●Introduction : _ The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV,andsimianvirus 40(SV40).It is a family of small, nonenveloped DNA viruses
_BKV infection, is an early complication of renal transplant, presents in the first year after transplantation.
_ It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection.
_ It may be simila to acute rejection, hence screening & diagnosis is crucial
_Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss.
_Gardner et al. were the first to detect BK polyomavirus(BKV)inbothurineandureteralepithelial 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 name polyoma represents the viruses’ capability to create many (poly) tumors
_Studies showed as much as 60–85% of the general population is seropositive for BKV.
_The virus consists of 3 parts:
1- The early viral gene region
2-The late viral gene region
3- The capsid protein VP1 in the Late Viral Gene Region is the main capsid protein.
_ BK has four genotypes: 1 is commonest accounting for greater than 80% worldwide followed by genotype 4, 15%.
_ 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.
_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
_The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis.
However, these typical features might be absent.
_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 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
( proximal).
_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.
_Routes of transmission:
1- Respiratory : respiratory tract and tonsils of children
2-Gastrointestinal transmission: BKV replication was shown in salivary gland cells and was detected in oral secretions.
3- Vertical transmission
4-Sexual transmission has been anticipated by Monini et al. as he detected BKV in 57% of genital tissue samples and 95% of sperm specimens.
5- Donor-derived infection:
●Clinical manifestation
_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
_ late-onset hemorrhagic cystitis
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
grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive 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 year.
_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 HIVinfection. Clinically, the patients might present with a picture of meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
_Pulmonary diseases: reactivated acute respiratory infection leading to severe interstitial pneumonitis
_Ophthalmologic manifestations: to date, there is only a single case report with bilateral atypical retinitis
● Screening :
Routinely monthly post tx for 3 – 6 months then every 3 month for 12 – 24 months then annually for 2 – 5 years
● Diagnosis
molecular techniques and renal tissue biopsy
● Ttt
Leflunamide
Cidofovir
Brincidofovir
Mtors
Quinolones have been described to inhibit the LTAg
artesunate
pravastatin
Rituximab
Iv ig
●Retransplantation following graft loss owing to BKVN is possible and can be done successfull ● Conclusion :
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes
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.
In 1971, Gardner et al. were the first to detect BK polyomavirus (BKV) in both urineand 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. Abundant large cells with intranuclear inclusions were present in the urine, named later as
‘Decoy cells’ for their resemblance to malignant cells
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 ofsmall, nonenveloped DNA viruses with icosahedral capsid of 40–45nm in diameter that can bear heating up to 50°C for 30 min with little effect on infectivity and has a circular double-stranded DNA of ∼5000 base pairs.
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. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN)
Routes of transmission of primary BK virus
Respiratory route: several authors had speculated the primary route oftransmission to be respiratory, as evident by the presence of BKV in the respiratory tract and tonsils of children.
Gastrointestinal transmission
Vertical transmission
Sexual transmission
Donor-derived infection
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.
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 BKpolyomavirus-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
BK virus-associated nephropathy Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
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
Screening
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 for active BKV replication may include identification of viral DNA-PCR in urine and bloodblood. However, no single diagnostic pathway has appeared as predominant.
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
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
Differential diagnosis Allograft rejection 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.
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 BKVspecific cellular immunity
BK virus infection in renal transplant recipients: an overview Summarise this article Introduction: BK virus (BKV), JC virus (JCV) and SV40 are human polyomaviruses – nonenveloped dsDNA viruses. BKV infection occurs mostly in first year post-renal-transplant, presenting as asymptomatic rise in creatinine, tubulointerstitial nephritis, and gradual cause allograft failure. It mimics (and associated with) acute rejection, producing diagnostic and therapeutic dilemma. BK virus variants: 4 genotypes identified on DNA-sequencing Genotype 1: most common (80%); has 4 subtypes Genotype 4: 15%; has 6 subtypes Genotype 2 and 3 are rare Immunological response to BK virus: BK viral replication occurs in immune-suppression state – characteristically in early posttransplant period (intense IS), following antirejection therapy. Factors favouring pathogenesis of BKVN: (a) defective immune surveillance by host T-lymphocytes, (b) absence of humoral immunity to BKV, (c) alloimmune activation, and (d) viral variation in molecular sequences
Pathogenesis of BK infection: Routes of transmission – 1. Respiratory route: primary 2. GIT transmission: some studies support fecal-oral transmission 3. Vertical transmission through placenta 4. Sexual transmission 5. Donor-derived infection 6. Urine and blood transmission Primary infection is subclinical, the virus then disseminated to the kidney and remains dormant in the urothelium and renal tubular cells, with intermittent reactivation (asymptomatic viruria). Virus also remains latent in leukocytes, brain and lymph nodes, reactivates after immunosuppressive therapy.
Clinical manifestations: Asymptomatic in immunocompetent hosts. In immunocompromised patients, particularly in renal allograft recipients, it causes allograft dysfunction (BKVN), ureteric stenosis, haemorrhagic cystitis. In hematopoietic stem cell transplant (HSCT) recipients, cause haemorrhagic cystitis; in HIV infected patients is disseminated, leading to multiorgan failure and death. Other clinical manifestations: less common
1. Neurological – meningoencephalitis, encephalitis, Guillain–Barre syndrome, vasculopathy.
2. Pulmonary – interstitial pneumonitis
3. Ophthalmic – bilateral atypical retinitis (rare)
May be b related to autoimmune diseases.
BK virus and malignancy: Expression of the early coding region-encoded proteins such as large and small tumor antigens (LTAg, STAg), confers oncogenic property, that drives host cells into neoplastic transformation. BK virus has been associated with urothelial tumors, with limited data. BKV-DNA has been isolated from high grade Ca UB. 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: Objectives: early detection of viruria / viremia; enable to intervene before graft dysfunction occurs. Decoy cells – abnormal large epithelial cells, that is shed in urine in 78% BKVN – detected by PAP or Silver stain. Urine electron microscopy (EM-Haufen) has a higher sensitivity and specificity for detecting BKVN than urine cytology, but requires further validation. Serology: The BK-PCR test has high sensitivity and specificity; identify infection 4weeks before nephritis occur. Virus culture: isolation of virus – grows slowly in tissue culture. Kidney biopsy: Allograft biopsy is the gold standard to diagnose BKVN, with a sensitivity of 94.7% for H&E and 68.4% for FISH. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival. Differential diagnosis: BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and IHC positive immuno-peroxidase staining for SV40, highlighting the virally infected cells.
Treatment of BKVN: Aim is to eradicate BKV, saving the kidney function. As BK viremia and BKVN indicate excess cumulative immunosuppression – “reducing immunosuppression” is the only validated therapy to treat BKVN, and restore antiviral immune response; however, it has to be balanced against the risk acute or chronic rejection.
Drugs with antiviral activities: – Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug that inhibits pyrimidine synthesis and can inhibit BKV replication in vitro. – Cidofovir is a nephrotoxic drug that may cause acute kidney injury, renal tubular acidosis, and proteinuria, and should be used carefully in kidney recipients. – MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression. – IVIG has the most potent antiviral influence. IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain. – Quinolones and statins have been found to reduce BKV proliferation, while rituximab has been associated with adverse effects. – Rituximab adjuvant therapy with cidofovir had no graft failure in 9 transplant patients with BKVN. Short-term and long-term allograft survival: BKVN related allograft damage is noted in 30-60% of cases, but therapeutic approaches have improved renal allograft survival. BKV nephropathy and concurrent acute rejection: Management of biopsy proven acute rejection with concomitant BKVN or management of anticipated rejection following decreased immunosuppression to treat BKVN remains debatable.
Post infection monitoring of BKV-PCR and renal function is essential to improve allograft outcome. Re-transplantation can be done successfully – need proper dose adjustment of IS. Conclusion: Early diagnosis of BKVN based on combination of molecular techniques and tissue analysis, and modification of immunosuppression has resulted in substantial improvement in allograft outcomes.
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 posttransplantation 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
1.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.
2.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 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.
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.
Postinfection 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.
Retransplantation
Retransplantation following graft loss owing to BKVN is possible and can be done successfully. Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression. The patient may get infected with BKV after retransplantation. Recurring BKV might reflect a previous BK variant or a new infection (de-novo BKV) acquired, because of the long period, in the posttransplantation stage.
Introduction:
There are two human polyomaviruses, BK virus (BKV) and JC virus (JCV)
BKV cause interstitial nephritis and allograft failure in renal transplant recipients, occurring within the first year after transplantation. 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.
It is nonenveloped DNA viruses with circular double strand DNA of -5000 base pairs and can bear heating up to 50°C Epidemiology of BK virus:
BKV is Polyomavirus hominis-1
Primary infection takes place during early childhood, and then the virus stays dormant throughout life in immune-competent BK virus structure:
BKV-DNA genome 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), which interacts and binds to cellular target proteins
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:
BKV has 4 genotypes according to the DNA sequence variations in the genomic region of VP1
Genotype 1:common =80% and has 4 subtypes
Genotype 1V =15% and has 6 subtypes
Genotype II and III are rare Immunological response to BK virus:
BK viral replication follows a state of immune suppression; BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
nephropathy (BKVN) [48]. Factors for 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 [13] Pathogenesis of BK infection:
Primary infection is subclinical then disseminated to the kidney 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 [3,4,24]. Also can remain latent in leukocytes, brain and lymph node the virus reactivate in the presence of immunosuppressive therapy. Routes of transmission of primary BK virus:
1. Respiratory route: primary
2. GIT transmission: some studies support orofecal transmission
3. Vertical transmission through placenta
4. Sexual transmission
5. Donor-derived infection
6. Urine and blood transmission Clinical manifestations:
BKV does not cause disease in immunocompetent people but in immunocompromised patients, particularly in renal allograft recipients, it cause different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
Outside renal transplantation, BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC, whereas in HIV infected patients, it may cause dissemination leading to multiorgan failure and death. Other less clinical manifestations include:
1. Neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
2. Pulmonary diseases: such as interstitial pneumonitis
3. Ophthalmologic manifestations: single case report with bilateral atypical retinitis.
Different studies describe the relationship between BKV and some autoimmune diseases. BK virus and malignancy:
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 BK virus and urothelial tumors:
BKV-LTAg play role in urological tumor with limited data 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. Decoy cells are abnormal BKV-infected epithelial cells that can be detected in urine and used to diagnose BKVN.
Urine electron microscopy (EM Haufen) has a higher sensitivity and specificity for detecting BKVN than urine cytology, but requires further validation. Serology:
The BK-PCR test has high sensitivity and specificity, which identify the infection before nephritis occur. Virus culture:
Used to isolate the virus but it grows slowly in tissue culture. Kidney biopsy:
Allograft biopsy is the gold standard to diagnose BKVN, with a sensitivity of 94.7% for H&E and 68.4% for FISH. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival. 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. Treatment strategy of BK virus nephropathy:
The aim of treating BKV is to eradicate the virus while saving the kidney function 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 Drugs with antiviral activities:
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug that inhibits pyrimidine synthesis and can inhibit BKV replication in vitro.
Cidofovir is a nephrotoxic drug that may cause acute kidney injury, renal tubular
acidosis, and proteinuria, and should be used carefully in kidney recipients.
MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression, and IVIG has the most potent antiviral influence. IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain.
Quinolones and statins have been found to reduce BKV proliferation, while rituximab has been associated with adverse effects. Rituximab adjuvant therapy with cidofovir had no graft failure in 9 transplant patients with BKVN. Short-term and long-term allograft survival:
BKVN has caused permanent allograft damage in 30-60% of cases, but therapeutic approaches have improved renal allograft survival. 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 Post infection monitoring:
Post infection monitoring of BKV-PCR and renal function is essential to improve allograft outcome. Retransplantation is possible and can be done successfully. 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
BKV- polyomavirus that can cause interstitial nephritis and allograft failure in KTR
Usually presenting as a gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection
belongs to the Polyomaviridae subgroup of papovaviruses, which includes JCV and simian virus 40 (SV40)
replication occurs during immune suppression states such as pregnancy, diabetes, HIV, cancer, and post-transplantation
immune system plays a crucial role in controlling BKV replication and resolution of BKVN
Defective immune surveillance, absence of humoral immunity to BKV, alloimmune activation, and viral variation in molecular sequences may contribute to the pathogenesis of BKVN. CD4+ and CD8+ T cells control BKV by reacting against nonstructural and capsid proteins
Humoral immunity also plays a role in BKVN, as patients with prior immunity to BKV may not show the disease’s manifestation. Allo-HLA-reactivity and heterologous immunity might also contribute to BKVN’s development.
commonly causes asymptomatic viruria in immunocompetent individuals, but can lead to severe clinical manifestations in immunocompromised patients, especially in kidney and hematopoietic stem cell transplant recipients.
also cause renal injury, known as BK virus-associated nephropathy (BKVN), which can progress to allograft failure
infection is thought to occur through primary infection in childhood, followed by dormancy in uroepithelial and renal tubular cells with intermittent reactivation.
can be transmitted via respiratory, fecal-oral, transplacental, or donor tissues, although the primary mode of transmission remains uncertain.
CLINICAL MANIFESTATIONS
BKVN,
ureteric stenosis
hemorrhagic cystitis.
Other less apparent clinical manifestations include neurological, pulmonary, and ophthalmologic manifestations, as well as a potential association with autoimmune diseases. Early diagnosis and reduction of immunosuppression are the mainstay of treatment for BKV infection.
also been found in tissue samples of various neoplasms, leading to the suggestion that it may have an oncogenic property.
SCREENING AND DIAGNOSIS
Screening for active BKV replication may include detection of viral DNA-PCR in urine and blood, identification of infected epithelial cells, or quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA. However, no single diagnostic pathway has emerged as predominant.
A quantitative BKV-DNA test has been successful in identifying early BK infection before the development of nephritis. However, not all recipients with BK viremia will develop nephritis, and a definite viral load cutoff associated with nephropathy has not yet been defined. BKV-PCR levels may differ substantially between assays, with significant differences in quantified viral loads, limiting the threshold of assay detection.
The gold standard for diagnosing BKVN is allograft biopsy, which ideally should be performed when BKV-PCR load insistently exceeds more than 10,000 copies/ml with or without allograft dysfunction.
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically. Three grades of histopathological severity have been identified, where grade A includes viral cytopathic changes of near-normal renal parenchyma, and grade C signifies diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation.
TREATMENT
BKVN has limited treatment options, with the aim of eradicating the virus while preserving kidney function.
The primary treatment for BKV is decreasing immunosuppression, as BK viremia and BKVN are associated with excessive cumulative immunosuppression.
Reduction or modification of immunosuppressive therapy with or without antiviral medications is the first-line approach.
Different regimens have been attempted upon recognition of viremia, including withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class, and steroid avoidance.
Other therapeutic options such as leflunomide, cidofovir, and mTORi, IVIG, quinolones, statins, and rituximab.
The effectiveness of these options remains uncertain, and adverse effects can occur. Reduction in immunosuppression remains a rational option even in the presence of allograft dysfunction and can result in clearance of viremia and a steadiness of allograft functions.
BK virus is belong to polyomavirus and chase interestitial nephrites and may cause severe tubulointerstitail nephrites that can lead to graft dysfunction which mimic Graft rejection .
BK virus was discovered in 1971 ,and it belong to papovavirus which include JCV and simia virus (sv40).
BK virus is having different genotype with genotype 1 and 1v being the most common type .
Usually BK virus is contaminated in eraly childhood in 60 to 80 % of the cases ,with flare mainly in immunodeficient state like pregnancy ,diabetes ,HIV, and in post transplantation .
The BK virus replication is manily is under control of immunity ,CD4+ and CD8+ T cells control BKV by reacting against nonstructural and capsid proteins. Humoral immunity also plays a role in BKVN, as patients with prior immunity to BKV may not show the disease’s manifestation.
The pathogenesis of BK virus is dependes mainly on the cummulative effect of IS and it can present asymptomatically with viuria or can cause severe allograft dysfucntion which mimic rejection .
Clinical manifestations of BKV infection include BKVN, ureteric stenosis, and hemorrhagic cystitis. It is crucial to say its assiciation with autoimmune disease . The main corner stone in managmenent is the reduction of IS .
