: thoughts on viral oncogenesis
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors .
It has been proposed that BKV has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation.
The LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Inactivation of tumor suppressor p53 and pRb in experimental mice by BKV–LTAg can induce urothelial malignancies.
Regardless of whether BKV has a causative part in human cancer development or not, it will remain a topic of debate
BK virus and urothelial tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, bladder carcinoma as the BKV-DNA was isolated in these tumors.
Alexiev et al, reported a similar experience, where all tumor cells had shown strong expression of BKV–LTAg, p53, p16, and Ki-67, in addition to the intranuclear virions in electron microscopy.
Despite this epidemiological evidence, urothelial malignancies concomitantly with BKV were reported to date in a few and isolated case reports.
Rollison et al, had carried out a tissue-based analysis in a series of bladder tumors (189 samples from 76 transitional cell carcinoma) to determine the potential role of BKV in bladder malignancies.
Roberts et al, reported no evidence of BKV–LTAg in urothelial malignancies from 20 immunocompetent patients
Risk factors
Several risk factors were implicated in the pathogenesis of BKVN.
The most consistent risk factor identified in the literature is the overall degree of immunosuppression.
Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; these risk factors have not been uniformly observed in all studies.
Screening and diagnostic tools
The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears.
Timing of screening
Prospective analyses had revealed that BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year.
In a cohort of Greek postrenal transplant recipients monitored prospectively for 18 months, the incidence of viremia and viruria showed bimodal peaks.
The first and the topmost peak was noticed in the third month, followed by a gradual decline and disappearance in the ninth month, whereas the second peak was noticed at.
12th months after transplant, but with fewer detected cases .
KDIGO guidelines. had recommended BKV screening to start at first month after transplant, monthly for the first 6 months, and every 3 months for up to 2 years
Screening tests
Viral replication starts early after transplantation and progresses through noticeable phases: viruria viremia followed by nephropathy.
Viral replication in the urine precedes BK viremia by ∼4 weeks, and there have been confined cases of patients developing viremia without viruria, this is uncommon.
Histological changes of BKVN are observed 12 weeks after BK viruria.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
No single diagnostic pathway has appeared as predominant.
Monitoring of the urine
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’.
Aggregates of BKV virions or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Urine cytology
Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients.
Such wide variation can be explained by screening strategies that were used in different centers and different immunosuppressive regimens.
Presence of Haufen bodies, which corresponds to upper levels of BK viremia, had a higher sensitivity and specificity for biopsy-proven BKVN
Haufen particles were absent in recipients with a lower BK viremia.
As this method represents singlecenter data, it requires further validation.
Variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis.
BK virus mRNA levels in urine
BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication.
This method is considered as highly specific and sensitive.
Though this assay is encouraging as a noninvasive tool and can provide additional diagnostic and prognostic data, yet it requires further validation.
Pros and cons of urinary tests in identifying BKVN: Urinary tests are highly sensitive for detecting active BKV infections.
Decoy cells
Widely available, useful marker in identification of BKV infection, but a poor diagnostic tool in predicting BKVN.
BKV-PCR levels may differ substantially between assays, with a magnitude of one to two log-folds in consecutive weekly analyses in commercially available quantitative PCR assays, which may yield significant differences in quantified viral loads and may limit the threshold of assay detection.
Most quantitative PCR primers and probes were designed against BK genotype I (Dunlop) strain as a reference
Using this genotype I strain as a reference might be as much as four-fold less sensitive for different strains, which is risky as uncommon BKV subtypes are often associated with BKVN, and such assays are unable to detect them at low viral levels.
Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels
Serum antibodies
Serum antibodies against BKV are commonly present among the general public.
BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain.
It has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients.
The positive donor BKV serostatus and negative recipient serostatus (BK D+/R−).
Have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients.
Kidney biopsy
The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks.
Such suggestion came from a prospective analysis of Hirsch et al , who demonstrated that BK viremia of more than or equal to 10 4 is characteristically present in recipients with proven biopsies of BKVN.
An alternative histological detection approach is through the identification of BKV via in-situ hybridization.
Fluorescence in-situ hybridization-based methodology is specific for BKV with a sensitivity of 94.7%.
Rapid viral load reduction has been related to steady or improved allograft function.
Treatment of presumptive BK virus nephropathy
The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications.
Regimens have been attempted upon recognition of viremia
These include withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance.
Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% or converting tacrolimus to cyclosporine or discontinuing CNI.
Withdrawal of the antimetabolite such as MMF is the most usual method; a study by.
Treatment of BK virus nephropathy in the setting of allograft dysfunction
Favorable renal allograft outcomes in the context of acute BKV infection were reported when immunosuppression reduction had started early upon detection of BK viremia, permitting early and appropriate therapeutic interference.
If the identification of BKVN is made at an advanced stage when nephropathy ensues, reducing immunosuppression is probably going to be less effective, owing to the advanced disease, with severe histological changes leading to progressive, irreversible renal damage.
Allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy .
Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises
Drugs with antiviral activities
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug which was developed to be used in rheumatoid arthritis.
Being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages.
It is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage.
Cidofovir showed in-vitro inhibitory action against polyomaviruses, though the mechanism of action is unclear as BKV lacks the viral polymerase gene, the known target of cidofovir.
Tacrolimus and MMF were replaced with sirolimus, which resulted in reduction of the BK viral load with concurrent improvement in estimated glomerular filtration rate.
Intravenous immunoglobulin
Has been used for BKVN for its immunomodulatory effects.
IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
In-vitro analysis has shown that IVIG has the most potent antiviral influence, with a selectivity index of more than 1000 as opposed to cidofovir and leflunomide selectivity index of 3.8 and 2.3, respectively.
with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection; the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression.