The BK virsu has been found to assvcociated with malignancy for that threr is belive that BK virus is oncogenic virus,screening for active BKV replication may include detection of viral DNA-PCR in urine and blood, identification of infected epithelial cells, or quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
BK DNA PCR quantitative test is being used to detect the early presence of BK virus even before nephrites . REal time PCR need to detect the BK vireamia .
The gold standre for diagnosing BKAN is by doing graft biopsy ,but usually this is need to be done oif the BK virus PCR load≥10000 copies/ml,Three grades of histopathological severity have been identified, where grade A includes viral cytopathic changes of near-normal renal parenchyma, and grade C signifies diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation Treatment of BK virus is depends mainly on eradicatin the virsu and keeps functioning great with reduction or switching strategy of IS is the main bases .Other therapeutic options include drugs with antiviral activities such as leflunomide, cidofovir, and mTOR inhibitors, intravenous immunoglobulin, quinolones, statins, and rituximab.
The big challenging is to treat the BKAN and rejection in the same time which is remain debatable and difficult to treat but the close follow up for the BK PCR and close monitoring for the graft function
INTRODUCTION BK virus (BKV) is a polyomavirus that can cause interstitial nephritis and allograft failure in renal transplant recipients, presenting as a gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection. BKV belongs to the Polyomaviridae subgroup of papovaviruses, which includes JCV and simian virus 40 (SV40). It has a circular double-stranded DNA genome that can be divided into three parts, with the noncoding control region (NCCR) regulating the virus’s expression of early and late genes. BKV can be categorized into four genotypes/subtypes according to DNA sequence variations in the genomic region of VP1, with genotypes I and IV being the most common.
IMMUNOLOGICAL RESPONSE OF VIRUS BK virus (BKV) replication occurs during immune suppression states such as pregnancy, diabetes, HIV, cancer, and post-transplantation. The immune system plays a crucial role in controlling BKV replication and resolution of BK virus nephropathy (BKVN). Defective immune surveillance, absence of humoral immunity to BKV, alloimmune activation, and viral variation in molecular sequences may contribute to the pathogenesis of BKVN. CD4+ and CD8+ T cells control BKV by reacting against nonstructural and capsid proteins. Humoral immunity also plays a role in BKVN, as patients with prior immunity to BKV may not show the disease’s manifestation. Allo-HLA-reactivity and heterologous immunity might also contribute to BKVN’s development.
PATHOGENESIS It commonly causes asymptomatic viruria in immunocompetent individuals, but can lead to severe clinical manifestations in immunocompromised patients, especially in kidney and hematopoietic stem cell transplant recipients. BKV can also cause renal injury, known as BK virus-associated nephropathy (BKVN), which can progress to allograft failure. The pathogenesis of BKV infection is thought to occur through primary infection in childhood, followed by dormancy in uroepithelial and renal tubular cells with intermittent reactivation. BKV can be transmitted via respiratory, fecal-oral, transplacental, or donor tissues, although the primary mode of transmission remains uncertain. Clinical manifestations of BKV infection include BKVN, ureteric stenosis, and hemorrhagic cystitis. Other less apparent clinical manifestations include neurological, pulmonary, and ophthalmologic manifestations, as well as a potential association with autoimmune diseases. Early diagnosis and reduction of immunosuppression are the mainstay of treatment for BKV infection.
BK VIRUS AND MALIGNANCY BK virus (BKV) is a common virus that can cause disease in immunocompromised individuals, especially in renal transplant recipients. It has also been found in tissue samples of various neoplasms, leading to the suggestion that it may have an oncogenic property. Several risk factors have been implicated in the pathogenesis of BKV-associated nephropathy, with immunosuppression being the most consistent factor. Screening for active BKV replication may include detection of viral DNA-PCR in urine and blood, identification of infected epithelial cells, or quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA. However, no single diagnostic pathway has emerged as predominant.
WORK UP
BK viremia, the presence of BK virus in the blood, is typically seen in immunocompromised patients and is measured using real-time PCR.
A quantitative BKV-DNA test has been successful in identifying early BK infection before the development of nephritis. However, not all recipients with BK viremia will develop nephritis, and a definite viral load cutoff associated with nephropathy has not yet been defined. BKV-PCR levels may differ substantially between assays, with significant differences in quantified viral loads, limiting the threshold of assay detection.
The gold standard for diagnosing BKVN is allograft biopsy, which ideally should be performed when BKV-PCR load insistently exceeds more than 10,000 copies/ml with or without allograft dysfunction. Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically. Three grades of histopathological severity have been identified, where grade A includes viral cytopathic changes of near-normal renal parenchyma, and grade C signifies diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation.
TREATMENT OPTIONS BK virus nephropathy (BKV) has limited treatment options, with the aim of eradicating the virus while preserving kidney function.
The primary treatment for BKV is decreasing immunosuppression, as BK viremia and BKVN are associated with excessive cumulative immunosuppression. Reduction or modification of immunosuppressive therapy with or without antiviral medications is the first-line approach. Different regimens have been attempted upon recognition of viremia, including withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class, and steroid avoidance.
Other therapeutic options include drugs with antiviral activities such as leflunomide, cidofovir, and mTOR inhibitors, intravenous immunoglobulin, quinolones, statins, and rituximab.
The effectiveness of these options remains uncertain, and adverse effects can occur. Reduction in immunosuppression remains a rational option even in the presence of allograft dysfunction and can result in clearance of viremia and a steadiness of allograft functions.
BK virus nephropathy (BKVN) is a condition that can lead to permanent damage to kidney transplants. 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. 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.
BKV
it is a polyomavirus along with JCV and SV40
BK stands for the initials of the patient where the virus was first detected in 1971
BKV is ubiquitous virus and the primary infection takes place in the childhood ,in general 60 to 80% of the population is sero positive
Immunological response to BK virus
Replication of virus follows immune operation like diabetes HIV pregnancy post transplant
Immediately after kidney transplantation, replication starts and it follows anti rejection therapy where intense immunosuppression is given
Uroepithelium is the target of BKV
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, (DECOY CELLS )
The damage of tubular capillary walls
will cause the vascular spread of the virus, leading to
dense inflammatory interstitial infiltrate and tubulitis.
ALLOIMMUNE ACTIVATION
a lack of HLA matches might predict better outcomes in recipients with
BKVN.
Primary infection with BKV is usually subclinical
BK virus stays dormant in the uroepithelium and renal
tubular cells for life
In the presence of immunosuppressive therapy, the virus activates and
starts to proliferate inside the interstitium
Transmission is possible through all routs
Clinical manifestation
immunocompetent – NIL
immunocompromised- BKV has been correlated with are the BKVN,
ureteric stenosis, and late-onset hemorrhagic cystitis
BKVN in different literature ranges between 2 and 15% of kidney
allograft recipients
risk factors for BKVN
overall degree of immunosuppression is main factor
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;
screening
BKVN is early complication of a kidney
transplant, and most cases arise in the first posttransplant year
screening start at first month after transplant, then monthly for the first 6 months,
and then every 3 months for up to 2 years.
first BK viruria starts ,
after 4 week BK viremia and after 12 weeks BKVN
Monitoring of the urine
detection of
BKV-infected epithelial cells named as ‘decoy cells,’ 100% NPV
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
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
serum antibody
significance is still uncertain
BK viremia of more than or equal to 104 is characteristically present in recipients with proven
biopsies of BKVN.
Renal biopsy
two cores at least and should have medulla to avoid false negativity
ACUTE REJECTION IS differential diagnosis
TREATMENT
decreasing immunosuppression is the only validated
therapy to treat BKVN and restore antiviral immune
response
under trial drugs –
leflunomide
cidofovir
mTOR inhibitors
IVIG
quinolones
Introduction:
There are two human polyomaviruses, BK virus (BKV) and JC virus (JCV)
BKV cause interstitial nephritis and allograft failure in renal transplant recipients, occurring within the first year after transplantation. 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.
It is nonenveloped DNA viruses with circular double strand DNA of -5000 base pairs and can bear heating up to 50°C Epidemiology of BK virus:
BKV is Polyomavirus hominis-1
Primary infection takes place during early childhood, and then the virus stays dormant throughout life in immune-competent BK virus structure:
BKV-DNA genome 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), which interacts and binds to cellular target proteins
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:
BKV has 4 genotypes according to the DNA sequence variations in the genomic region of VP1
Genotype 1:common =80% and has 4 subtypes
Genotype 1V =15% and has 6 subtypes
Genotype II and III are rare Immunological response to BK virus:
BK viral replication follows a state of immune suppression; BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
nephropathy (BKVN) [48]. Factors for 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 [13] Pathogenesis of BK infection:
Primary infection is subclinical then disseminated to the kidney 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 [3,4,24]. Also can remain latent in leukocytes, brain and lymph node the virus reactivate in the presence of immunosuppressive therapy. Routes of transmission of primary BK virus:
1. Respiratory route: primary
2. GIT transmission: some studies support orofecal transmission
3. Vertical transmission through placenta
4. Sexual transmission
5. Donor-derived infection
6. Urine and blood transmission Clinical manifestations:
BKV does not cause disease in immunocompetent people but in immunocompromised patients, particularly in renal allograft recipients, it cause different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
Outside renal transplantation, BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC, whereas in HIV infected patients, it may cause dissemination leading to multiorgan failure and death. Other less clinical manifestations include:
1. Neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
2. Pulmonary diseases: such as interstitial pneumonitis
3. Ophthalmologic manifestations: single case report with bilateral atypical retinitis.
Different studies describe the relationship between BKV and some autoimmune diseases. BK virus and malignancy:
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 BK virus and urothelial tumors:
BKV-LTAg play role in urological tumor with limited data 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. Decoy cells are abnormal BKV-infected epithelial cells that can be detected in urine and used to diagnose BKVN. Urine electron microscopy (EM Haufen) has a higher sensitivity and specificity for detecting BKVN than urine cytology, but requires further validation. Serology: The BK-PCR test has high sensitivity and specificity, which identify the infection before nephritis occur. Virus culture: Used to isolate the virus but it grows slowly in tissue culture. Kidney biopsy: Allograft biopsy is the gold standard to diagnose BKVN, with a sensitivity of 94.7% for H&E and 68.4% for FISH. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival. 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. Treatment strategy of BK virus nephropathy:
The aim of treating BKV is to eradicate the virus while saving the kidney function 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 Drugs with antiviral activities:
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug that inhibits pyrimidine synthesis and can inhibit BKV replication in vitro.
Cidofovir is a nephrotoxic drug that may cause acute kidney injury, renal tubular
acidosis, and proteinuria, and should be used carefully in kidney recipients.
MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression, and IVIG has the most potent antiviral influence. IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain.
Quinolones and statins have been found to reduce BKV proliferation, while rituximab has been associated with adverse effects. Rituximab adjuvant therapy with cidofovir had no graft failure in 9 transplant patients with BKVN. Short-term and long-term allograft survival: BKVN has caused permanent allograft damage in 30-60% of cases, but therapeutic approaches have improved renal allograft survival.
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 Post infection monitoring:
Post infection monitoring of BKV-PCR and renal function is essential to improve allograft outcome. Retransplantation is possible and can be done successfully. 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
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
note : this is the same summary in week 9 , journal club n.4 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. Hemorrhagic 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. 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
Polyomaviridae virions (BKV, JCV,SV40) – Nonenveloped DNA virus
Initials of Sudanese kidney transplant recipient presented with ureteric stenosis and renal failure.
Primary infection takes place in early childhood and remains domain in immuno-competent people
Pathogenesis of BK infection
Primary infection in childhood (respiratory symptoms) with the route of transmission can be either from respiratory, fecal-oral, transplacenta and donor tissue
Disseminated to secondary organ ie: kidneys and stay dormant in uroepithelial cells
Proliferate in an immunocompromised individual into the interstitium and ptc
Clinical manifestations
BKV nephropathy
Ureteric stenosis
Haemorrhagic cystitis
Others
Neurological manifestations (meningoencephalitis, encephalitis, GBS and vasculopathy)
Pulmonary ds (interstitial pneumonitis)
Ophthalmological manifestations (retinitis)
Hepatic ds
Screening and diagnostic tools
Timing: monthly for the first 6 months then every 3 months up till 2 years
Diagnostic tests: DNA-PCR, Decoy cells, EM Haufen
Others: Virus culture and kidney biopsy (SV40 stained)
I. BK virus infection in renal transplant recipients: an overview Please summarise this article.
BK virus (BKV) and JC virus (JCV), were discovered in 1971. 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. BK virus and renal transplantation
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.
Abundant large cells with intranuclear inclusions were present in the urine, named later as ‘decoy cells’ for their resemblance to malignant cells.
In 1978 had defined histological changes consistent with polyomavirus nephritis in a kidney biopsy of a patient who was shedding BKV in the urine. 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, non enveloped DNA viruses.
These new group members were termed based on the site of discovery, their geographical areas. Epidemiology of BK virus
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
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:
(1) The early viral gene region: 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
Had 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. Immunological response to BK virus
BK viral replication follows: pregnancy, diabetes, HIV infection, cancer, and post transplantation period(follow antirejection therapy). The role of cell-mediated immunity
The major components of cellular-mediated immunity to control the BKV and play a role in BK clearance are CD4+ and CD8+ T cells . 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.
Role of alloimmune activation Anotherpossible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity. CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans. Pathogenesis of BK infection
manifests as a mild respiratory symptom in childhood 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 ,within termittent reactivation that manifests as asymptomatic viruria.
BKV can remain latent in leukocytes, brain tissues,and lymphnodes. Routes of transmission of primary BK virus
1.Respiratory (respiratory tract and tonsils of children)
2.fecal-oral(salivary gland cells)
3. transplacental(cross the placenta and stay dormant in fetal organs, suggesting the possibility of vertical transmission)
4. sexual transmission
4.from donor tissues (BKV infection could be from either the donor or the recipient) Clinical manifestations
Urinary shedding of BKV was reported in 7% of healthy immune competent individuals.
1.ureteric stenosis, and late-onset hemorrhagic cystitis.
2.BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia.
3. The onset of nephritis might occur as early as 6 days after renaltransplantoraslateas5years.
4.The prevalence of ureteric stenosis is 2–6%.
5.The patients might present with bladder cramps, painful voiding,hematuria,and/or flank pain.
6.Primary central nervous system disease or reactivated central nervous system infection.
7.Reactivated acute respiratory infection leading to severe interstitial pneumonitis in association.
8. Bilateral atypical retinitis(rare).
9. Hepatitis was reported in a patient with bone marrow transplant.
10. BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis.
11. 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
Ureteral stent insertion. Serology
BK viral loads are measured with real-time PCR.
Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successfull inidentifying early BK infection before the development of nephritis.
BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively. Virus culture
BKV grows slowly in tissue culture, which might extend from weeks to months. Kidney biopsy
Allograft biopsy remains the gold standard to diagnose BKVN(nephropathy), which ideally should be performed whenBKV-PCRloadinsistentlyexceedsmorethan10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction. Treatment strategy of BK virus nephropathy
Reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Withdrawal of antimetabolite drugs .
Change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide.
Reducing the dose of calcineurin inhibitor (CNI) by 25–50%. Leflunomide
Is an immunomodulator, prodrug, and antirheumatic disease-modifying drug .
It inhibit pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects. Cidofovir
Is a cytosine analog and viral DNApolymerase inhibitor that is used to manage other viral infections such as CMV. mTOR inhibitors
mTOR inhibitors have shown effectiveness in in-vitro analysis in inhibiting BK replication and early gene expression. The mTOR inhibitors(sirolimus and everolimus) are thought to produce their inhibitory effect on BKV replication by restoring the down regulation of translation that occurs under cellular stress, thus delay the viral replication. Intravenous immunoglobulin
used for BKVN for its immune modulatory effects. has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes. Short-term and long-term allograft survival
Therapeutic approaches have revealed substantial short-term improvements, such as eliminating the circulating viremia.
The documented acute rejection rates following a reduction in immunosuppression varied from 6 to 12%. BK nephropathy with concurrent acute rejection
More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in 10–30% of the cases.
Combination of anti rejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection. Postinfection monitoring
To improve allograft outcome we do Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression.
BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression. 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: 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.
Introduction
BKV infection often causes of 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.
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 gave the name ‘BK’.
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 and has a circular double-stranded DNA of ∼5000 base pairs.
Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent. Studies showed as much as 60–85% of the general population is seropositive for BKV.