Other therapeutic options for treating BK virus nephropathy
LTAg helicase activity and have in-vitro and invivo activity against BKV. It has been found beneficial in combination with leflunomide for treating BKVN,with a significant decrease in BK viremia.
Patients who had received rituximab as an adjuvant therapy with cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN.
In both groups, the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine.
In the late 1990s and early 2000s, BKVN caused permanent allograft damage in 30–60% of cases
This happened as a result of lack of awareness, delayed diagnosis, misdiagnosis, and coincidental utilization of escalated immunosuppression for possible acute rejection episodes.
BK nephropathy with concurrent acute rejection
Management of proven allograft biopsies of acute rejection with concomitant BKVN or management of anticipated rejection following a decrease of immunosuppression to treat BKVN remains debatable.
More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in.
Reports have depicted clinical improvement, steady or worse allograft outcomes, following steroid pulses.
Celik et al, found a reduction in immunosuppression is more than capable in reducing
IVIG Contain neutralizing antibodies against BKV and are immunomodulatory
MTOR inhibitors Inhibits the proliferation of BKV-specific T-cell and controls the differentiation of memory.
Occurs, such as gastritis, C difficile, hepatoxicity, neurological adverse effects, and altered mental status.
Inhibit BK viral proliferation in a primary human renal cell culture
Statins Prevent caveolae-mediated endocytosis Adverse muscle events and hepatic dysfunction.
Viral load than steroid pulses in biopsies with BKVN and tubulitis.
Hirsch et al, suggested a combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection.
An initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.
In the absence of typical features, such as strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage, which could be indicators for acute rejection, the management should be tailored for each patient individually.
The delayed improvement in renal functions following a reduction in immunosuppression is likely to reflect the slow resolution of the cellular infiltrate.
Upon clearance of viremia and BKVN, the advantage of up-titrating immunosuppression to avoid further late acute rejection or chronic rejection remains obscure.
Postinfection monitoring
Close observation of BKV-PCR and renal function with any treatment, following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome.
The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
It should be done on a monthly bases until clearance of BK viremia and stabilization of renal function achieved.
Recurring BKV might reflect a previous BK variant or a new infection acquired, because of the long period, in the posttransplantation stage.
Findings
Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population.
BK viruria can increase up to 35% during pregnancy, and BKV can cross the placenta and stay dormant in fetal organs, suggesting the possibility of vertical transmission.
Conclusion
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment
Level of evidence is 5
Please summarise this article.Introduction
o BKV is a significant cause of interstitial nephritis and allograft failure in renal transplant recipients
o Often presents within the first year after transplantation
o It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection
o BKV belongs to the Polyomaviridae (PyV) virions. It is small, nonenveloped DNA viruses with icosahedral capsid of 40–45nmindiameter
Aim of the study: discuss the most recent evidence of virology, pathogenesis, clinical features, diagnostic tools, screening protocols, treatment strategy, and short-term and long-term renal allograft survival concerning BKV infection
Epidemiology of BK virus
o BKV is a ubiquitous virus that infects most humans around the world
o Primary infection predominantly occur during early childhood
o 60–85% of the general population is seropositive for BKV
BK virus structure
BKV-DNA genome is divided into three parts:
1. The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen)
2. The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus
3. The capsid protein VP1 in the LVGR: is the main capsid protein present on the surface and is responsible for receptor binding to the host cells, facilitating virus entry into the cell
BK virus variants
Four genotypes/subtypes:
1. Genotype I: accounts for > 80% worldwide followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population
2. Genotype 2: rare
3. Genotype 3: rare
4. Genotype 4: the second most common and accounts for 15%
Immunological response to BK virus
o BKV replication begins early in the posttransplant period
o The immune system plays an essential part in controlling BKV replication and resolution of BKVN (cell-mediated immunity, humoral immunity, alloimmune activation, and other factors)
Possible factors that add to the pathogenesis of BKVN:
1. defective immune surveillance by the host Tlymphocytes
2. absence of humoral immunity to BKV
3. alloimmune activation, and
4. viral variation in molecular sequences
Pathogenesis of BK infection
o Primary infection is usually subclinical and rarely manifests as a mild respiratory symptom in childhood
o Infect tonsils first then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys
o Stay dormant in the uroepithelium, renal tubular cells, leukocytes, brain tissues, and lymphnodes
o In thepresence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries
Routes of transmission of primary BK virus
1. Respiratory route
2. Gastrointestinal transmission
3. Vertical transmission
4. Sexual transmission
5. Donor-derived infection
6. Other possible: urine and blood
Clinical manifestations
1. BK virus and renal disease: BKVN
2. BK virus-associated nephropathy: begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure
3. Ureteric stenosis: in 2–6%. Treatment is percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications
4. Hemorrhagic cystitis: in HSCT recipients. The patients present with bladder cramps, painful voiding, hematuria, and/or flank pain. Four degrees of disease severity (I-IV). Management involves vigorous intravenous hydration
5. BK nephropathy in the native kidney: AKI without significant proteinuria
6. BK virus and hepatic disease: hepatitis (one patient with bone marrow transplant)
7. BK virus and autoimmune diseases: SLE, polymyositis, and rheumatoid arthritis
8. Others:
o Neurological manifestations: meningoencephalitis, encephalitis, GBS, and vasculopathy
o Pulmonary diseases: interstitial pneumonitis
o Ophthalmologic manifestations: bilateral atypical retinitis (single case report)
BK virus and malignancy
1. Brain tumors of glial and neural origin (ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas)
2. pancreatic islets cell tumors
3. Kaposi sarcoma
4. Ewing sarcoma
5. osteogenic sarcoma
6. prostatic carcinoma
7. urothelial tumors (particularly bladder carcinoma)
Risk factors
o Overall degree of immunosuppression (the most important risk)
o Other risk factors include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion
Screening and diagnostic tools
The aim is to identify early viruria or viremia before graft dysfunction appears
Timing of screening: at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years (American Society of Transplantation Infectious Diseases Guidelines)
Urine:
1. Urine cytology (Decoy cells)
2. Urine electron microscopy (EM Haufen)
3. Quantitative measurements of urinary BK virus-viral loads
4. BK virus mRNA levels in urine
Serology:
1. Serum BK-PCR
2. Serum antibodies
Virus culture:
o grows slowly in tissue culture
Kidney biopsy:
o the gold standard to diagnose BKVN
o should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction
o biopsy findings can be focal or isolated to the medulla and missed on one-third of biopsies giving a false-negative result; therefore, a minimum of two biopsy cores, preferably including medulla, should be inspected to make the correct diagnosis
o histological grading systems for BK virus nephropathy:
Class A: A variable number of virus-infected cells with NO or MINIMAL injury to tubular epithelial cells
Class B: Tubular epithelial cell necrosis or lysis with denudation of basement membrane across a length of more than two cells
Class C: Any degree of tubular injury with interstitial fibrosis affecting >50% of the cortex