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 is the main
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1, Genotype I 80% worldwide, genotype IV 15% and genotypes II and III are relatively rare
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 transplantation period. 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. T cells react against both nonstructural and BK capsid proteins and can be measured by the enzyme-linked immunosorbent spot (ELISPOT) and tetramer staining. The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
Role of alloimmune activation
Awadalla et al. had linked the higher degree of HLA mismatches with an increase in the incidences of BKVN, which hypothesizes the role of alloimmune activation wereas Drachenberg et al. 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 BKVN. Therefore, 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
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.
Routes of transmission of primary BK virus
Respiratory route, Gastrointestinal transmission, Vertical transmission, Sexual transmission, Donor-derived infection, urine and blood
Clinical manifestations
Ureteric stenosis, late-onset hemorrhagic cystitis (HC), BKpolyomavirus-associated nephropathy (BKVN)(onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years)
Others manifestation
Meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy, acute respiratory infection leading to severe interstitial pneumonitis, bilateral atypical retinitis (rarely), hepatitis.
Association with autoimmune disease and malignancy has been proposed.
Risk factors
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.
Timing of screening
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.
Monitoring of the urine
Monitoring of the urine 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
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.
BK virus mRNA levels in urine-This method is considered as 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, other test includes 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 log10 genome (copies/ml)) 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.
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.
Banff working proposal.
Class 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
Allograft rejection
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 some BKV cases and is linked with more aggressive disease.
IHC staining of renal tissues or urinary sediments with anti-HLA DR, which has been related to acute rejection. 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
Decreasing immunosuppression is the only validated therapy to treat BKVN
Treatment of presumptive BK virus nephropathy
Switching a drug within the same class or to a different class and steroid avoidance these 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
Treatment of BK virus nephropathy in the setting of allograft dysfunction
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: Pyrimidine depletion and tyrosine kinase inhibition: A/E Hemolytic anemia thrombocytopenia, and thrombotic microangiopathy
Cidofovir: Inhibits viral replication; mechanism unknown: A/E Potentially nephrotoxic and severe anterior uveitis.
IVIG: Contain neutralizing antibodies against BKV and are immunomodulatory, A/E May led 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, A/E Hyperlipidemia, bone marrow toxicity, mucositis and oral ulcerations, and lymphedema.
Fluoroquinolones: Inhibit BKV replication in vitro and inhibit the large T antigen helicase activity, A/E 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, A/E Anorexia, dizziness, nausea, and diarrhea.
Pravastatin: Prevent caveolae-mediated endocytosis, A/E Adverse muscle events and hepatic dysfunction Short-term and long-term allograft survival
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.
BK nephropathy with concurrent acute rejection
Hirsch et al. suggested a combination of antirejection therapy with a subsequent reduction in immunosuppression.
Post infection monitoring. 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 achieve
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 consider changing to sirolimus or adding leflunomide. Inability to clear BKV can lead to worse allograft outcomes.
Re-Transplantation
Generally, pretransplant clearance of BK viremia is essential. Allograft nephrectomy is not necessary before re-transplantation.
BKV viruria, viremia, and BK nephropathy can recur and cause allograft loss
BKV infection 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 virus and renal transplantation: historical perception:
Gardner et al. is the first to detect BK virus (BKV) in 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.
Polyomaviridae variants :
The Polyomaviridae (PyV) are a family of small, nonenveloped DNA viruses includes (BKV,JCV, and simian virus 40 (SV40) ) which is having 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, with primary infection occurring in early childhood and remaining dormant throughout life.
BK virus structure:
The BK virus genome is divided into three parts: the early viral gene region, the noncoding control region (NCCR), and the late viral gene region (LVGR). The NCCR regulates the expression of the virus early and late genes, while the LVGR encodes the capsid proteins VP-1, VP-2, and VP-3
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 and genotypes II and III. 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, IV/b-3, IV/c-1, and I/c-2). These subgroups may reflect different geographical and migration patterns of the human population. The clinical and immunological consequences of these genotypes on clinical aspects and the course of the disease are still unknown.
Immunological response to BK virus:
The immune system plays an essential role in controlling BKV replication and resolution of BKVN due to defective immune surveillance, lack of humoral immunity, alloimmune activation, and viral variation. Humoral immunity, antibody mediated immunity, and allo-human leukocyte activation may all play a role 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 primary BKV transmission include respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations:
BKV does not cause disease in healthy individuals, but is associated with different clinical features in immunocompromised patients, such as BKVN,ureteric stenosis, and late-onset hemorrhagic cystitis (HC). Outside renal transplantation, BKV is commonly encountered in patients with HSCT. BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis can occur as early as 6 days after transplant or as late as 5 years. 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 and ureteral dilatation.
BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection, but has been linked to neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy in patients with HSCT or HIV infection. Pulmonary diseases such as reactivated acute respiratory infection and severe interstitial pneumonitis have been reported in HIV-infected patients, and ophthalmologic manifestations such as bilateral atypical retinitis and retinal necrosis have been reported. However, further data are needed before labeling BKV to cause an ophthalmological manifestation. BK virus and autoimmune diseases have been linked in the literature, with a prevalence of 16% in patients with systemic lupus erythematosus and an increase in the prevalence of persistence/or recurrent BK viruria in patients with lupus. However, there is no article that describes BKV activation in patients at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference.
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.
BK virus and urothelial tumors:
BKV-LTAg may play a role in the pathogenesis of urothelial tumors, but evidence is limited.
Risk factors:
Risk factors for BKVN include overall immunosuppression, male sex, older recipient age, previous rejection episodes, HLA mismatching, cold ischemia, BK serostatus, and ureteral stent insertion.
Screening and diagnostic tools:
Screening and diagnostic tools are used to identify recipients with BKVN and act before graft dysfunction appears. Decoy cells are abnormal BKV-infected epithelial cells that can be detected in urine and used to diagnose BKVN.
Urine electron microscopy (EM Haufen) has a higher sensitivity and specificity for detecting BKVN than urine cytology, but requires further validation.
Serology: Quantitative BKV-PCR has been successful in identifying early BK infection before nephritis, but not all recipients will develop nephritis. The BK-PCR test has high sensitivity and specificity, but is interlaboratory dependent and should be interpreted in light of clinical condition.
Virus culture:
Virus culture can be used to isolate BKV, but it grows slowly in tissue culture.
kidney biopsy :
Allograft biopsy is the gold standard to diagnose BKVN, with a sensitivity of 94.7% for H&E and 68.4% for FISH. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival.
Differential diagnosis:
BKVN can be distinguished from acute rejection by presence of BKV inclusion bodies, immunohistology, and IHC staining.
Treatment strategy of BK virus nephropathy: Reducing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response, but should be balanced against risk of rejection.
Drugs with antiviral activities:
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug that inhibits pyrimidine synthesis and can inhibit BKV replication in vitro. Cidofovir is a nephrotoxic drug that may cause acute kidney injury, renal tubular acidosis, and proteinuria, and should be used carefully in kidney recipients. MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression, and IVIG has the most potent antiviral influence. IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain. Quinolones and statins have been found to reduce BKV proliferation, while rituximab has been associated with adverse effects. Rituximab adjuvant therapy with cidofovir had no graft failure in 9 transplant patients with BKVN.
Short-term and long-term allograft survival:
BKVN has caused permanent allograft damage in 30-60% of cases, but therapeutic approaches have improved renal allograft survival.
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. Treatment should be tailored for each patient individually.
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.
● 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
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. 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 the 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.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Monitoring BKVN using quantitative plasma BKV-PCR is important to improve allograft outcomes.’
BK virus infection in renal transplant recipients: an overview
BKV belong to polyoma virus, identified in 1971
one of the causes of interstitial nephritis and graft failure among renal transplant patients.
also known as polyomavirus hominid-1
usually primary infection during childhood, which either asymptomatic or mild respiratory tract symptoms in immunocompetent people
after that ,the virus will stay dormant throughout life and may re activate when the immune system compromised
60-85% of general population were seropositive
BKV-DNA genome composed of 3 parts:
1.early viral gene region
2.late viral gene region
3.capsid protein VP1 in the LVGR
BKV subdivided into 4 genotypes:
Genotype 1 ….80% (most common)
Genotype 4 ….15%
Genotype 2 & 3 …..rare
The immune system responsible for controlling viral replication & resolution of BKVN
Route of transmission:
1.respiratory
2.GIT
3.vertical
4.sexual
5.donor-derived
6.urine
7.blood
The clinical presentation varies from asymptomatic to BKVN, ureteric stenosis and late onset hemorrhagic cystitis…
when the viral within the uroepithelium starting replication and shedding of virus into urine (viruria),then after several weeks (~ 4 weeks) virus seen within blood (viremia),then around 12 weeks BKVN
BKV viruria …..30-40%
BKV viremia ….10-15%
BKVN ………….2-15%
ureteric stenosis…2-6%
BKVHC …..rare after kidney transplantation while more common among hematopoietic stem cell transplanataion
BKV may involve brain, respiratory tract, eye ,liver and causing autoimmune diseases
BKV seen or associated with some malignancies such as urothelial carcinoma
Diagnosis:
A.Urine
1.urine cytology ( decoy cells) large cells with intranuclear inclusion of virus make resemble of malignant cells ,which is not diagnostic 100% and absence dose not exclude BKV infection
2.urine electromicroscopy EM (haufen)
3.urine PCR : Quantitative viral load and BKVmRNA
B.Serology:
1.BKV-PCR
2.serum Ab
C.viral culture (require weeks-months)
D. renal biopsy (three patterns /classes which are resemble of rejection)
different screening program available, the one most popular is screening PCR at 1st month post transplantation ,then monthly up to 6 months, then every 3 months up to 2 year and in some centers annually
there is no definitive antiviral or vaccination …..the main treatment is reduction of immunosuppressive medications
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate, ‘there is no definitive antiviral or vaccination …..the main treatment is reduction of immunosuppressive medications’.
BK virus infection in renal transplant recipients: an overview Summary of this article: What is BK virus?
Human Polyomavirus: multi-bodies Small (30 to 45 nm) double-stranded DNA viruses, non-enveloped DNA group of viruses.
Immunosuppressed population Group include:
BK: Nephropathy JC: progressive multifocal leukoencephalopathy Merkel cell: Merkel cell carcinoma A Touch of History;
What does BK stand for?
Discovered In 1970 from a Sudanese kidney transplantation recipient with a ureteric stricture(Gardner et al. were the first to detect BK polyomavirus (BKV) in urine
BKV nephropathy was diagnosed by a needle biopsy in a renal transplant recipient suspected of having acute rejection. This case was diagnosed in 1993 at Pittsburgh. Epidemic of BKVN in the 1990s may be resulted from using more potent immunosuppressive drugs such as tacrolimus, mycophenolate mofetil and sirolimus. BKV infection is a significant cause of interstitial nephritis and allograft failure in renal transplant recipients, presenting as an asymptomatic rise in creatinine.
Primary Infection is usually acquired in childhood, through either feco-oral, respiratory route or during transplantation with the graft, other forms of transmission may happen including vertical and sexual transmission.
Virus likely persists in the renal epithelium; it infects renal tubules and uroepithelium of most people (around 60-85% of people are infected) and infection remain lifelong.
Replication in immunosuppression status, in immunocompetent individuals the infection is usually benign and asymptomatic.
In immune-compromised renal transplant recipients, infection can be acquired either due to reactivation of latent infection or newly transmitted from the donor kidney, infection is either subclinical or it may become symptomatic causing BK nephropathy with subsequent graft dysfunction and probable graft loss. BK infection has a stereotypical pattern, starting by viruria, then viremia and lastly nephropathy (occurring in 2-15 % of transplant recipients) Pathogenesis of BKVN is a combination of defective T cell or humoral response to BKV, alloimmune activation, or viral variation in molecular sequences.
BK virus can cause graft loss by the following mechanisms:
BK virus infects tubular epithelium causing interstitial inflammation, tubular injury with subsequent fibrosis. Secondary immunological response cause further allograft damage.
Epidemiology:
Approx. 80% of the general population has a detectable antibody to BKV, which appears early in life and remains elevated throughout life.
The prevalence of this virus in the ESRD population, kidney donors, and transplant recipients has not been well defined.
The prevalence of BK viruria, viremia, and nephritis after renal Tx has been estimated at 30, 13, and 8%, respectively. BKV-induced nephropathy occurs in up to 10% among kidney allograft recipients. Overall, the reported incidence of allograft failureranges from 15-50%.
It is also seen in other Solid organ transplantsbut at a much lower rate.
also observed in patients with HIV infection, other immunodeficiencystates and rarely also in SLE. How does the recipient get it:
Donor Derived: latent infections in the Allograft epithelial cells.
Recipients who had BKV infection and received a kidney from the same donor have been shown to have identical BKV genotypes, supporting donor transmission.
Recipients whose donors had higher BKV antibody titers were more likely to develop BKV infection than those with lower titers, also supporting donor transmission. Recipient: Reactivation of previously acquired infection.
feco-oral and respiratory routes have been suggested.
Other routes include blood transfusion, trans placentally, through semen, &organ transplantation Risk factors for BK viremia A- The intensity of immunosuppression
It is more common in HLA mismatched transplantation due to aggressive immunosuppression used.
It is more common also in patients with frequent rejection episodes. No specific drug is linked to infection, but tacrolimus may be associated with more infection than cyclosporine, and m TOR may be associated with lower incidence of infection. B- Donor factors
BKV serostatus, such as transplanting kidney from BK + donor to BK – recipient The presence of donor viruria before transplantation C- Recipient factors
Older age Male sex The use of ureteric stent as a prophylaxis of ureteric leak Damage of transplanted kidney related to Ischemia or rejection. The role of cell-mediated immunity
Cell-mediated immunity is essential for controlling the BKV and preventing its spread. CD4+ and CD8+ T cells react against capsid proteins and CTL kill BK-infected cells after recognition of damaged segments of viral DNA.
Without proper immunological regulation, progressive lytic infection can lead to viral leakage, necrosis, and allograft dysfunction.
The role of humoral immunity
Humoral immunity and antibody-mediated immunity are important in the pathogenesis of BKVN, as kidney recipients from a seropositive donor are more likely to develop viremia.
Role of alloimmune activation
Alloimmune activation is a possible immunological factor involved in the development of BKVN, as it involves T cells that cross-react to both BKV and allo-antigens, allowing BKV to escape immunological surveillance.
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:
BKV infection is usually subclinical or mild respiratory symptom in childhood but 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.
Immunosuppression => viral replication
Ascending infection via cell-to-cell spread => progressive lytic infection.
This results in large nuclear and peri-nuclear virus-containing inclusions in the tubule cells.
Lysis of these infected cells results in viral seepage into=>
a. the tubule lumen and urine but also
b. the interstitial and to surrounding cells.
Subsequent tubular cell necrosis leads to cast formation and denudation of the basement membrane.
Destruction of tubular capillary walls results in vascular spread of the virus. heterogeneous interstitial infiltration of inflammatory cells as well as tubulitis Clinical Manifestation of BK virus:
Most of cases are asymptomatic.
Timing:
85% of those who develop viremiado so by month 3-4 post transplantation. 95% of BKVN in the first 2 years.
Asymptomatic:
Asymptomatic Viruria 30-40%, 2-3 months
Asymptomatic Vireamia 10-20%, 3-6 months
Asymptomatic raise of Creatinine, BKVN 2%-5%
Symptomatic: BK virus and renal disease:
BK virus infection causes viruria, which can progress to viremia and eventually to BKVN/PyVAN.
Incidence of BKVN varies depending on immunosuppressive regimens and screening strategies. BK virus-associated nephropathy
Treatment of ureteric stenosis involves percutaneous nephrostomy and dilatation.
Hemorrhagic cystitis
Hemorrhagic cystitis (BKV-HC) is rare in renal transplant and can present with bladder cramps, painful voiding, hematuria, and/or flank pain. Management involves vigorous intravenous hydration and Cidofovir given locally through bladder installation for remission. Less common manifestations include:
BKV can cause neurological manifestations, pulmonary diseases, and ophthalmologic manifestations.
vasculopathy, meningoencephalopathy, retinitis, pneumonitis, hepatitis, GBS and variety of neoplasms.
Graft dysfunction (BK nephropathy) in the form of increase in the serum creatinine associated with pyuria, hematuria and/or cellular casts.
Ureteritis and ureteric stenosis secondary to BKV infection is uncommon but some studies reported association.
Debatable and unclear association with genitourinary malignancies Other rare manifestations including CNS infection, pulmonary, hepatic disease, and ophthalmic manifestations (bilateral atypical retinitis) BK virus and malignancy: thoughts on viral oncogenesis
BKV-DNA has been identified in tissue samples of different neoplasms, including brain tumors, 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 due to expression of early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive cells into a neoplastic transformation.
Additionally, BKV-LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Regardless of whether BKV has a causative part in human cancer development, it will remain a topic of debate. BK virus and urothelial tumors
BKV has been linked to urothelial malignancies, particularly bladder carcinoma, as evidenced by Geetha et al. and Alexiev et al., who found high levels of BKV-LTAg in the nucleus of almost every tumor cell and none in the non-neoplastic urothelium.
However, no evidence of BKV-LTAg in urothelial malignancies has been reported to date. Screening of BK virus Screening is recommended monthly in the first 6 months then /3 months for 2 years post transplantation and then annually till 5 years after transplantation.
Urine PCR has high sensitivity but low specificity for BK nephropathy and is not used frequently in screening.
Decoy cells have high sensitivity (100% in one study), but low specificity for BK nephropathy (71%) and it can be mistaken with other viruses such as CMV and adenovirus.
Blood PCR is the best method for screening since it correlates well with BK nephropathy, it is sensitive (sensitivity 100%) and more specific (specificity 88%) than urinary PCR, but it is less sensitive in detection of strains other than serotype 1
Protocol biopsies may be done to detect hidden BK nephropathy.
The best method is to screen using decoy cells and reserve blood test (PCR) in the setting of graft dysfunction or if decoy cells were detected Diagnosis
A- Viruria (urine PCR, urine decoy cells)
Sensitive but nonspecific (most of patients are asymptomatic and do not progress to BK nephropathy)
May be replaced by decoy cells which represents renal tubular or uroepithelial cells containing intranuclear viral inclusions and reflects higher urinary viral load. But it can be present in other viral infections including CMV.
Both have low positive predictive value for progression to nephropathy. Detection of viruria is an indication for doing PCR blood. B- Viremia (PCR)
Sensitive (sensitivity 100%) and more specific (specificity 88%) than urinary PCR Level > 10000 copies/ml have a very high positive predictive value of nephropathy if associated with sustained viruria > 2 weeks and some recommend settling the diagnosis of BK nephropathy at this level of viremia without biopsy.
The presence of viremia is an indication for reduction of immunosuppression. C- BK nephropathy
Occur mostly in the first year after transplantation but can occur from 6 days after transplantation up to 5 years’ .
Presents by graft dysfunction (increase in serum creatinine associated with pyuria, hematuria and/or cellular casts), the diagnosis is confirmed by renal biopsy. Renal biopsy for BK nephropathy
At least 2 biopsy cores should be taken since the injury is usually focal, and medulla should be included since BK virus is more likely to be present in the medulla and around 1/3 of cases are missed with one core. The diagnosis requires the presence of the following: A- Characteristic cytopathy (not specific) including.
Intranuclear basophilic viral inclusions without surrounding hallo, Interstitial mononuclear and PNL infiltration, tubulitis and tubular injury.
BK nephropathy is classified into 3 grades.
Grade 1 – pvl 1, ci ≤1 Grade 2 – pvl 1, ci ≥2 or pvl 2, any ci score or pvl 3, ci ≤1 Grade 3 – pvl 3, ci ≥2 NB: pvl 1 (tubulitis <1%), pvl 2( tubulitis 1-10%), pvl 3 (tubulitis > 10%) And B– Positive IHC test for SV40 which includes using of antibodies directed against the cross-reacting SV40 large T antigen. Specificity of the test is 100%, but it does not differentiate between BK and JC virus associated nephropathy. Sensitivity may be lower due to focal injury since BK virus is more likely to be present in the medulla so at least 2 biopsy cores should be taken, and the medulla should be included. Treatment;
Reduction of immunosuppression which represents the main line of therapy with monitoring of viral load by plasma PCR.
No single protocol is available, but options include reduction of MMF by 50%, stop MMF, reduce CNI dose, shift from tacrolimus to cyclosporine, shift from MMF to azathioprine.
Monitor viral load (plasma PCR) /2-4 weeks, clearance of viremia precedes viruria by weeks to months so monitoring of viruria has no clinical implication in follow up.
Monitor renal functions/2-4 weeks (especially in patients with graft dysfunction) Several agents were tried in the treatment of BK nephropathy due to their in vitro anti-BKPyV activity, including IVIG, leflunomide, cidofovir, and quinolone. All these are not routinely recommended as there is no clear evidence of their superiority on reduction of immunosuppression alone.
If there is concurrent BK nephropathy and AR the treatment is debatable some recommend given pulse steroids without reduction of immunosuppression then reduce immunosuppression after treating rejection, others reduce immunosuppression and do not treat AR even with pulse steroids.
If patient develop AR after reduction of immunosuppression it is generally not recommended to augment immunosuppression again if there is biopsy proven BK nephropathy Re-transplantation after graft failure due to BK nephropathy;
Kidney Re-Transplantation with an excellent graft survival at 1(98%) and 3 years (94%) after transplantation.
Viral clearance should be confirmed before transplantation.
Recommend HLA and ABO compatible transplantation, to avoid aggressive immunosuppression.
There is no evidence to support allograft nephrectomy is necessary before retransplantation.
Recurring BKV might reflect a previous BK variant or DeNovo infection.
No a specific treatment and early diagnosis of BKVN has significantly improved allograft outcome.
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘there is no evidence to support allograft nephrectomy is necessary before retransplantation’.
BK virus infection in renal transplant recipients: an overview. Please summarise this article. INTRODUCTION.
BK Virus is plays a key role in interstitial nephritis and allograft failure in KTR.
BKV first found in a sudanese KTR with ureteric stenosis and graft dysfunction
Epidemiology and BKV structure.
Primary infection happens in childhood then it becomes latent infection until pt gets immunocompromised. A prevalence of 41.8% has been quoted in Iran.
The viral genome is has 3 regions; early viral gene region, late viral gene region and capsid protein.
BKV grouped as 4 genotypes with genotype 1 and 4 causing most of the infection and 2 and 3 causing less infection.
Immunological response to BKV and Pathogenesis.
Replication occurs dysfunctional immunity state; pregnancy, DM, HIV, Ca and post transplantation(esp during intense immunosuppression).
CD4 and CD8 both are vital in clearing BKV and when they are dysfunctional, gradual lytic infection occurs with varied manifestation.
Those with prior immunity will not manifest severe infection while D+/R- pair get dx in comparison to D-/R- pair.
HLA alloreactivity ; either T cells that react to BKV and alloantigen or the increase in BKVN in those with higher HLA mismatches all suggest to alloimmune activation as a cause of BKV infection.
BK virus residing in renal epithelial cells also play a key in BKV infection.
After primary infection, it establishes a latent infection in uroepithelial cells and reactivates once the immune system becomes dysfunctional with diverse clinical results.
Route of transmission of primary BKV.
Respiratory .
Gastrointestinal
Vertical
Sexual .
Donor derived.
Urine and blood.
Clinical Manifestations.
7% of immunocompetent shed BKV in urine without symptoms..
BKV and renal dx- viruria occurs initially then viremia followed by BKVN.30-40% of KTR get viruria with 10-15% get viremia and BKVN at ~2-15% of KTR.
BKVN -viruria, viremia and later hematuria and allograft failure btn 6/7 post op – 5 yrs post op.
Ureteric stenosis – Happens in 2-6% and tx with RIS, nephrostomy and ureteral dilatation.
Hemorrhagic cystitis – > HCST vis a vis KTR.Manifests as bladder cramps, dysuria, hematuria +/- flank pains. Tx approach 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 linked to BKV activation and replication.
BKV and Malignancy.
Early coding protein ;LTAg and STA cause neoplastic transformation, Agroprotein and LTAg arrest cell cycle leading to continuous replication with resultant malignancy.
It has also been found in a few cases though not with finality in 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 happens in 1st 1 yr post transplantation.
Viruria precedes viremia by 4/52 with BKVN occurring 12 weeks post viruria.
Follow up on urine;urine decoy cells, haufen cells or urinary BKV DNA PCR.BKmRNA levels is more sensitive.
Serum BK PCR can be 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 done and it has no clinical relevance.
BKV culture from urine is doable but is not used due to long wait time.
Renal biopsy is gold standard and should be done with VL more than 10000 COPIES/ML +/- graft dysfunction. BKVN causes sclerosis, interstitial nephritis and BKV inclusion bodies. IHC with antibodies against BKV or SV40 has ~100% specificity for polyomavirus nephropathy but cant differentiate BKV from JCV.
Screening algorithm -Screen at 1/12 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 Viral Load for > 3/52.
Ddx;
Allograft rejection.
Diseases with early (1-12/52) and late (>3/12) renal allograft dysfunction.
Tx of BKVN. –Reduction in immunosuppression 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 blocks BKV replication. It is a pyrimidine synthesis inhibitor and should not be administered with an antimetabolite. Efficacy is not clear. We need to monitor LFTS and A77 1726 trough levels and other SE ;Hemolysis, aplastic anemia, thrombocytopenia TMA and HTN.
Cidofovir- Reestablishes p53 and pRB functionality and cause apoptosis of BKV infected cells. Needs to be renal doses and pt to be well hydrated to avoid nephrotoxicity.Brincidofovir is a pro drug without nephrotoxicity.
MTORi -Delays viral replication and blocks proliferation of BKV specific T cells and thus reduce BKV replication.
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 is varied and should be personalized with some medics suggesting combined anti rejection therapy and afterwards reduction in immunosuppression.
Post infection monitoring.
Serum creatinine – 1-2 weekly..
Plasma BK PCR – 2-4 weekly for 8 weeks then monthly until BK viremia disappears.
If viremia continues to be detected irrespective of RIS, further reduction to be made or change to sirolimus +/- leflunomide.
Re-transplantation.
Pre-transplant disappearance of viremia vital.
Allograft nephrectomy though a possibility must not be done in all pts..
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘Allograft nephrectomy though a possibility must not be done in all pts’.
🎯It is a repeated article from week 9: 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.
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘Early diagnosis through screening protocols and surveillance biopsy is associated with better graft outcome’.
1.Please summarise this article. Virology
The human BKV is a member of the Polyomaviridae (PyV) virions, a subclass of papovaviruses that includes the JCV, SV40, & BKV.
BKV is a small (40–45nm capsid), non-enveloped DNA virus.
BKV tolerates heating (50°C for 30 min) without effect on infectivity.
The term “polyoma” refers to the ability of viruses to produce many tumors.
BKV is a common virus that affects the majority of people worldwide. Children are first infected & the virus remains latent for the rest of their lives.
60–85% of the general population is seropositive for BKV.
BKV-DNA genome is divided into 3 parts:
The NCCR which regulates the expression of the virus early & late genes that control differentiation & activation of the host cell.
The early viral gene region encoding the regulatory nonstructural proteins (STA & LTAg) that shift the host cell into S phase cycle for efficient viral replication.
The late viral gene region that encodes the capsid proteins (VP-1, VP-2, & VP-3) within the nucleus & lead to the release of a large number of virions through cell lysis.
The primary surface-located capsid protein in the LVGR, VP1, is in charge of receptor interaction to host cells, permitting virus entry into the cell.
Immunological response to BK virus
Because of the severe immunosuppression, BKV replication typically starts early in the post-TX period & may occur after anti-rejection medication. The role of cell-mediated immunity
The main elements of cellular-mediated immunity that control the BKV and participate in BK clearance are CD4+ and CD8+ T cells. The role of humoral immunity
Humoral immunity may play a part in the pathogenesis of BKVN since patients with a H/O immunity to the virus may not manifest symptoms, regardless of the viral load. Role of allo-HLA alloimmune activation & heterologous immunity.
T cells cross-react to both BKV & allo-antigens. Because the allo-HLA molecules that represent BKV-peptides cannot be recognized by the host BKV-specific effector memory T cells, BKV is able to evade immunological monitoring.
================== Pathogenesis
Primary BKV infection is usually subclinical.
BKV enters the circulation via infected tonsils, infects the PBMN cells, & then spread to secondary locations, such as the kidneys.
The virus become latent, uroepithelium & renal tubular cells after resolution of primary infection.
IS therapy causes the virus to become active, multiply in the interstitium, cross into the PTCs & lead to tubular cell lysis & viruria. The degree of injury, inflammation, & fibrosis determines the outcome. Routes of transmission of primary BK virus
Respiratory route
Gastrointestinal transmission
Vertical transmission
Sexual transmission
Donor-derived infection
Urine & blood
================== Clinical features
After infection, the first multiplies in the uroepithelial cells, appears in the urine (viruria), progressing a few weeks later to the blood (viremia), & ultimately causing BKVN (PyVAN).
BK viruria occurs in 30–40% of KTX recipients & 10–15% of recipients develop BK viremia.
BKVN is seen in 2 to 15% of KTX recipients.
BKVN can occur as early as 6 days after KTX or as late as 5 years.
Ureteric stenosis occurs in 2–6% & it can rarely lead to allograft dysfunction necessating intervention (
percutaneous nephrostomy & percutaneous ureteral dilatation, with concurrent reduction of IS medications).
BKV-associated HC or non-HC is typically observed in HSCT recipients, however it can also be seen in KTX recipients.
BKVN can occur in native kidneys of HSCT, heart & lung transplant recipients, & in immunocompromised HIV-infected patients. It presents with AKI & significant proteinuria, & characteristic kidney biopsy features. Rare manifestations of BKV
CNS disease: meningoencephalitis, encephalitis,
Guillain–Barre syndrome, & vasculopathy.
Pulmonary diseases: reactivated acute respiratory infection & severe interstitial pneumonitis.
Eye disease: bilateral atypical retinitis.
Liver: hepatitis
Autoimmune disease: SLE, polymyositis, & RA.
Malignancy: BKV-DNA is seen in tissues of different neoplasms (brain tumors, pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors).
Risk factors
The overall degree of immunosuppression
Male sex
Older recipient age
Previous rejection episodes
Degree of HLA mismatching
Prolonged CIT
BK serostatus
Certain ethnic groups
Lower total lymphocyte percentage
Ureteral stent insertion
================== Screening and diagnostic tools Timing of screening
BKV screening started at 1stmonth post-TX, then monthly for the 1st6 months, & then every 3 months for up to 2 years (AST Infectious Diseases Guidelines & KDIGO guidelines). Common screening methods for BK virus
Decoy cells: useful in identification of BKV infection, buta poor diagnostic tool in predicting BKVN. Not useful for monitoringdecline in viral load.
Haufen: Highly predictive for BKVN, but not practical for routine use (requires EM).
Urinary BK-PCR: Measurement variations between laboratories limit its use.
Urinary BK-Mrna: Still under assessment & requires further validation.
Plasma BK-PCR: 100% sensitivity & NPV but low PPV Broadly available but costly.
Allograft biopsy:
It is the gold standard to diagnose BKVN.
Ideally should be done when BKV-PCR load insistently exceeds > 10 000 copies/ml (4 log 10 genome (copies/ml)) with or without allograft dysfunction.
Macroscopy: streaky fibrosis of the medulla with cortical scars.
Microscopy: sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis & mononuclear cell infiltrates.
BK viral inclusions within tubular epithelium can be seen (H&E & PAS staining).
Alternatively BKV can be identified via in-situ hybridization. Differential diagnosis AR: treating the presumed AR with increased IS drugs may aggravate BKVN. BKVN may co-exist with AR.
The presence of BKV inclusion bodies & immunohistology findings of positive immunoperoxidase staining for SV40, which emphasize the virally infected cells, allow BKVN to be distinguished from AR.
Other differential diagnosis includes any disease associated with early (1–12 weeks post-TX) & late (≥3 months) renal allograft dysfunction.
================== Available therapeutic options for BK virus 1.Immunosuppression reduction:
May rebuild the immune responses against BKV.
Can induce AR.
There is no standard strategy for IS modification; however, different regimens have been tried upon recognition of viremia.
Approaches include withdrawal of antimetabolite drugs or change from MMF to azathioprine, sirolimus, or leflunomide, reducing the dose of CNI by 25–50% (target lower level of cyclosporine 50–100 ng/ml & tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI. 2.Leflunomide:
Acts by pyrimidine depletion & tyrosine kinase inhibition
Hemolytic anemia thrombocytopenia, & TMA are recognized adverse effects. 3.Cidofovir:
Inhibits viral replication, mechanism unknown.