Differential diagnosis
1. Allograft rejection: is challenging.
2. Any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction
BKVN can be distinguished from acute rejection by:
1. Presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40
2. absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful
3. IHC staining of renal tissues or urinary sediments with anti-HLADR (acuterejection)
4. A higher quantity of CD20+ cells in the tissue infiltrates (BKVN)
5. expression of genes related to inflammation and acute rejection (such as CD8, interferon-gamma, CXCR3, and perforin): higher in patients with BKVN
Treatment strategy
Treatment of presumptive BK virus nephropathy:
o Reduction/or modifications in immunosuppressive therapy with or without antiviral medications
o Withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance
Treatment of BK virus nephropathy in the setting of allograft dysfunction:
o Acute BKV: immunosuppression reduction
o Advance BKVN: reducing immunosuppression is probably to be less effective
Drugs with antiviral activities:
1. Leflunomide
2. Cidofovir
3. mTOR inhibitors
4. Intravenous immunoglobulin
5. Others (quinolones, artesunate, pravastatin, and rituximab)
Short-term and long-term allograft survival
o Renal allograft survival for recipients with BKVN had improved considerably in the past years
BK nephropathy with concurrent acute rejection
o Management is debatable
o Initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN
o In the absence of typical features (strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage), the management should be individually
Postinfection monitoring
o Serum creatinine test every 1–2 weeksandplasmaBK-PCRlevelat2–4-weekintervals for 8 weeks then monthly bases until clearance of BK viremia
o BK viremia clears in 7–20 weeks (the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression)
o If viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide
Retransplantation
o Retransplantation following graft loss owing to BKVN is possible and can be done successfully
o Pretransplant clearance of BK viremia is essential after minimizing immunosuppression
o Allograft nephrectomy is not necessary before retransplantation
Conclusions
o Early diagnosis of BKVN (by molecular techniques and tissue analysis) has resulted in substantial improvement in allograft outcomes
What is the level of evidence provided by this article?Level V
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
I like your well-structured detailed summary.
IV. BK virus infection in renal transplant recipients: an overview1.Please summarize this article.
Introduction
Epidemiology of BK virus
BKV-DNA genome can be divided into 3 parts:
1.The early viral gene region:
2.The late viral gene region (LVGR):
3.The capsid protein VP1:
BK virus variants
The role of cell-mediated immunity
The role of humoral immunity
Role of alloimmune activation
Pathogenesis
Routes of transmission of primary BK virus
Clinical manifestations
1.BKVN (2–15%):
2.Ureteric stenosis (2–6%):
3.Hemorrhagic cystitis
4.BKVN in native kidneys:
5.Other less common manifestations:
6.Malignancy:
7.Urothelial tumors:
Risk factors of BKVN:
Screening & diagnostic tools
Screening tests:
1.Urine decoy cells:
2.Haufen:
3.Urinary BK-PCR:
4.Urinary BK-mRNA:
5.Plasma BK-PCR:
6.Serum antibodies:
7.Virus culture:
8.Kidney biopsy:
Histology:
Suggested screening:
Differential diagnosis
1.Allograft rejection:
It is important to differentiate between AR & BKVN as treating the presumed rejection with increased IS may result in progression of BKVN.
BKVN may exist concurrently with AR.
BKV inclusions & positive IHC for SV40 staining can distinguish BKVN from AR.
Absence of features of AR (endotheliitis & extensive tubulitis & absence of C4d deposits in PTBM are also helpful.
C4d staining occurs in some BKV cases & is linked with more aggressive disease.
2. Any disease associated with early (1–12 weeks after TX) & late (≥3 months after TX) renal allograft dysfunction.
Treatment
Approaches include:
Other therapeutic options for treating BKVN:
Postinfection monitoring
Retransplantation
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1. What is the level of evidence provided by this article?
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
Introduction
BKV can lead to interstitial nephritis and allograft failure in renal transplant recipients.
It occurs within the first year after transplantation. It manifests by gradual creatinine increase with tubulointerstitial nephritis, similar to acute rejection.
BK virus and renal transplantation
It was first detected in a Sudanese kidney transplant recipient with ureteric stenosis and renal failure.
Abundant large cells with intranuclear inclusions detected in the urine as ‘decoy cells’.
Polyomaviridae variants
It belongs to the Polyomaviridae (PyV)virions, a subgroup of papovaviruses comprising BKV,JCV, and simian virus 40 (SV40). 12 more human polyomaviruses have been isolated
BKV Epidemiology
Polyomavirus hominis-1, well known as BKV, is a popular virus that infects most humans.