Potentially nephrotoxic & cause severe anterior uveitis. 4.IVIG:
Contain neutralizing ant-BKV antibodies & are immuno-modulatory.
May cause paradoxical rise in viral load. 5.mTOR inhibitors:
Inhibit the proliferation of BKV-specific T-cell & controls the differentiation of memory CD8 T cell’,
A/E: Hyperlipidemia, bone marrow toxicity, mucositis &
oral ulcerations, & lymphedema. 6.Fluoroquinolones:
Inhibit BKV replication in vitro & inhibit the large T antigen helicase activity.
A/E: gastritis, C difficile, hepatoxicity, neurological adverse effects, & altered mental status. 7.Artesunate:
Inhibit BK viral proliferation in a primary human renal cell culture.
A/E: Anorexia, dizziness, nausea, & diarrhea. 8.Statins:
Prevent caveolae-mediated endocytosis.
A/E: muscle damage & hepatic dysfunction.
================== Short-term and long-term renal allograft survival
The KTX survival for recipients with BKVN has significantly increased in recent years.
Treatment techniques have produced notable short-term improvements, such as removing the circulating viremia, but greater research is required to fully understand the long-term effects, such as late acute & chronic rejections.
AR rates following a reduction in IS range from 6 to 12%. BKVN with concurrent AR
More than half of biopsies can show tubulitis, & any decrease in immunosuppression can precipitate rejection in 10–30% of the cases.
Celik et al. found a reduction in IS load is more than capable in reducing viral load than steroid pulses in biopsies with BKVN & tubulitis.
Hirsch et al. suggested a combination of antirejection therapy with a subsequent IS reduction in once BKVN is diagnosed concurrent with AR.
Generally, an initial IS reduction without steroid pulses should be considered upon detection of BKVN. Postinfection monitoring
Improved allograft prognosis requires careful monitoring of BKV-PCR & renal function throughout any course of therapy, especially after AR has been treated or IS has been reduced. Retransplantation following graft loss due to BKVN
Successful retransplantations are reported (Ramos et al, USA-OPTN registry data).
Pretransplant clearance of BK viremia is essential after minimizing immunosuppression.
Although allograft nephrectomy is not required prior to re-TX, it sounds logical to remove the infected graft in the presence of active viral replication.
BKV viruria, viremia, & BK nephropathy can recur & cause allograft loss. Conclusion
Despite the lack of a specific treatment, an early diagnosis of BKVN has significantly improved allograft results.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Early diagnosis of BKVN has resulted in substantial improvement in allograft outcomes’.
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. 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. 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. 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.
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your list of comments in relation to renal re-transplantation. Your comment on graft nephrectomy is confusing to me
Thanks; our Prof. sorry, I meant
After failed graft due to BKvN, and planning for retransplantation; allograft nephrectomy is not necessary before re-transplantation and no evidence support this approach.
BK virus in kidney transplant recipients Summary of the Article Introduction BK infection is considered a possible cause of graft dysfunction and its presents as a gradual asymptomatic rise in serum creatinine. Polyomaviridae variants
BKV belongs to the Polyomaviridae virions, a subgroup of papovaviruses.
Non-enveloped DNA viruses and the name polyoma means the virus capable of creating many tumors.
Epidemiology
Primary infection during early childhood, and then stay dormant in the human-competent immune system, so about 60-85% are seropositive for BKV.
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 BKVN with concomitant acute rejection
Combination of anti-rejection therapy with a subsequent reduction of IS.
Post-infection monitoring include
BKV-PCR, every 2-4 wks, and 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 like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation that 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.
However, you have typed that the following possible options: leflunomide, quinolone, artesunate, pravastatin, IVIG, rituximab. I would state that there is no robust evidence supporting using these drugs.
Summary BKV Introduction
BKV belongs to the Polyomaviridae family that comprises of JCV, BKV and SV40.
Additional 12 human polyomaviridae viruses have been identified.
BKV primary infections usually occurs in childhood then 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: genotype 1 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:
1. Defective immune clearance by the host T cells
2. Absent humoral immunity
3. Alloimmune activation
4. Viral variation of molecular sequences
Pathogenesis of BKV infection
Primary infection is 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 in interstitial and spreads to the peri-tubular capillaries leading tubular cell lysis and viruria.
Reaction between the BKV and immune system leads to various 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
Common 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:
1. Asymptomatic hematuria
2. Symptomatic hematuria
3. Hematuria with clots
4. 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:
1. Neurological-encephalitis, meningitis, GBS
2. Pulmonary disease- Interstitial pneumonitis
3. Ophthalmic- Only one case of bilateral atypical retinitis has been reported to date.
4. Hepatic-hepatitis
5. Autoimmune-persist 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 they 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
Haufen are 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 genotypes.
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% for polyomavirus nephropathy; though it does not differentiate between BKV and JCV.
FISH has higher sensitivity and specificity than IHC and H&E staining, however its use is limited in clinical setting.
Suggested algorithm for screening
Recipients should be screened for decoy cells every 3 months, when decoy cells are detected, additional test should be carried out that include urine and plasma PCR with the possibility of doing kidney biopsy in the setting of deteriorating 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.
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
Decreasing immunosuppression is the inly validated therapy, and should be balanced against the risk of rejection.
MMF are first withdrawn however some studies have shown that CNI may inhibit the anti-BKV T cell reaction thus challenging this approach.
Leflunomide
It is a pyrimidine synthesis inhibitor, hence cannot be combined with other anti-proliferative drugs.
Thus, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage (withdrawal of antimetabolite and reduction of CNI).
Adverse effects include hemolysis, aplastic anaemia, 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 target of cidofovir.
It’s exclusively excreted through urine, resulting in high renal tubular cell concentrations.
It’s 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 neutralising antibodies and is able to neutralise 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.
Other drugs:Quinolones/artesunate/statins/rituximab
Further prospective randomised studies are required to validate the use of this drugs.
Post infectious monitoring
Scr should be monitored every 1–2 weeks and plasma BKV-PCR level every 2–4-week for 8 weeks. Then monthly until clearance of BK viremia or at viral burden falls below threshold value and stabilisation of renal function is 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
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.
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your list of comments in relation to renal re-transplantation. Your comment on graft nephrectomy is confusing to me
Thank you prof.
Graft nephrectomy is not recommended prior to re-transplantation.
However in a case of active BKV infection during time of re-transplantation then nephrectomy can be done though there is no evidence to support this approach.
Three decades after its discovery in 1971, BK virus (BKV) and JC virus (JCV) were shown to induce interstitial nephritis and allograft failure in renal transplant patients. BKV infection is one of many possible causes of renal dysfunction in kidney transplant recipients, often within the first year. Asymptomatic creatinine increases with tubulointerstitial nephritis may resemble acute rejection, creating a diagnostic and management conundrum.
Epidemiology of BK virus:
Polyomavirus hominins-1, better known as BKV, is a ubiquitous virus that infects most people around the globe. Initial infection typically takes place during early infancy, and thereafter, the virus stays latent throughout life in immune-competent people. 60–85% of the general population is BKV-positive. However, there is a paucity of data related to BKV prevalence in Middle Eastern countries and in Africa, and a single study discovered was from Iran, with a seroprevalence of 41.8%.
Pathogenesis of BK infection:
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.
Clinical manifestations:
Graft dysfunction, also known as BK nephropathy, manifests itself in the majority of patients as asymptomatic elevations in blood creatinine levels, which are often accompanied by pyuria, hematuria, and/or cellular casts.
While ureteritis and ureteric stenosis as a result of BKV infection are rather rare, certain studies have indicated a link between the two.
It rarely manifests itself as hemorrhagic cystitis.
A relationship with genitourinary cancers that is both debatable and uncertain exists.
Additional, far less common signs include infections of the central nervous system, lung illness, liver disease, and eye disease.
Oncogenesis and BK virus:
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, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, and Ewing sarcoma.
Common screening methods for BK virus:
The objective is to detect early signs of viruria or viremia before graft dysfunction manifests itself.
Screening should begin one month after the transplant, continue once per month for the first six months, and then move to once every three months for the next two years. Urine: Urine cytology (Decoy cells), Urine electron microscopy (EM Haufen), Quantitative assessment of the levels of BK virus and viral load in the urine, BK virus mRNA levels in urine Serology: Serum BK-PCR, Serum antibodies
Virus culture: o has a sluggish growth rate in tissue culture
Kidney biopsy serves as the gold standard for diagnosing BKVN.
BK virus nephropathy treatment:
Immunosuppressive therapy, with or without antivirals, was the initial BKV treatment. Modifying immunosuppressive treatment is not conventional.
Such approaches can include withdrawing antimetabolite drugs, changing 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.
Medications that inhibit the activity of viruses
· Leflunomide. · Cidofovir.\s· mTOR inhibitors.\s· Intravenous immunoglobulin
Other therapeutic approaches for the treatment of nephropathy caused by the BK virus
Quinolones; artesunate
statins; rituximab.
I appreciate your comments on BKV in renal transplantation. However, in the heading ‘Treatment; your have typed that the following possible options: leflunomide, quinolone, artesunate, pravastatin, IVIG, rituximab. I would state that there is no robust evidence supporting using these drugs.
It is first identified early in 1971 as a cause of ureteric stricture post transplantation
Human polyomaviruses (HPyVs) are small, double-stranded, non-enveloped DNA group of viruses
12 types exist till 2007, the most common and important types that are involved in diseases in immunocompromised patients are:
JC polyomavirus (JCPyV) that can cause progressive multifocal leukoencephalopathy (PML)
BK polyomavirus (BKPyV) is associated with BK nephropathy in renal transplant recipients and hemorrhagic cystitis in hematopoietic cell transplantation recipients
Merkel cell polyomavirus (MCPyV), which is associated with Merkel cell carcinoma
Trichodysplasia spinulosa polyomavirus (TSPyV) which is associated with trichodysplasia spinulosa.
BK polyomavirus is a small, double stranded, non-enveloped DNA virus. 4 serotypes exsists, the most common is genotype 1 (80%), followed by genotype 4 (15%). Its genome encodes for 6 viral proteins, 2 early, 1 none coding and 3 late proteins. The early proteins include large (T) and small tumor antigen (t).
Infection is usually acquired in childhood, through either feco-oral, respiratory route or during transplantation with the graft, other forms of transmission may happen including vertical and sexual transmission
It infects renal tubules and uroepithelium of most of people (around 60-85% of people are infected) and infection remain lifelong
In immune-competent individuals the infection is usually benign and asymptomatic.
In immune-compromised renal transplant recipients, infection can be acquired either due to reactivation of latent infection or newly transmitted from the donor kidney, infection is either subclinical or it may become symptomatic causing BK nephropathy with subsequent graft dysfunction and probable graft loss.
BK infection has a stereotypical pattern, starting by viruria, then viremia and lastly nephropathy (occurring in 2-15 % of transplant recipients)
Pathogenesis of BKVN is a combination of defective T cell or humoral response to BKV, alloimmune activation, or viral variation in molecular sequences
so BK virus can cause graft loss by the following mechanisms:
BK virus infects tubular epithelium causing interstitial inflammation, tubular injury with subsequent fibrosis
Secondary immunological response cause further allograft damage.
Risk factors for BK viremia
A- The intensity of immunosuppression
It is more common in HLA mismatched transplantation due to aggressive immunosuppression used
It is more common also in patients with frequent rejection episodes
No specific drug is linked to infection but tacrolimus may be associated with more infection than cyclosporine, and m TOR may be associated with lower incidence of infection.
B- Donor factors
BK serostatus, such as transplanting kidney from BK + donor to BK – recipient
The presence of donor viruria before transplantation
C- Recipient factors
Older age
Male sex
The use of ureterisc stent as a prophylaxis of ureteric leak
Damage of transplanted kidney related to Ischemia or rejection
Clinical presentation of BK virus
Most of cases are asymptomatic
Graft dysfunction (BK nephropathy) in the form of increase in the serum creatinine associated with pyuria, hematuria and/or cellular casts
Ureteritis and ureteric stenosis secondary to BKV infection is uncommon but some studies reported association
Rarely presents with hemorrhagic cystitis
Debatable and unclear association with genitourinary malignancies
Other rare manifestations including CNS infection, pulmonary, hepatic disease and ophthalmic manifestations (bilateral atypical retinitis)
Screening of BK virus
Screening is recommended monthly in the first 6 months then /3 months for 2 years post transplantation and then annually till 5 years after tranplnatation.
Urine PCR has high sensitivity but low specificity for BK nephropathy and is not used frequently in screening
Decoy cells have high sensitivity (100% in one study), but low specificity for BK nephropathy (71%) and it can be mistaken with other viruses such as CMV and adenovirus.
Blood PCR is the best method for screening since it correlate well with BK nephropathy, it is sensitive (sensitivity 100%) and more specific (specificity 88%) than urinary PCR but it is less sensitive in detection of strains other than serotype 1
Protocol biopsies may be done to detect hidden BK nephropathy
The best method is to screen using decoy cells and reserve blood test (PCR ) in the setting of graft dysfunction or if decoy cells were detected
Diagnosis
A- Viruria (urine PCR, urine decoy cells)
Sensitive but nonspecific (most of patients are asymptomatic and do not progress to BK nephropathy)
May be replaced by decoy cells which represents renal tubular or uroepithelial cells containing intranucelar viral inclusions and reflects higher urinary viral load. But it can be present in other viral infections including CMV
Both have low positive predictive value for progression to nephropathy
Detection of viruria is an indication for doing PCR blood
B- Viremia (PCR )
Sensitive (sensitivity 100%) and more specific (specificity 88%) than urinary PCR
Level > 10000 copies/ml have a very high positive predictive value of nephropathy if associated with sustained viruria > 2 weeks and some recommend settling the diagnosis of BK nephropathy at this level of viremia without biopsy
The presence of viremia is an indication for reduction of immunosuppression
C- BK nephropathy
Occur mostly in the first year after transplantation but can occur from 6 days after transplantation up to 5 years’ after
Presents by graft dysfunction (increase in serum creatinine associated with pyuria, hematuria and/or cellular casts), the diagnosis is confirmed by renal biopsy.
Renal biopsy for BK nephropathy
At least 2 biopsy cores should be taken since the injury is usually focal, and medulla should be included since BK virus is more likely to be present in the medulla and around 1/3 of cases are missed with one core
The diagnosis requires the presence of the following:
A- Characteristic cytopathy (not specific) including
Intranuclear basophilic viral inclusions without surrounding hallo, Interstitial mononuclear and PNL infiltration, tubulitis and tubular injury
BK nephropathy is classified into 3 grades
grade 1 – pvl 1, ci ≤1
grade 2 – pvl 1, ci ≥2 or pvl 2, any ci score or pvl 3, ci ≤1
B– Positive IHC test for SV40 which includes using of antibodies directed against the cross-reacting SV40 large T antigen. Specificity of the test is 100%, but it does not differentiate between BK and JC virus associated nephropathy. Sensitivity may be lower due to focal injury since BK virus is more likely to be present in the medulla so at least 2 biopsy cores should be taken and the medulla should be included
Treatment
Reduction of immunosuppression which represents the main line of therapy with monitoring of viral load by plasma PCR.
No single protocol is available, but options include reduction of MMF by 50%, stop MMF, reduce CNI dose, shift from tacrolimus to cyclosporine, shift from MMF to azathioprine
Monitor viral load (plasma PCR) /2-4 weeks, clearance of viremia precedes viruria by weeks to months so monitoring of viruria has no clinical implication in follow up
Monitor renal functions/2-4 weeks (especially in patients with graft dysfunction)
Several agents were tried in the treatment of BK nephropathy due to their in vitro anti-BKPyV activity, including IVIG, leflunomide, cidofovir, and quinolone. All these are not routinely recommended as there is no clear evidence of their superiority on reduction of immunosuppression alone
If there is concurrent BK nephropathy and AR the treatment is debatable some recommend given pulse steroids without reduction of immunosuppression then reduce immunosuppression after treating rejection, others reduce immunosuppression and do not treat AR even with pulse steroids.
If patient develop AR after reduction of immunosuppression it is generally not recommended to augment immunosuppression again if there is biopsy proven BK nephropathy
Re-transplantation after graft failure due to BK nephropathy
Kidney Re-Transplantation is feasible with excellent graft survival at 1(98%) and 3 years (94%) after transplantation
Viral clearance should be confirmed before transplantation
Consider HLA and ABO compatible transplantation, in order to avoid aggressive immunosuppression.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments in regards to retransplantation, “Consider HLA and ABO compatible transplantation, in order to avoid aggressive immunosuppression.”
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.
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. 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.
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.
.I appreciate your comments on BKV in renal transplantation. However, in the heading ‘Treatment; your have typed that the following possible options: Quinolone, artesunate, pravastatin, IVIG, rituximab. I would state that there is no robust evidence supporting using these drugs.
This article is focussed on BKV infection in kidney transplant recipients. An overview of the different aspects related to this infection in the transplant population has been discussed. The various headings that have been discussed in this study include BKV virology, pathogenesis, clinical features, diagnosis, treatment, screening, and how this infection can impact short term and long term renal graft survival. This article is based on recent evidence.
Discussion
Virus structure and family
The human BKV belongs to the family Polyomaviridae, which is a subgroup of papovaviruses. The other viruses in this family include SV40 and JCV. These viruses are non enveloped and have a diameter of 40-45 nm, bearing heat upto 50 deg celsius without its infectivity getting affected. It has double stranded DNA.
BKV DNA genome has three parts, namely:
Noncoding control region (NCCR), which regulates viral expression
Early viral gene region, which encodes regulatory nonstructural proteins called small T antigen and large T antigen. These antigens interact with and bind to cellular target proteins such as Rb, p107, p130 and p53.
Late viral gene region, which encodes capsid proteins VP-1, VP-2, and VP-3 in the nucleus. VP-1 is the main protein on the surface which enables receptor binding to the host cells and allows the virus to enter into the cell. It is highly immunogenic, and once inside the host cell, travels to the nucleus and establishes dormant or lytic infection.
Epidemiology
BKV infects humans all over the world. It predominantly affects children, and then stays dormant throughout life in immunocompetent people. It is possible that 85% of the population are seropositive for BKV in the UK.
Variants
There are four genotypes or subtypes which have been categorized according to the DNA sequence variations in VP-1.
Genotype 1 is the predominant subtype.
Genotypes 2 and 3 are rare
Genotype 4 is the second most frequent subtype to infect people.
Continuous duplication of BK genome during activation can lead to rearranged variant viruses being generated. This is because of the deletion and duplication that occurs in the NCCR sequence.
Immunological response to BK virus
BKV replicates in immunosuppressed individuals, thus seen in states such as pregnancy, diabetes, cancer, HIV, and in the post transplant period. In the post transplant period, replication can occur early and can follow anti rejection therapy due to the intense immunosuppression. This is because the immune system plays a vital role in the elimination of the virus, especially in preventing viral replication, and thus when the immune system is suppressed with medication, it can lead to potent and widespread BK viral replication. Defective immune surveillance by T cells and absence of humoral immunity to BKV can lead to BKV pathogenesis in the host.
Transmission routes
Respiratory – infected tonsils
GI – BKV can be detected in oral secretions and replication can occur in salivary gland cells.
Vertical transmission – Transplacental passage can transmit the virus to the baby. This burden is also added to by the increase in BK viruria during pregnancy.
Sexual transmission
Donor derived infection
Through urine and blood – BKV can be detected in urine samples and peripheral blood leukocytes.
Clinical features
Immunocompetent people are not affected by exposure to BKV, however, the virus may be detected in urine of such individuals.
BKVN
Ureteric stenosis
Late onset hemorrhagic cystitis
Commonly seen in kidney transplant and HSCT
Bilateral atypical retinitis
Acute respiratory infection could lead to severe interstitial pneumonitis
Headache, dizziness, confusion, paraplegia, ataxia and seizures are all possible associations.
Risk factors
Older age of recipient
Male gender
Previous rejection episodes
Degree of HLA mismatching
Prolonged cold ischemia
BK aerostats
Lower total lymphocytes percentage
Ureteral stent insertion
Certain ethnic groups
Screening
The goal of screening is to identify viruria or viremia early so that treatment can be done before graft dysfunction is seen. KDIGO guidelines recommend screening for BKV at first month post transplant, then monthly for the first 6 months, and then every 3 months for unto 2 years.
Viral replication can start in the early post transplant period, with a pattern of viruria followed by viremia and then nephropathy.
Monitoring in urine includes detection of BKV infected epithelial cells named as ‘decoy cells’ or aggregates of BKV virions. This can be done through quantification of urinary BKV viral load by BKV DNA OCR or reverse transcriptase PCR for BKV RNA.
Biopsy
Histological features include macroscopic appearance of streaky fibrosis of the medulla with circumscribed cortical scars and microscopic appearance of sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis. Mononuclear cell infiltrates can be seen. H&E staining can identify BK viral inclusions within the tubular epithelium.
Differential diagnosis
Allograft rejection
Any disease causing early or late graft dysfunction
Treatment
The aim of treatment is to eradicate virus while saving kidney function. Treatment options include :
reduction in immunosuppression
switching drugs within the same class in IS regimen
Withdrawal of MMF is a commonly applied option
antiviral medication such as leflunomide
IVIG
Quinolones, artesunate, pravastatin, and Rituximab can help in treating BKVN.
Post infection monitoring
Serum creatinine is tested every week and plasma BK PCR level checked every 2 weeks for 8 weeks. Following this, monthly checks are done until clearance of BK viremia and stabilization of renal function.
Conclusion
Early diagnosis of BKV can give a possible good outcome for both the patient and the graft. This can be done through molecular techniques and tissue analysis. A variety of options are involved in treatment, but individualized treatment plans for each patient are recommended. The different options of treatment include reduction in immunosuppression dosage or switching IS drugs to help the immune system eliminate virus. Graft function is to be monitored to reduce risk of allograft rejection. In addition, antiviral medications such as leflunomide can help in achieving faster and more effective results. Post infection monitoring for 2 months followed by regular checks every month until full clearance of BKV is crucial.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Early diagnosis of BKVN has resulted in substantial improvement in allograft outcomes’.
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.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Early diagnosis of BKVN has resulted in substantial improvement in allograft outcomes’.
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
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Early diagnosis of BKVN (by molecular techniques and tissue analysis) has resulted in substantial improvement in allograft outcomes’.
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 the 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, particularly with the use of depleting agents
Male sex
Older recipient age
Previous rejection episode
Degree of HLA mismatch
Prolong cold ischemic time
BK serostatus D+/R-, also a very common risk factor
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 is very key
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
Close watch on kidney functions because of the risk of graft rejection
Other medications that have been used with varying outcomes
Leflunomide
Cidofovir or Brancidofovir which is less nephrotoxic
Immunoglobulin
Quinolones
Artesunate
Pravastatin
Rituximab
Unfortunately non of the above medication has had an effective outcome in the treatment of the BKVN.
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 the 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 a period of undetected BKV
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘In spite of three decades of research in the field of BKV, there still remain some unanswered question’.
BK virus infection in renal transplant recipients: an overview
Please summarise this article.
Introduction
BKV infection is a significant cause of interstitial nephritis and allograft failure in renal transplant recipients, presenting as an asymptomatic rise in creatinine.
BK virus and renal transplantation: historical perception
Gardner et al. were the first to detect BK polyomavirus (BKV) in urine and ureteral epithelial cells of a Sudanese kidney transplant recipient.
This virus was found to have high homology with JCV and caused severe interstitial nephritis and allograft failure in kidney transplant recipients.
Increased awareness and better diagnostic laboratory techniques contributed to the ever-increasing incidence of BKV infection.
Polyomaviridae variants
The Polyomaviridae (PyV) is a subgroup of papovaviruses, consisting of BKV, JCV, and SV40.
It is a family of small, nonenveloped DNA viruses with icosahedral capsids and circular double-stranded DNA.
Additional human polyomaviruses have been isolated since 2007.
Epidemiology of BK virus
BKV is a ubiquitous virus that infects most humans worldwide, with as much as 60-85% of the general population being seropositive.
BK virus structure
The BKV-DNA genome is divided into three parts: the noncoding control region (NCCR), the early viral gene region (EVGR), and the late viral gene region (LVGR).
The NCCR regulates the expression of the virus early and late genes, while the EVGR encodes the capsid proteins VP-1, VP-2, and VP-3.
The LVGR also encodes a small cytoplasmic protein called agnoprotein.
BK virus variants
BKV can be categorized into four genotypes/subtypes, with genotype I being the predominant subtype and genotype IV being the second most frequent.
Phylogenetic analysis has recognized four more subgroups and six subgroups of subtype IV.
Rearranged and archetype variants present secondary to variations in the NCCR, with clinical and immunological consequences still undefined.
The role of cell-mediated immunity
Cell-mediated immunity is essential for controlling the BKV and preventing its spread. CD4+ and CD8+ T cells react against capsid proteins and CTL kill BK-infected cells after recognition of damaged segments of viral DNA.
Without proper immunological regulation, progressive lytic infection can lead to viral leakage, necrosis, and allograft dysfunction.
The role of humoral immunity
Humoral immunity and antibody-mediated immunity are important in the pathogenesis of BKVN, as kidney recipients from a seropositive donor are more likely to develop viremia.
Role of alloimmune activation
Alloimmune activation is a possible immunological factor involved in the development of BKVN, as it involves T cells that cross-react to both BKV and allo-antigens, allowing BKV to escape immunological surveillance.
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 infection is usually subclinical or mild respiratory symptom in childhood, but 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 primary BKV virus has been theorized to be respiratory, fecal-oral, transplacental, or from donor tissues.
Respiratory transmission has been suggested due to the presence of BKV in the respiratory tract and tonsils of children.
Gastrointestinal transmission has been suggested due to the presence of BKV replication in salivary gland cells and oral secretions.
Vertical transmission has been suggested due to the presence of BKV-DNA particles in the products of healthy pregnancies and aborted fetuses.
Sexual transmission has been suggested due to the presence of BKV in 57% of genital tissue samples and 95% of sperm specimens.
Donor-derived infection has been suggested due to the source of posttransplant BKV infection being from either the donor or the recipient.
BKV has been associated with various clinical features in immunocompromised patients, including BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
BK virus and renal disease
BK virus infection causes viruria, which can progress to viremia and eventually to BKVN/PyVAN.
Incidence of BKVN varies depending on immunosuppressive regimens and screening strategies.
BK virus-associated nephropathy
BKV-associated nephropathy causes irreversible injury and allograft failure.
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6%.
Treatment of ureteric stenosis involves percutaneous nephrostomy and dilatation.
Hemorrhagic cystitis
Hemorrhagic cystitis (BKV-HC) is rare in renal transplant and can present 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
BK nephropathy in native kidneys of HSCT, transplant, and HIV-infected patients.
Other less apparent clinical manifestations include the following:
BKV can cause neurological manifestations, pulmonary diseases, and ophthalmologic manifestations.
Neurological manifestations include meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
Pulmonary diseases include severe interstitial pneumonitis and bilateral atypical retinitis.
Further data is needed before labeling BKV as an ophthalmological manifestation.
BKV has been linked to hepatitis and 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, which can induce antidouble-stranded DNA and histone antibodies.
There is no article that describes BKV activation in patients with systemic lupus erythematosus at postrenal transplantation state.
BK virus and malignancy: thoughts on viral oncogenesis
BKV-DNA has been identified in tissue samples of different neoplasms, including brain tumors, 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 due to expression of early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive cells into a neoplastic transformation.
Additionally, BKV-LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Regardless of whether BKV has a causative part in human cancer development, it will remain a topic of debate.
BK virus and urothelial tumors
BKV has been linked to urothelial malignancies, particularly bladder carcinoma, as evidenced by Geetha et al. and Alexiev et al., who found high levels of BKV-LTAg in the nucleus of almost every tumor cell and none in the non-neoplastic urothelium.
However, no evidence of BKV-LTAg in urothelial malignancies has been reported to date.
Risk factors for BKVN include immunosuppression, male sex, older recipient age, previous rejection episodes, HLA mismatching, cold ischemia, BK serostatus, ethnic groups, and ureteral stent insertion.
================================================================= Screening and diagnostic tools
Screening and diagnostic tools are used to identify recipients with viruria or viremia and to act before graft dysfunction appears.
Prospective analyses have revealed that BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year.
Viral replication starts early after transplantation and progresses through noticeable phases.
Monitoring of the urine may include detection of BKV-infected epithelial cells, aggregates of BKV virions, or quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
Cytological analysis of urinary smear may reveal decoy cells, which are infected tubular epithelial cells with an enlarged nucleus.
Urine electron microscopy (EM Haufen) is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, which has a higher sensitivity and specificity for biopsy-proven BKVN.
However, it requires further validation and cannot be applied for routine clinical practice due to the expense and inaccessibility of electron microscopy.
Quantitative measurements of urinary BK virus-viral loads
Quantitative measurements of urinary BK virus-viral loads have been used to identify patients at risk for BKVN. Recently, BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication.
Urinary tests are highly sensitive for detecting active BKV infections, but lack specificity for BKVN. Serum BK-PCR is the preferred screening technique at most transplant institutions, but not all recipients with BK viremia will develop nephritis.
A definite viral load cutoff associated with nephropathy has not yet been defined.
The most important details in this text are that plasma BKV-PCR has high sensitivity and specificity in anticipating BKVN, but there is substantial interlaboratory variations in measuring BK viral loads with lack of international standardization.
Serum antibodies against BKV are commonly present among the general public and have no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients.
Additionally, the positive donor BKV serostatus and negative recipient serostatus have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients.
Virus culture
Virus culture is used for research, but grows slowly.
Kidney biopsy is the gold standard to diagnose BKVN, which should be performed when BKV-PCR load exceeds 10 000 copies/ml.
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen, and BK viral inclusions can be identified via H&E and PAS staining.
Fluorescence in-situ hybridization (FISH) analysis is specific for BKV with a sensitivity of 94.7% and a specificity of 100%.
BKVN has a specificity of nearly 100% for polyomavirus nephropathy, but its use in clinical practice is limited.
Three grades of histopathological severity have been identified, with the Banff grading system having a moderately good intraobserver agreement.
False-negative biopsies may occur, making diagnosis difficult. BK-PCR of allograft biopsy tissue is not an applicable investigation to diagnose BKVN.
Renal biopsy is the gold standard for diagnosis of BKVN, but can be missed
The most important details in this text are the steps-wise methodology for BKV screening in renal transplant recipients, as recommended by Hirsch et al., Ramos et al., Buehrig et al., Khamash et al., and American Society of Transplantation guidelines.
Screening 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.
Allograft biopsy can be considered in individuals with persistent high viral loads for more than or equal to 3 weeks.
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies, positive immunoperoxidase staining for SV40, absence of definitive features of acute cellular rejection, IHC staining of renal tissues or urinary sediments with anti-HLA DR, higher quantity of CD20+ cells in tissue infiltrates, increased expression of genes related to inflammation and acute rejection, and increased expression of transcription molecules associated with graft fibrosis.
BKVN and acute rejection can present concurrently.
Another differential diagnosis
Disease associated with early and late renal allograft dysfunction after transplantation.
==================================================================== Treatment strategy of BK virus nephropathy
Treatment strategy of BKV nephropathy is to eradicate the virus while saving the kidney function.
There is no standard strategy for modifying immunosuppressant’s therapy, but different regimens have been attempted upon recognition of viremia.
Different approaches include withdrawal of antimetabolite drugs, switching a drug within the same class or to a different class, and steroid avoidance.
Withdrawal of the antimetabolite may limit proinflammatory and profibrotic cytokines.
Treatment of BK virus nephropathy in the setting of allograft dysfunction
Reducing immunosuppression is a rational option for treating BK virus nephropathy in the presence of allograft dysfunction, as it may result in clearance of viremia and increase BKV-specific IgG-antibodies titer and cellular immunity.
Drugs with antiviral activities Leflunomide
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug used in rheumatoid arthritis.
It can inhibit pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects.
Cidofovir is a cytosine analog and viral DNA-polmerase inhibitor used to manage other viral infections such as CMV.
Cidofovir is an antiviral drug used to treat BKVN, but its mechanism of action is unclear.
It is given as slow intravenous infusion with a maximum dose of 1 mg/kg/dose.
It is nephrotoxic and can cause acute kidney injury, acidosis, proteinuria, and severe anterior uveitis.