The infection is caught during childhood and remains dormant in immunocompetent cases
BK virus structure
BKV-DNA genome include the noncoding control region (NCCR) ,the early viral gene region,the late viral gene region LVGR , and the capsid protein VP1 in the LVGR is the main capsid protien
BK virus variants
BKV can be divided into 4 genotypes according to the DNA sequence variations in the genomic region of VP1 ,genotype I and IV are the most common.
4 more subgroups were detected
Immunological response to BK virus
Immunosuppression enhances the virus replication as in diabetes and pregnancy.
It’s replication occur early in the posttransplant period and can occur after antirejection treatment .
BKVN pathogenesis is due to defective immune surveillance ,absence of humoral immunity , alloimmune activation, and viral variation in molecular sequences.
Cell mediated immunity role
T cells react against non structural and BK capsid proteins ,Cytotoxic T cells attack BK-infected cells after recognition of damaged segments of viral DNA.
Progressive lytic infection can lead to large nuclear and peri-nuclear viral inclusion in the tubular cells formation then dissemination can lead to cast formation and damage of tubular capillaries causing viral dissemination which can cause allograft dysfunction.
Humoral immunity role
BKV seropositive donors are likely to transmit infection to recipients.
Antibody medicated immunity has a role in BKV infection.
Alloimmune activation
(HLA)-reactivity and heterologous immunity have a role in BKVN development. BKV can escape the immunological surveillance.
A study showed correlation between HLA mismatch and BKVN, Another study demonstrated that HLA matches absence indicate better outcomes in recipients with BKVN
Other factors
BKV tropism to renal tubular epithelial cells.
BKV infection pathogenesis
Usually primary infection is subclinical.
Then the virus can be dormant for life in renal tubular epithelial cells also it can be latent in leucocytes ,lymph nodes and brain tissue.
When the patient is immunosuppressed the virus is reactivated and emerge to peritubular capillaries and cause viruria afterwards the conflict between the virus and the immune system leads to BKVN.
Primary BKV transmission route
It can be via respiratory, fecal-oral, transplacental, or donor tissues also transmission through urine and blood was a suggested route as well.
Clinical presentation
It’s usually asymptomatic in immunocompetent cases .
Present in immunocompromised patients as renal transplant recipients as BKVN,ureteric stenosis, and late-onset hemorrhagic cystitis.
In (HSCT) recipients present with hemorrhagic and non-hemorrhagic cystitis
For HIVinfected patients, it can be disseminated leading to multiorgan affection and mortality.
Less common manifestations include
neurological presentations in the forum of meningioencephalitis ,Guillian barre syndrome specially in HIV infection or HSCT.
pulmonary manifestations as severe interstitial pneumonitis,
Opthalmological manifestations as atypical retinitis
Hepatitis was noticed as BKV manifestation
BKV had been implicated in autoimmune diseases as SLE , rheumatoid and polymyositis
BKV has a relation with tumors as brain tumors, islet cell tumor ,Ewing
sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors and Kaposi sarcoma
BKV can have a main role in uroepithelial malignancy
Risk factors
Include immunosuppression degree ,male sex, older age, rejection attacks, HLA mismatching, prolonged cold ischemia, BK serostatus, ethnic groups, lower total lymphocyte percentage,and ureteral stent insertion.
Screening
It has to be done early post transplant, as infection is common in the first year
KDIGO guidelines recommended BKV screening to start at first month after transplant, then monthly for the first 6 months,and then every 3 months for up to 2 years.
Viral replication in the urine starts before BK viremia by ∼4 weeks, and
BKVN pathological changes are observed 12 weeks after BK viruria.
Active BKV replication screening through identification of viral DNA-PCR in urine and blood.
Urine monitoring by detection of BKV-infected epithelial cells ‘decoy cells,’or aggregates of BKV virions ‘Haufen’ or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA
A study reported 100% sensitivity , 71% specificity for decoy cells
Haufen bodies detection in urine EM indicates upper levels of BK viremia and biopsy-proven BKVN but is an expensive non practical test.
Urinary BKV-PCR has 100% sensitivity and 78% specificity meanwhile lab measurements are variable
BK virus mRNA levels in urine is considered a highly specific and sensitive method for detecting active viral replication and BKVN occurrence but needs more validation due to similarity with acute cellular rejection
BKV-PCR has 100% sensitivity and 88% specificity for BKVN than BK viruria
So it is preferred for screening
A quantitative BKV-PCR > 4logs (1×104) copies/ml can correlate with BKVN on allograft biopsy as suggested by a study.
Serial levels of viremia is the best method to detect BK activity cure after immunosuppression reduction.
Serological testing importance is uncertain.
Virus cultures are non practical.
Kidney biopsy for presumptive BKVN can detect recipients with significant viruria and /or persistent viremia
Allograft biopsy is the main test to diagnose BKVN, it is done when BKV-PCR load >10000 copies/ml in presence or absence of graft dysfunction.
Meanwhile lesions can be focal or isolated to the medulla therefore taking 2 core biopsies with the involvement of the medulla is crucial.
It appears under microscope as sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis with mononuclear cell infiltrates. BK viral inclusions within tubular epithelium can be seen .
Fluorescence in-situ hybridization (FISH) analysis enables BKV detection in renal transplant tissues through bright nuclear fluorescence technique.
Positive Immunohistochemistry using specific antibodies against BKV or the cross-reacting SV40 LTAg has 100% specificity for polyomavirus nephropathy; but it does not differentiate between BKV and JCV.
There are 3 histological grading system as grade A involves viral cytopathic changes of near-normal renal parenchyma, with minimal tubular atrophy, interstitial fibrosis, or inflammation, till stage C, with diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation
A study suggested BKV algorithm including starting with urine cytology for decoy cells every 3 months, and when decoy cells were positive, quantification of viral level in the plasma with the probability of allograft biopsy if kidney function worsened.
Others suggested surveillance biopsies to detect silent BKVN at 3 rd or 4 th month then 12th month post transplantation which improved graft outcomes.
AST guidelines recommend annual screening till the fifth year post transplant; meanwhile screening after 2years is not recommended unless allograft dysfunction occur.
Differential diagnosis
Allograft rejection
Differentiation from BKVN is difficult and is done by analysis of blood or urine PCR , and by BKV inclusion bodies detection and immunohistology of positive immunoperoxidase staining for SV40 or urinary sediments with anti-HLA DR, related to acute rejection
Differentiation is important because increased immunosuppression to treat rejection can worsen BKVN meanwhile it can be more challenging as both can occur together.
CD20+ cells in a big quantity infiltrating the tissue has been associated with BKVN
Also other DD include early and late cases of renal allograft dysfunction.
Treatment of BKVN
Involves reduction of immunosuppression and returning antiviral response.
Treatment of presumptive BK virus nephropathy
By reducing immunosuppression as changing classes in the forum of antimetabolite drugs removal or switch mycophenolate mofetil (MMF) to azathioprine,sirolimus, or leflunomide, lower CNI dose by 25-50% and avoiding steroids with or without antiviral therapy.
Treatment of BK virus nephropathy with allograft dysfunction
Immunosuppression reduction have to start early as soon as BK viremia is detected allowing suitable intervention before an advanced stage of BKVN occur with irreversible injury
Antiviral drugs
Leflunomide can inhibit viral replication and have to be given with removal of antimetabolites as MMF or azathioprine and decreasing CNI dose.
Cidofovir has inhibitory action against poliovirus but it is nephrotoxic and has other side effects therefore it’s use have to be with caution.
Brincidofovir(CMX001) is a prodrug of cidofovir, orally administered without nephrotoxicity active against all DNA viruses.
mTOR inhibitors
It inhibits BK replication and it improves the immune reaction after BKV infection
IVIG
It has immunomodulatory effect, it’s use along side with Immunosuppressives reduction medications in treating BKVN with concurrent acute rejection
Other options include quinolones, artesunate, statins and rituximab.
Short and long term allograft survival
Renal allograft survival for recipients with BKVN had improved .
BK nephropathy with concurrent acute rejection
It’ s therapy and intervention is controversial , therefore treatment has to be individualised.
Post infection monitoring
BKV-PCR and kidney function tracking with treatment is crucial especially after acute rejection treatment or reduction of immunosuppression.
Retransplant after BKVN can be done
Conclusion
Early detection and diagnosis of BKV can improve the graft outcome
level of evidence is V
I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant. Typing whole sentence in bold amounts to shouting.
I like your well-structured detailed summary.
Introduction
The two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients.
BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation.
It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma
BK virus and renal transplantation history
In 1971, Gardner et al were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure.
They named the virus ‘BK’ after the initials of this patient.
Numerous reports on various aspects of BKV in renal transplant recipients have been reported.
This virus was found to have high homology with JCV, the other human polyomavirus, discovered as a cause of progressive multifocal leukoencephalopathy.
BKV was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipients.
Polyomaviridae varients
Virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40)
It is a family of small, nonenveloped DNA viruses with icosahedral capsid of.
A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017
These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV; HPyV6, HPyV7, HPyV9, and HPyV12; New Jersey polyomavirus (NJPyV, known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14)
Epidemiology of BK virus
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
Primary infection predominantly takes place during early childhood, and the virus stays dormant throughout life in immune-competent people [2,10,24,25].
60–85% of the general population is seropositive for BKV (Table 1).
There is scarcity in data related to BKV prevalence in Middle East countries and Africa, and a single report found was from Iran, with a seroprevalence of 41.8% [37].
Such variation in percentages can be clarified by the age of the tested population, the sample size, and the antibodies threshold that is viewed as positive
BK virus structure
BKV-DNA genome can be divided into three parts, BKV genome structure, adapted from De Gascun and Carr.
(1) The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen), which interacts and binds to cellular target proteins to shift the host cell into S phase cycle for efficient viral replication.
(2) The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus
VP1 is highly immunogenic and is the target for neutralizing antibody, cellular immune recognition, and required for virion assembly and hemagglutination of human erythrocytes.
Once it gets inside the cell, the virus travels to the nucleus and establishes a dormant or lytic infection.
BK virus varients
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1.
As with subtype I subgroups, each of the subtype IV subgroups may reflect different geographical and migration pattern of the human population.
The subgroup of subtype I (I/b-2) has been noticed mostly in American and European populations, whereas subgroup I/c dominates in Asians.
Americans and Europeans, whereas the other subgroups are more common in Asian populations.
Apart from the genotypic variations of VP1 region, additional two other forms of BKV present secondary to variations in the NCCR, namely, rearranged and archetype variants.
Continuous duplication of BK genome during activation process can result in deletion and duplication in the NCCR sequences, with subsequent generation of rearranged variant viruses.
The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined.
Immunological response to BK virus
BK viral replication follows a state of immune suppression; it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period.
BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
BKV replication and resolution of BK virus nephropathy (BKVN).
CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance.
Progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells.
The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination.
Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation.
Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss.
The role of humoral immunity
Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies.
Bohl and colleagues found the kidney recipients from a seropositive donor were more likely to develop BK viremia compared with others who had a kidney from a seronegative donor.
The role of antibodymediated immunity was validated in BKV infection.
The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated
Role of alloimmune activation
Another possible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity.