A new promising antiviral drug brincidofovir (CMX001) is a prodrug of cidofovir, but its use is still experimental.
mTOR inhibitors
mTOR inhibitors (sirolimus and everolimus) have been shown to inhibit BKV replication and early gene expression.
However, their clinical efficacy is questionable due to concomitant use of immunosuppression and contradictory results.
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.
Other therapeutic options for treating BK virus nephropathy
Quinolones, artesunate, statins, and rituximab are available for treating BKVN.
Quinolones have been found beneficial in combination with leflunomide, while artesunate has been found to decrease BKV proliferation.
Rituximab has 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 these therapies.
In the late 1990s and early 2000s, BKVN caused permanent allograft damage in 30-60% of cases.
However, renal allograft survival for recipients with BKVN has 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. Chen et al. reported 99.2, 90.7, and 85.7% allograft survival rates following a diagnosis of BKVN.
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 in immunosuppression is debatable.
Steroid pulses can reduce viral load, but combination of antirejection therapy with a subsequent reduction in immunosuppression should be considered.
Delayed improvement in renal functions following a reduction in immunosuppression is likely due to slow resolution of the cellular infiltrate.
Postinfection monitoring
Postinfection monitoring of BKV-PCR and renal function is essential to improve allograft outcomes.
The most common approach is to follow transplant recipients with serum creatinine tests and plasma BK-PCR levels for 8 weeks.
If viremia persists, further reduction should be considered.
Retransplantation
Retransplantation following graft loss due to BKVN is possible and successful, with excellent 1- and 3-year graft survival.
Pretransplant clearance of BK viremia is essential, and allograft nephrectomy is not necessary.
BKV viruria, viremia, and nephropathy can recur and cause allograft loss.
I like your well-structured rather extensive summary, analysis and take home messages typed as conclusion. Typing whole sentence in bold amounts to shouting.
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.
Epidemiology of BK virus
-Primary infection occurs mainly during childhood, and the virus remain dormant in immunocompetent individuals.
– 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: 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 yet 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 like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation that transplant nephrectomy is not necessary for retransplantation.
BKV is a significant cause of interstitial nephritis & graft failure in kidney transplant recipients(KTR).
It always a differential diagnosis of renal dysfunction in KTR.
It is commonly asymptomatic, & can be presented as gradual rise in creatinine with tubulointerstitial nephritis similar to acute rejection.
BKV & renal transplantation:
First notice in KTR when presented with ureteric stenosis & renal failure(1971).
Decoy cells are large cells with intranuclear inclusion occur in urine.
In 1978 histological changes of polyoma virus nephritis described in kidney biopsy.
Increase incidence of BKV infection due to increase awareness among nephrologist & better diagnostic lab techniques.
BKV is a DNA virus & 12 polyoma virus present in human.
Primary infection occurs during early childhood & the virus stay dormant through life in immune competent people.
60%-85% o general population is seropositive.
BKV DNA genome devised into early viral gene region, late viral region, & capsized protein.
BKV had 4 genotype (I-IV), & I & IV are the common genotype while II & III are rare.
Each genotype had subgroups which reflect different geographical & migration pattern of human population.
Immunological response of BKV:
Viral replication increased during immunosuppression e.g. pregnancy,DM, HIV infection, cancer, & post transplantation.
Other factors increase viral replication are:
defective immune surveillance by host T cells: CD4 & CD8 T cells are major component of cellular mediated immunity to control the BKV BK clearance.
Absence of humeral immunity to BKV: humoral immunity had a role in pathogenesis of BKVN & patients with BKVN have the highest rise in BKV-specific IgG with persistently rise in IgM.
Allo-immune activation: host-specific effector memory T cells can’t recognize all-HLA molecule thus it permit BKV to escape immunological surveillance
Viral vibration in molecular sequence.
Pathogenesis of BKV infection:
Primary infection usually subclinical or with mild respiratory symptoms in childhood.
The virus dormant in uroepithelial cells & renal tubular cells for life, also can be dormant in brain tissue & lymph nodes.
Tissue damage result either from direct viral cytolytic effect or as secondary inflammatory response .
Route of transmission:
Respiratory.
GI.
vertical.
sexual donor derived infection
urine & blood.
Clinical manifestation:
BKN
ureteric stenosis.
hemorrhagic cystitis(HSCT)
BKVN in native kidney
neurological manifestation
Pulmonary disease.
ophthalmic manifestation
BKV & hepatic disease
BKV & autoimmune disease.
BVK & malignancy:
BKV had oncogenic propensity through expression of LTAg & SAT which can drive cells into neoplastic transformation.
The association between BKV & urinary bladder cancer is not documented.
Risk factors of BKVN:
degree of immunosuppression
male gender
old age recipients
previous rejection episodes.
degree of HLA mismatch
prolonged CIT
BBKV serostatus
certain ethnic group low total lymphocytes percentage.
uretral stent insertion.
Screening & diagnosis:
Screening is important in early detection of viremia & viuria to prevent graft dysfunction.
AST & KDIGO guidelines recommend to screen at first month post transplantation then monthly for 3-6 months, every 3 months for 2-5 years & any time with unexplained increased in serum creatinine & following treatment of acute rejection. If PCR<10000 reduce immunosuppression dose & if >10000 do graft biopsy.
Screening & diagnosis done by:
Urine cytology for decoy cells it indicates BKV infection but it is not useful for diagnosis of BKVN, sensitivity 100% & specificity 71%(PPV 29% & NPV 100%) when matched to graft biopsy.
Urine electrons microscopy (EM Haufen) associated with high sensitivity 100% & specificity 99%.
Urine BKV PCR sensitivity 100% & specificity 78%.
Urine mRNA level with sensitivity 100% & specificity 97%.
Serum BKV PCR with sensitivity 100& & specificity 88% for develop BKVN (preferred screening test).
Serum Abs(D+/R-) is a risk factor to develop BKV disease.
Virus culture difficult outside research
Kidney biopsy: gold standard of BKVN diagnosis & should be done if viral load persistent >10000copies/ml with or without graft dysfunction.
Differential diagnosis : acute rejection & any cause of early or late graft dysfunction.
Treatment:
Reduction of immunosuppression (risk of rejection should be balanced with reduction of immunosuppression)
Antivirals e.g. leflonumide, cidofovir
mTOR-inhibitors inhibit BKV replication.
Quinolone
artesunate
pravastatin
IVIG
rituximab.
Short & long term graft survival:
Short term outcome imroved
Long term outcome as late acute & chronic rejection need more evaluation.
Acute rejection after reduction of immunosuppression 6-12%.
BKVN with concurrent rejection:
Management of proven acute rejection with BKVN still debatable
Reduced immunosuppression without steroid pulse should be considered when BKVN detected.
In absence of clear evidence or features of acute rejection, the management should be specified for each patient individually.
Close monitoring of BKV PCR & renal function after treatment of acute rejection or reduction reduction of immunosuppression is very important to improve graft outcome.
After reduction of immunosuppression in BKVN, follow-up of creatinine 1-2 weeks interval & PCR at 2-4 weeks interval for 8 weeks, then monthly until clearance of viremia & stabilization of renal function.
BKV viremia clear at 7-20 weeks, but initially decline may take 4-10 weeks after immunosuppression reduction.
Persistence of viremia despite immunosuppression reduction need further reduction or change to sirolimus or add leflonumide.
Re-transplantation:
Patients with graft loss due to BKVN can be re-transplanted successfully.
1 & 3 years graft survival in re-transplant is 98.5% & 93.6%.
Petransplant clearance of BKViremia is essential after immunosuppression reduction, & graft nephrectomy may be done if theres active viral replication.
Recurrence of BKV infection either reactivation of previous variant or new infection(de novo).
I appreciate your comments on BKV in renal transplantation. However, in the heading ‘Treatment; your have typed that the following possible options: antivirals e.g. leflonumide, cidofovir, mTOR-inhibitors inhibit BKV replication, Quinolone, artesunate, pravastatin, IVIG, rituximab.
I would state that there is no robust evidence supporting using these drugs.
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 immune suppression, 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 not that 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
I like your well-structured detailed summary, analysis and take home messages typed as conclusion.
I appreciate your comments on BKV in renal transplantation. I agree that ‘Evidence is not that robust for using these drugs and some are nephrotoxic: Leflunomide, cidofovir, and Quinolones
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 protein 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 HSCTrecipients present with hemorrhagic and non-hemorrhagic cystitis
· For HIV infected 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,
-ophthalmological 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 polyomavirus 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
●Introduction :
_ The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV,andsimianvirus 40(SV40).It is a family of small, nonenveloped DNA viruses
_BKV infection, is an early complication of renal transplant, presents in the first year after transplantation.
_ It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection.
_ It may be simila to acute rejection, hence screening & diagnosis is crucial
_Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss.
_Gardner et al. were the first to detect BK polyomavirus(BKV)inbothurineandureteralepithelial 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 name polyoma represents the viruses’ capability to create many (poly) tumors
_Studies showed as much as 60–85% of the general population is seropositive for BKV.
_The virus consists of 3 parts:
1- The early viral gene region
2-The late viral gene region
3- The capsid protein VP1 in the Late Viral Gene Region is the main capsid protein.
_ BK has four genotypes: 1 is commonest accounting for greater than 80% worldwide followed by genotype 4, 15%.
_ 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.
_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
_The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis.
However, these typical features might be absent.
_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 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
( proximal).
_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.
_Routes of transmission:
1- Respiratory : respiratory tract and tonsils of children
2-Gastrointestinal transmission: BKV replication was shown in salivary gland cells and was detected in oral secretions.
3- Vertical transmission
4-Sexual transmission has been anticipated by Monini et al. as he detected BKV in 57% of genital tissue samples and 95% of sperm specimens.
5- Donor-derived infection:
●Clinical manifestation
_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
_ late-onset hemorrhagic cystitis
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
grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive 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 year.
_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 HIVinfection. Clinically, the patients might present with a picture of meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
_Pulmonary diseases: reactivated acute respiratory infection leading to severe interstitial pneumonitis
_Ophthalmologic manifestations: to date, there is only a single case report with bilateral atypical retinitis
● Screening :
Routinely monthly post tx for 3 – 6 months then every 3 month for 12 – 24 months then annually for 2 – 5 years
● Diagnosis
molecular techniques and renal tissue biopsy
● Ttt
Leflunamide
Cidofovir
Brincidofovir
Mtors
Quinolones have been described to inhibit the LTAg
artesunate
pravastatin
Rituximab
Iv ig
●Retransplantation following graft loss owing to BKVN is possible and can be done successfull
● Conclusion :
An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes
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.
In 1971, Gardner et al. were the first to detect BK polyomavirus (BKV) in both urineand 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. Abundant large cells with intranuclear inclusions were present in the urine, named later as
‘Decoy cells’ for their resemblance to malignant cells
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 ofsmall, nonenveloped DNA viruses with icosahedral capsid of 40–45nm in diameter that can bear heating up to 50°C for 30 min with little effect on infectivity and has a circular double-stranded DNA of ∼5000 base pairs.
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. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN)
Routes of transmission of primary BK virus
Respiratory route: several authors had speculated the primary route oftransmission to be respiratory, as evident by the presence of BKV in the respiratory tract and tonsils of children.
Gastrointestinal transmission
Vertical transmission
Sexual transmission
Donor-derived infection
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.
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 BKpolyomavirus-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
BK virus-associated nephropathy Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
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
Screening
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 for active BKV replication may include identification of viral DNA-PCR in urine and bloodblood. However, no single diagnostic pathway has appeared as predominant.
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
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
Differential diagnosis Allograft rejection 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.
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 BKVspecific cellular immunity
BK virus infection in renal transplant recipients: an overview
Summarise this article
Introduction:
BK virus (BKV), JC virus (JCV) and SV40 are human polyomaviruses – nonenveloped dsDNA viruses.
BKV infection occurs mostly in first year post-renal-transplant, presenting as asymptomatic rise in creatinine, tubulointerstitial nephritis, and gradual cause allograft failure. It mimics (and associated with) acute rejection, producing diagnostic and therapeutic dilemma.
BK virus variants: 4 genotypes identified on DNA-sequencing
Genotype 1: most common (80%); has 4 subtypes
Genotype 4: 15%; has 6 subtypes
Genotype 2 and 3 are rare
Immunological response to BK virus:
BK viral replication occurs in immune-suppression state – characteristically in early posttransplant period (intense IS), following antirejection therapy.
Factors favouring pathogenesis of BKVN:
(a) defective immune surveillance by host T-lymphocytes,
(b) absence of humoral immunity to BKV,
(c) alloimmune activation, and
(d) viral variation in molecular sequences
Pathogenesis of BK infection:
Routes of transmission –
1. Respiratory route: primary
2. GIT transmission: some studies support fecal-oral transmission
3. Vertical transmission through placenta
4. Sexual transmission
5. Donor-derived infection
6. Urine and blood transmission
Primary infection is subclinical, the virus then disseminated to the kidney and remains dormant in the urothelium and renal tubular cells, with intermittent reactivation (asymptomatic viruria). Virus also remains latent in leukocytes, brain and lymph nodes, reactivates after immunosuppressive therapy.
Clinical manifestations:
Asymptomatic in immunocompetent hosts. In immunocompromised patients, particularly in renal allograft recipients, it causes allograft dysfunction (BKVN), ureteric stenosis, haemorrhagic cystitis.
In hematopoietic stem cell transplant (HSCT) recipients, cause haemorrhagic cystitis; in HIV infected patients is disseminated, leading to multiorgan failure and death.
Other clinical manifestations: less common
1. Neurological – meningoencephalitis, encephalitis, Guillain–Barre syndrome, vasculopathy.
2. Pulmonary – interstitial pneumonitis
3. Ophthalmic – bilateral atypical retinitis (rare)
May be b related to autoimmune diseases.
BK virus and malignancy:
Expression of the early coding region-encoded proteins such as large and small tumor antigens (LTAg, STAg), confers oncogenic property, that drives host cells into neoplastic transformation.
BK virus has been associated with urothelial tumors, with limited data. BKV-DNA has been isolated from high grade Ca UB.
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:
Objectives: early detection of viruria / viremia; enable to intervene before graft dysfunction occurs.
Decoy cells – abnormal large epithelial cells, that is shed in urine in 78% BKVN – detected by PAP or Silver stain.
Urine electron microscopy (EM-Haufen) has a higher sensitivity and specificity for detecting BKVN than urine cytology, but requires further validation.
Serology:
The BK-PCR test has high sensitivity and specificity; identify infection 4weeks before nephritis occur.
Virus culture: isolation of virus – grows slowly in tissue culture.
Kidney biopsy:
Allograft biopsy is the gold standard to diagnose BKVN, with a sensitivity of 94.7% for H&E and 68.4% for FISH. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival.
Differential diagnosis:
BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and IHC positive immuno-peroxidase staining for SV40, highlighting the virally infected cells.
Treatment of BKVN:
Aim is to eradicate BKV, saving the kidney function.
As BK viremia and BKVN indicate excess cumulative immunosuppression – “reducing immunosuppression” is the only validated therapy to treat BKVN, and restore antiviral immune response; however, it has to be balanced against the risk acute or chronic rejection.
Drugs with antiviral activities:
– Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug that inhibits pyrimidine synthesis and can inhibit BKV replication in vitro.
– Cidofovir is a nephrotoxic drug that may cause acute kidney injury, renal tubular acidosis, and proteinuria, and should be used carefully in kidney recipients.
– MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression.
– IVIG has the most potent antiviral influence. IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain.
– Quinolones and statins have been found to reduce BKV proliferation, while rituximab has been associated with adverse effects.
– Rituximab adjuvant therapy with cidofovir had no graft failure in 9 transplant patients with BKVN.
Short-term and long-term allograft survival:
BKVN related allograft damage is noted in 30-60% of cases, but therapeutic approaches have improved renal allograft survival.
BKV nephropathy and concurrent acute rejection:
Management of biopsy proven acute rejection with concomitant BKVN or management of anticipated rejection following decreased immunosuppression to treat BKVN remains debatable.
Post infection monitoring of BKV-PCR and renal function is essential to improve allograft outcome.
Re-transplantation can be done successfully – need proper dose adjustment of IS.
Conclusion:
Early diagnosis of BKVN based on combination of molecular techniques and tissue analysis, and modification of immunosuppression has resulted in substantial improvement in allograft outcomes.
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 posttransplantation 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
1.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.
2.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 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.
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.
Postinfection 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.