The latter concerns with T cells, which cross-react to both BKV and allo-antigens.
Murine kidney allografts were more susceptible to polyomavirus infection, which cause an increase in allo-reactive T cells that lacked crossreactivity to the virus.
CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans.
Showed a reverse association between allograft survival and the level of HLA matches in patients with BKVN, suggesting a lack of HLA matches might predict better outcomes in recipients with
The role of other factors
In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role.
Moriyama et al had demonstrated that a blockage of caveolin-induced endocytosis, either directly or through small interference RNA depletion of caveolin-1, produced substantial reduction in BKV infectivity as measured by immunofluorescence, as BKV particles were found in vitro to colocalize with caveolin-1, and not to a clathrin, in the human renal proximal tubular epithelium.
The pathogenesis of BKV disease is probably related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium
Pathogenesis of BK infection
Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood.
It has been proposed that BKV goes into the circulatory system through infected tonsils, and infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys.
Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria.
BKV can remain latent in leukocytes, brain tissues, and lymph nodes.
In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria.
Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses.
The sophisticated reactions between the BKV and the immune system result in different clinical features of BKV disease.
Routes of transmission of primary BK virus
The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
The supportive studies are mainly epidemiological, and none of them had isolated BKV on respiratory samples.
In a study of 99 hospitalized pediatric patients, 45% of the collected stool samples and rectal swabs tested positive for polyomavirus DNA, supporting the fecal-oral transmission of BKV.
A different study had failed to demonstrate BKV in either maternal or fetal tissues.
A negative BK recipient who had a kidney from BKV-infected donor has been noted to have similar genotypes, thereby, supporting donor transmission.
(6) Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes.
Clinical manifestation
Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals; BKV does not cause disease in immunocompetent people.
In renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC) .
BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC, whereas in HIV-.
Infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement, and eventually leads to death.
BK virus and renal disease
Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine, which can progress a few weeks later to blood and eventually to BK-.
The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years.
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6% . Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen, and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen, and treatment should involve a percutaneous nephrostomy and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications.
Hemorrhagic cystitis
BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients.
The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain.
Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy.
BKV-HC is extremely rare in renal transplant.
Severe cases of BKV-HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation.
Locally through bladder installation was suggested as a therapeutic option for HC, the remission varied from 2 to 7 weeks following hematuria
BK nephropathy in native kidney
BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients.Other less apparent clinical manifestations include the following: Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection.
Such infections are primarily seen in patients with HSCT or HIV infection.
Autopsy showed that BKV infection was present in the brain, kidneys, and peripheral blood smear
As it is a single case, further data are required before labeling BKV to cause an ophthalmological manifestation.
Reported manifestations of BKV in immunocompromised patients, including renal transplant recipients and patients with HSCT and HIV infection.
BK virus and autoimmune disease
BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immunecompromised individuals.
Taguchi and colleagues were the first to report the isolation of BKV from a urine sample of two patients with lupus.
Several cases were reported since with a prevalence of BKV viruria of 16% in patients with systemic lupus erythematosus.
There is an increase in the prevalence with persistence/or recurrent BK viruria in patients with lupus.
Such a relationship could be explained with a compromised immune system secondary to the systemic illness or the intensified immunosuppression.
There is no article that describes BKV activation in patients with systemic lupus erythematosus at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease.
BK virus and malignancy
The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors.
It has been proposed that BKV has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation.
The LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Inactivation of tumor suppressor p53 and pRb in experimental mice by BKV-LTAg can induce urothelial malignancies.
Tumor cells are likely more vulnerable to BKV than normal urothelium, as the infection happens mainly in proliferating cells, and that positivity is a result instead of being a reason for neoplastic transformation.
Regardless of whether BKV has a causative part in human cancer development or not, it will remain a topic of debate
BK and urethral tumors
Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, bladder carcinoma as the BKV-DNA was isolated in these tumors.
Alexiev et al reported a similar experience, where all tumor cells had shown strong expression of BKV-LTAg, p53, p16, and Ki-67, in addition to the intranuclear virions in electron microscopy.
Despite this epidemiological evidence, urothelial malignancies concomitantly with BKV were reported to date in a few and isolated case reports.
Rollison et al, had carried out a tissue-based analysis in a series of bladder tumors (189 samples from 76 transitional cell carcinoma) to determine the potential role of BKV in bladder malignancies.
Roberts et al [139], reported no evidence of BKV-LTAg in urothelial malignancies from 20 immunocompetent patients
Risk factors
Several risk factors were implicated in the pathogenesis of BKVN.
The most consistent risk factor identified in the literature is the overall degree of immunosuppression.
Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; these risk factors have not been uniformly observed in all studies.
Timimg of screening
Prospective analyses had revealed that BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year.
In a cohort of Greek postrenal transplant recipients monitored prospectively for 18 months, the incidence of viremia and viruria showed bimodal peaks.
The first and the topmost peak was noticed in the third month, followed by a gradual decline and disappearance in the ninth month, whereas the second peak was noticed at.
12th months after transplant, but with fewer detected cases.
KDIGO guidelines had recommended BKV screening to start at first month after transplant, monthly for the first 6 months, and every 3 months for up to 2 years
Screening test
Viral replication starts early after transplantation and progresses through noticeable phases: viruria viremia followed by nephropathy.
Viral replication in the urine precedes BK viremia by ∼4 weeks, and there have been confined cases of patients developing viremia without viruria, this is uncommon.
Histological changes of BKVN are observed 12 weeks after BK viruria.
Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood.
No single diagnostic pathway has appeared as predominant.
Monitoring of the urine
Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’.
Aggregates of BKV virions or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Urine cytology
Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients.
Such wide variation can be explained by screening strategies that were used in different centers and different immunosuppressive regimens.
Urine electron microscopy (EM Haufen): in contrast to decoy cells, Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, forming cast-like three-dimensional aggregates, which can be noticed in a urinary smear of kidney recipients using negative-staining electron microscopy.
Presence of Haufen bodies, which corresponds to upper levels of BK viremia, had a higher sensitivity and specificity for biopsy-proven BKVN
Haufen particles were absent in recipients with a lower BK viremia .
As this method represents singlecenter data, it requires further validation.
Variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis.
BK virus mRNA levels in urine
BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication.
This method is considered as highly specific and sensitive.
In predicting patients who might develop BKVN, using 6.5×10 5 BKV-VP1 mRNAs/ng RNA in urinary cells as a cutoff value.
Though this assay is encouraging as a noninvasive tool and can provide additional diagnostic and prognostic data, yet it requires further validation.
Pros and cons of urinary tests in identifying BKVN: Urinary tests are highly sensitive for detecting active BKV infections.
Decoy cells
Widely available, useful marker in identification of BKV infection, but a poor diagnostic tool in predicting BKVN.
BKV-PCR levels may differ substantially between assays, with a magnitude of one to two log-folds in consecutive weekly analyses in commercially available quantitative PCR assays, which may yield significant differences in quantified viral loads and may limit the threshold of assay detection.
Most quantitative PCR primers and probes were designed against BK genotype I (Dunlop) strain as a reference
Using this genotype I strain as a reference might be as much as four-fold less sensitive for different strains, which is risky as uncommon BKV subtypes are often associated with BKVN, and such assays are unable to detect them at low viral levels.
Most quantitative PCR probes were designed against BK genotype I strain as a reference, which might be unable to detect other BK viral strains at lower viral levels
Serum antibodies
Serum antibodies against BKV are commonly present among the general public.
BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain.
It has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients.
The positive donor BKV serostatus and negative recipient serostatus (BK D+/R−).
Have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients.
Findings
Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population.
BK viruria can increase up to 35% during pregnancy, and BKV can cross the placenta and stay dormant in fetal organs, suggesting the possibility of vertical transmission.
Kidney biopsy
The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks.
Plasma BK-PCR has high sensitivity and specificity in anticipating BKVN, different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without.
Such suggestion came from a prospective analysis of Hirsch et al, who demonstrated that BK viremia of more than or equal to 10 4 is characteristically present in recipients with proven biopsies of BKVN.
An alternative histological detection approach is through the identification of BKV via in-situ hybridization.
Fluorescence in-situ hybridization-based methodology is specific for BKV with a sensitivity of 94.7%.
Drugs with antiviral activities
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug which was developed to be used in rheumatoid arthritis.
Being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages
It is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage.
Notwithstanding, a few factors have limited use of this medication: (a) higher dosage of the drug (≥40 mg/day) is necessary to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity; (b) monitoring of the trough A77 1726 level is not accessible in all laboratories; and (c) the immunosuppressive effectiveness of leflunomide is weak, and the favorable results associated with the use of this drug may primarily reflect reduced immunosuppression.
Tacrolimus and MMF were replaced with sirolimus, which resulted in reduction of the BK viral load with concurrent improvement in estimated glomerular filtration rate.
Intravenous immunoglobulin
Has been used for BKVN for its immunomodulatory effects. IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
Other therapeutic options for treating BK virus nephropathy Quinolones have been described to inhibit the LTAg helicase activity and have in-vitro and invivo activity against BKV.
It has been found beneficial in combination with leflunomide for treating BKVN, with a significant decrease in BK viremia.
This happened as a result of lack of awareness, delayed diagnosis, misdiagnosis, and coincidental utilization of escalated immunosuppression for possible acute rejection episodes.
Chen et al [250] reported 1-, 3-, and 5-year allograft survival rates following a diagnosis of BKVN (n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograft survival (P= 0.042)
Postinfection monitoring
Close observation of BKV-PCR and renal function with any treatment, following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome .
The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks.
It should be done on a monthly bases until clearance of BK viremia and stabilization of renal function achieved.
Recurring BKV might reflect a previous BK variant or a new infection acquired, because of the long period, in the posttransplantation stage.
Findings
Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening.
(n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograft survival (P= 0.042)
conclusion
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment
Introduction
· Polyomavirus (BKV & JC) were discovered in 1971
· BKV belongs to polyomaviridae family
· Small, non-enveloped DNA viruses with icosahedral capsid and it has three parts; early viral gene region (non-structural proteins e.g., small & large T antigens), large viral gene region (capsid proteins VP1-3), and the capsid protein VP1 in the LVGR
· Additional 12 viruses were added to the group over the last two decades
Epidemiology
· The primary infection occurs in childhood and around 60 t0 85% of general population is positive for BKV
Risk factors
· BKV infection developed in situations of defective immune surveillance, absence of humoral immunity, alloimmune activation, and viral vibration in molecular sequences
Transmission
· Respiratory (the primary rout of transmission), feco-oral, vertical transmission, sexual transmission, donor-derived, urine & blood
Pathogenesis
· Primary infection is usually asymptomatic or subtle respiratory illness in childhood
· Through the tonsils the virus goes to the circulation infect the mononuclear cells, reaches the kidney and stay dormant in the uroepithelium
· Following immunosuppression, the virus gets activated in the interstitium and crossing into peritubular capillaries causing inflammation, fibrosis, and damage. The interactions between the virus and the immune system will determine the clinical presentation
Clinical manifestations
A.Immune-competent host
· BKV cause no thing
B.Immune compromised host
-HIV
· Severe viremia & multi-organ failure leading to death
-Kidney transplantation
· BKVN
· Ureteric stenosis
· Late-onset hemorrhagic cystitis (HC)
-Hematopoietic stem cell transplant (HSCT)
· Hemorrhagic cystitis
· Non-hemorrhagic cystitis
-Other manifestations are rare including CNS, lung, liver and autoimmune diseases
BK virus & malignancy: thoughts on viral oncogenes
This was demonstrated in animal studies and may be due to;
· BKV-infected cells (agnoprotein and LTAg) are unable to arrest cell cycle driving cells into a neoplastic transformation
· Inhibition of regulators of cellular apoptosis (LTAg) e.g., Rb and P53 and this have led to urothelial malignancies in experimental mice
Screening for BKVN
· First month after transplantation, then monthly for 6 months, and then every 3 months for up to 2 years.
· Screening is carried out by DNA-PCR in urine & blood
Monitoring of urine
· Decoy cells (100% sensitivity & 70% specificity)
· Haufen bodies
· DNA-PCR
Kidney biopsy
· The gold standard (viral inclusion bodies, SV40 positive, tubulointerstitial inflammation, tubular atrophy & fibrosis)
· May miss the diagnosis in one-third due focal disease or disease isolated to medulla
· Take cores preferably involving medulla for increasing the chance of diagnosis
Differential diagnosis
· Allograft rejection
· Other causes of allograft dysfunctions
Treatment strategy
Reduction of immune suppression
· Reduction of immune-suppression e.g., change MMF to AZA, sirolimus, or leflunamide, reduce CNIs by 25% to 50% or change tacrolimus to cyclosporin or hold CNIs
· mTORI may be effective and improves immune reaction following BKV infection
Antiviral drugs & Antibacterial
Evidence is robust for using these drugs and some are nephrotoxic. Examples are:
· Leflunomide, cidofovir, and Quinolones
Monitoring after infection
· SCr every 1 to 2 weeks
· BKV-PCR every 2 to 4 weeks for 8 weeks
Re-transplantation
· Pre-transplant clearance of BK viremia following reduction of immune suppression is mandatory before re-transplantation
Conclusion
There is no specific treatment for BKV infection but early recognition and diagnosis is associated with improvement in overall allograft function
Narrative review, level 5
However, I would not agree with your conclusion and suggestion, as I quote your reply, “Evidence is robust for using these drugs and some are nephrotoxic. Examples are:
· Leflunomide, cidofovir, and Quinolones.”
Many thanks Dr Ben,
Welcome prof for your comments, sorry i was a typo = I missed to right not robust. It is clearly that we need more studies on these drugs but it is something that can be considered on case by case bases.
Thnxs prof
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant. Typing whole sentence in bold amounts to shouting.
Noted prof
IV. BK virus infection in renal transplant recipients: an overview
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Please summarise this article.
Introduction
BK virus and renal transplantation: historical perception
Polyomaviridae variants
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Epidemiology of BK virus
BK virus structure
BK virus variants
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Immunological response to BK virus
The role of cell-mediated immunity
The role of humoral immunity
Role of alloimmune activation
The role of other factors
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Pathogenesis of BK infection
Routes of transmission of primary BK virus
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Clinical manifestations
BK virus and renal disease
BK virus-associated nephropathy
Ureteric stenosis
Hemorrhagic cystitis
BK nephropathy in the native kidney
Other less apparent clinical manifestations include the following:
Ophthalmologic manifestations
BK virus and autoimmune diseases
BK virus and malignancy: thoughts on viral oncogenesis
BK virus and urothelial tumors
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Risk factors
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Screening and diagnostic tools
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Timing of screening
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Screening tests
Monitoring of the urine
Quantitative measurements
BK virus mRNA levels in urine
Pros and cons of urinary tests in identifying BKVN:
====================================================================
Serology
Serum BK-PCR
Pros and cons of the BK-PCR test:
Serum antibodies
Virus culture is rarely used outside a research setting, and BKV grows slowly in tissue culture.
====================================================================
Kidney biopsy
Pros and cons of kidney biopsy
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Suggested algorithm for screening
====================================================================
Differential diagnosis
Allograft rejection
Other differential diagnosis includes any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction.
====================================================================
Treatment strategy of BK virus nephropathy
Drugs with antiviral activities
Leflunomide
Cidofovir
mTOR inhibitors
Intravenous immunoglobulin
Other therapeutic options for treating BK virus
=================================================================
Short-term and long-term allograft survival
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BK nephropathy with concurrent acute rejection
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Postinfection monitoring
===================================================================
Retransplantation
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Conclusion
===================================================================
What is the level of evidence provided by this article?
The level of evidence is V
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant. Typing whole sentence in bold amounts to shouting.
Introduction:
BKV & renal transplantation:
Immunological response to BKV:
Pathogenesis of BKV infection:
Clinical manifestation:
BKV & malignancy:
Screening & diagnosis of BKVN:
Differential diagnosis:
Treatment:
BKN with concurrent acute rejection:
Re-transplantation:
Level of evidence is 5
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this review article on BK virus in renal transplant.
Thank you Professor
Introduction:
BKV, one of two human polyomaviruses discovered in 1971, was shown to induce interstitial nephritis and allograft failure in renal transplant patients three decades later. In the first year following kidney transplantation, BKV infection is one of several possible reasons of renal failure. Asymptomatic creatinine increases with tubulointerstitial nephritis may resemble acute rejection, creating a diagnostic and management conundrum.
BK epidemics:
BKV—polyomavirus hominins-1—infects most persons worldwide. In immune-competent humans, the virus remains latent after early childhood infection. 60–85% of the general population is BKV-positive. The only study on BKV prevalence in the Middle East and Africa came from Iran, with a seroprevalence of 41.8%. The age of the studied population, sample size, and antibody threshold explain such percentage variations.