Retransplantation
Retransplantation following graft loss owing to BKVN is possible and can be done successfully. Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression. The patient may get infected with BKV after retransplantation. Recurring BKV might reflect a previous BK variant or a new infection (de-novo BKV) acquired, because of the long period, in the posttransplantation stage.
Introduction:
There are two human polyomaviruses, BK virus (BKV) and JC virus (JCV)
BKV cause interstitial nephritis and allograft failure in renal transplant recipients, occurring within the first year after transplantation. 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.
It is nonenveloped DNA viruses with circular double strand DNA of -5000 base pairs and can bear heating up to 50°C
Epidemiology of BK virus:
BKV is Polyomavirus hominis-1
Primary infection takes place during early childhood, and then the virus stays dormant throughout life in immune-competent
BK virus structure:
BKV-DNA genome 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), which interacts and binds to cellular target proteins
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:
BKV has 4 genotypes according to the DNA sequence variations in the genomic region of VP1
Genotype 1:common =80% and has 4 subtypes
Genotype 1V =15% and has 6 subtypes
Genotype II and III are rare
Immunological response to BK virus:
BK viral replication follows a state of immune suppression; BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
nephropathy (BKVN) [48]. Factors for 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 [13]
Pathogenesis of BK infection:
Primary infection is subclinical then disseminated to the kidney 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 [3,4,24]. Also can remain latent in leukocytes, brain and lymph node the virus reactivate in the presence of immunosuppressive therapy.
Routes of transmission of primary BK virus:
1. Respiratory route: primary
2. GIT transmission: some studies support orofecal transmission
3. Vertical transmission through placenta
4. Sexual transmission
5. Donor-derived infection
6. Urine and blood transmission
Clinical manifestations:
BKV does not cause disease in immunocompetent people but in immunocompromised patients, particularly in renal allograft recipients, it cause different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
Outside renal transplantation, BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC, whereas in HIV infected patients, it may cause dissemination leading to multiorgan failure and death.
Other less clinical manifestations include:
1. Neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
2. Pulmonary diseases: such as interstitial pneumonitis
3. Ophthalmologic manifestations: single case report with bilateral atypical retinitis.
Different studies describe the relationship between BKV and some autoimmune diseases.
BK virus and malignancy:
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
BK virus and urothelial tumors:
BKV-LTAg play role in urological tumor with limited data
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. Decoy cells are abnormal BKV-infected epithelial cells that can be detected in urine and used to diagnose BKVN.
Urine electron microscopy (EM Haufen) has a higher sensitivity and specificity for detecting BKVN than urine cytology, but requires further validation.
Serology:
The BK-PCR test has high sensitivity and specificity, which identify the infection before nephritis occur.
Virus culture:
Used to isolate the virus but it grows slowly in tissue culture.
Kidney biopsy:
Allograft biopsy is the gold standard to diagnose BKVN, with a sensitivity of 94.7% for H&E and 68.4% for FISH. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival.
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.
Treatment strategy of BK virus nephropathy:
The aim of treating BKV is to eradicate the virus while saving the kidney function 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
Drugs with antiviral activities:
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug that inhibits pyrimidine synthesis and can inhibit BKV replication in vitro.
Cidofovir is a nephrotoxic drug that may cause acute kidney injury, renal tubular
acidosis, and proteinuria, and should be used carefully in kidney recipients.
MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression, and IVIG has the most potent antiviral influence. IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain.
Quinolones and statins have been found to reduce BKV proliferation, while rituximab has been associated with adverse effects. Rituximab adjuvant therapy with cidofovir had no graft failure in 9 transplant patients with BKVN.
Short-term and long-term allograft survival:
BKVN has caused permanent allograft damage in 30-60% of cases, but therapeutic approaches have improved renal allograft survival.
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
Post infection monitoring:
Post infection monitoring of BKV-PCR and renal function is essential to improve allograft outcome. Retransplantation is possible and can be done successfully.
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
BKV- polyomavirus that can cause interstitial nephritis and allograft failure in KTR
Usually presenting as a gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection
belongs to the Polyomaviridae subgroup of papovaviruses, which includes JCV and simian virus 40 (SV40)
replication occurs during immune suppression states such as pregnancy, diabetes, HIV, cancer, and post-transplantation
immune system plays a crucial role in controlling BKV replication and resolution of BKVN
Defective immune surveillance, absence of humoral immunity to BKV, alloimmune activation, and viral variation in molecular sequences may contribute to the pathogenesis of BKVN. CD4+ and CD8+ T cells control BKV by reacting against nonstructural and capsid proteins
Humoral immunity also plays a role in BKVN, as patients with prior immunity to BKV may not show the disease’s manifestation. Allo-HLA-reactivity and heterologous immunity might also contribute to BKVN’s development.
commonly causes asymptomatic viruria in immunocompetent individuals, but can lead to severe clinical manifestations in immunocompromised patients, especially in kidney and hematopoietic stem cell transplant recipients.
also cause renal injury, known as BK virus-associated nephropathy (BKVN), which can progress to allograft failure
infection is thought to occur through primary infection in childhood, followed by dormancy in uroepithelial and renal tubular cells with intermittent reactivation.
can be transmitted via respiratory, fecal-oral, transplacental, or donor tissues, although the primary mode of transmission remains uncertain.
CLINICAL MANIFESTATIONS
Other less apparent clinical manifestations include neurological, pulmonary, and ophthalmologic manifestations, as well as a potential association with autoimmune diseases. Early diagnosis and reduction of immunosuppression are the mainstay of treatment for BKV infection.
also been found in tissue samples of various neoplasms, leading to the suggestion that it may have an oncogenic property.
SCREENING AND DIAGNOSIS
Screening for active BKV replication may include detection of viral DNA-PCR in urine and blood, identification of infected epithelial cells, or quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA. However, no single diagnostic pathway has emerged as predominant.
A quantitative BKV-DNA test has been successful in identifying early BK infection before the development of nephritis. However, not all recipients with BK viremia will develop nephritis, and a definite viral load cutoff associated with nephropathy has not yet been defined. BKV-PCR levels may differ substantially between assays, with significant differences in quantified viral loads, limiting the threshold of assay detection.
The gold standard for diagnosing BKVN is allograft biopsy, which ideally should be performed when BKV-PCR load insistently exceeds more than 10,000 copies/ml with or without allograft dysfunction.
Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically. Three grades of histopathological severity have been identified, where grade A includes viral cytopathic changes of near-normal renal parenchyma, and grade C signifies diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation.
TREATMENT
BKVN has limited treatment options, with the aim of eradicating the virus while preserving kidney function.
The primary treatment for BKV is decreasing immunosuppression, as BK viremia and BKVN are associated with excessive cumulative immunosuppression.
Reduction or modification of immunosuppressive therapy with or without antiviral medications is the first-line approach.
Different regimens have been attempted upon recognition of viremia, including withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class, and steroid avoidance.
Other therapeutic options such as leflunomide, cidofovir, and mTORi, IVIG, quinolones, statins, and rituximab.
The effectiveness of these options remains uncertain, and adverse effects can occur. Reduction in immunosuppression remains a rational option even in the presence of allograft dysfunction and can result in clearance of viremia and a steadiness of allograft functions.
BK virus is belong to polyomavirus and chase interestitial nephrites and may cause severe tubulointerstitail nephrites that can lead to graft dysfunction which mimic Graft rejection .
BK virus was discovered in 1971 ,and it belong to papovavirus which include JCV and simia virus (sv40).
BK virus is having different genotype with genotype 1 and 1v being the most common type .
Usually BK virus is contaminated in eraly childhood in 60 to 80 % of the cases ,with flare mainly in immunodeficient state like pregnancy ,diabetes ,HIV, and in post transplantation .
The BK virus replication is manily is under control of immunity ,CD4+ and CD8+ T cells control BKV by reacting against nonstructural and capsid proteins. Humoral immunity also plays a role in BKVN, as patients with prior immunity to BKV may not show the disease’s manifestation.
The pathogenesis of BK virus is dependes mainly on the cummulative effect of IS and it can present asymptomatically with viuria or can cause severe allograft dysfucntion which mimic rejection .
Clinical manifestations of BKV infection include BKVN, ureteric stenosis, and hemorrhagic cystitis. It is crucial to say its assiciation with autoimmune disease .
The main corner stone in managmenent is the reduction of IS .
The BK virsu has been found to assvcociated with malignancy for that threr is belive that BK virus is oncogenic virus,screening for active BKV replication may include detection of viral DNA-PCR in urine and blood, identification of infected epithelial cells, or quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA.
BK DNA PCR quantitative test is being used to detect the early presence of BK virus even before nephrites .
REal time PCR need to detect the BK vireamia .
The gold standre for diagnosing BKAN is by doing graft biopsy ,but usually this is need to be done oif the BK virus PCR load≥10000 copies/ml,Three grades of histopathological severity have been identified, where grade A includes viral cytopathic changes of near-normal renal parenchyma, and grade C signifies diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation
Treatment of BK virus is depends mainly on eradicatin the virsu and keeps functioning great with reduction or switching strategy of IS is the main bases .Other therapeutic options include drugs with antiviral activities such as leflunomide, cidofovir, and mTOR inhibitors, intravenous immunoglobulin, quinolones, statins, and rituximab.
The big challenging is to treat the BKAN and rejection in the same time which is remain debatable and difficult to treat but the close follow up for the BK PCR and close monitoring for the graft function
INTRODUCTION
BK virus (BKV) is a polyomavirus that can cause interstitial nephritis and allograft failure in renal transplant recipients, presenting as a gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection. BKV belongs to the Polyomaviridae subgroup of papovaviruses, which includes JCV and simian virus 40 (SV40). It has a circular double-stranded DNA genome that can be divided into three parts, with the noncoding control region (NCCR) regulating the virus’s expression of early and late genes. BKV can be categorized into four genotypes/subtypes according to DNA sequence variations in the genomic region of VP1, with genotypes I and IV being the most common.
IMMUNOLOGICAL RESPONSE OF VIRUS
BK virus (BKV) replication occurs during immune suppression states such as pregnancy, diabetes, HIV, cancer, and post-transplantation. The immune system plays a crucial role in controlling BKV replication and resolution of BK virus nephropathy (BKVN). Defective immune surveillance, absence of humoral immunity to BKV, alloimmune activation, and viral variation in molecular sequences may contribute to the pathogenesis of BKVN. CD4+ and CD8+ T cells control BKV by reacting against nonstructural and capsid proteins. Humoral immunity also plays a role in BKVN, as patients with prior immunity to BKV may not show the disease’s manifestation. Allo-HLA-reactivity and heterologous immunity might also contribute to BKVN’s development.
PATHOGENESIS
It commonly causes asymptomatic viruria in immunocompetent individuals, but can lead to severe clinical manifestations in immunocompromised patients, especially in kidney and hematopoietic stem cell transplant recipients. BKV can also cause renal injury, known as BK virus-associated nephropathy (BKVN), which can progress to allograft failure.
The pathogenesis of BKV infection is thought to occur through primary infection in childhood, followed by dormancy in uroepithelial and renal tubular cells with intermittent reactivation. BKV can be transmitted via respiratory, fecal-oral, transplacental, or donor tissues, although the primary mode of transmission remains uncertain.
Clinical manifestations of BKV infection include BKVN, ureteric stenosis, and hemorrhagic cystitis. Other less apparent clinical manifestations include neurological, pulmonary, and ophthalmologic manifestations, as well as a potential association with autoimmune diseases. Early diagnosis and reduction of immunosuppression are the mainstay of treatment for BKV infection.
BK VIRUS AND MALIGNANCY
BK virus (BKV) is a common virus that can cause disease in immunocompromised individuals, especially in renal transplant recipients. It has also been found in tissue samples of various neoplasms, leading to the suggestion that it may have an oncogenic property.
Several risk factors have been implicated in the pathogenesis of BKV-associated nephropathy, with immunosuppression being the most consistent factor. Screening for active BKV replication may include detection of viral DNA-PCR in urine and blood, identification of infected epithelial cells, or quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA. However, no single diagnostic pathway has emerged as predominant.
WORK UP
TREATMENT OPTIONS
BK virus nephropathy (BKV) has limited treatment options, with the aim of eradicating the virus while preserving kidney function.
The effectiveness of these options remains uncertain, and adverse effects can occur. Reduction in immunosuppression remains a rational option even in the presence of allograft dysfunction and can result in clearance of viremia and a steadiness of allograft functions.
BK virus nephropathy (BKVN) is a condition that can lead to permanent damage to kidney transplants. 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. 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.
BKV
it is a polyomavirus along with JCV and SV40
BK stands for the initials of the patient where the virus was first detected in 1971
BKV is ubiquitous virus and the primary infection takes place in the childhood ,in general 60 to 80% of the population is sero positive
Immunological response to BK virus
Replication of virus follows immune operation like diabetes HIV pregnancy post transplant
Immediately after kidney transplantation, replication starts and it follows anti rejection therapy where intense immunosuppression is given
Uroepithelium is the target of BKV
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, (DECOY CELLS )
The damage of tubular capillary walls
will cause the vascular spread of the virus, leading to
dense inflammatory interstitial infiltrate and tubulitis.
ALLOIMMUNE ACTIVATION
a lack of HLA matches might predict better outcomes in recipients with
BKVN.
Primary infection with BKV is usually subclinical
BK virus stays dormant in the uroepithelium and renal
tubular cells for life
In the presence of immunosuppressive therapy, the virus activates and
starts to proliferate inside the interstitium
Transmission is possible through all routs
Clinical manifestation
immunocompetent – NIL
immunocompromised- BKV has been correlated with are the BKVN,
ureteric stenosis, and late-onset hemorrhagic cystitis
BKVN in different literature ranges between 2 and 15% of kidney
allograft recipients
risk factors for BKVN
overall degree of immunosuppression is main factor
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;
screening
BKVN is early complication of a kidney
transplant, and most cases arise in the first posttransplant year
screening start at first month after transplant, then monthly for the first 6 months,
and then every 3 months for up to 2 years.
first BK viruria starts ,
after 4 week BK viremia and after 12 weeks BKVN
Monitoring of the urine
detection of
BKV-infected epithelial cells named as ‘decoy cells,’ 100% NPV
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
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
serum antibody
significance is still uncertain
BK viremia of more than or equal to 104 is characteristically present in recipients with proven
biopsies of BKVN.
Renal biopsy
two cores at least and should have medulla to avoid false negativity
ACUTE REJECTION IS differential diagnosis
TREATMENT
decreasing immunosuppression is the only validated
therapy to treat BKVN and restore antiviral immune
response
under trial drugs –
leflunomide
cidofovir
mTOR inhibitors
IVIG
quinolones
THERE ARE MANY KNOWN UNKNONS IN BKVN
Introduction:
There are two human polyomaviruses, BK virus (BKV) and JC virus (JCV)
BKV cause interstitial nephritis and allograft failure in renal transplant recipients, occurring within the first year after transplantation. 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.
It is nonenveloped DNA viruses with circular double strand DNA of -5000 base pairs and can bear heating up to 50°C
Epidemiology of BK virus:
BKV is Polyomavirus hominis-1
Primary infection takes place during early childhood, and then the virus stays dormant throughout life in immune-competent
BK virus structure:
BKV-DNA genome 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), which interacts and binds to cellular target proteins
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:
BKV has 4 genotypes according to the DNA sequence variations in the genomic region of VP1
Genotype 1:common =80% and has 4 subtypes
Genotype 1V =15% and has 6 subtypes
Genotype II and III are rare
Immunological response to BK virus:
BK viral replication follows a state of immune suppression; BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression.
nephropathy (BKVN) [48]. Factors for 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 [13]
Pathogenesis of BK infection:
Primary infection is subclinical then disseminated to the kidney 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 [3,4,24]. Also can remain latent in leukocytes, brain and lymph node the virus reactivate in the presence of immunosuppressive therapy.
Routes of transmission of primary BK virus:
1. Respiratory route: primary
2. GIT transmission: some studies support orofecal transmission
3. Vertical transmission through placenta
4. Sexual transmission
5. Donor-derived infection
6. Urine and blood transmission
Clinical manifestations:
BKV does not cause disease in immunocompetent people but in immunocompromised patients, particularly in renal allograft recipients, it cause different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis.
Outside renal transplantation, BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC, whereas in HIV infected patients, it may cause dissemination leading to multiorgan failure and death.
Other less clinical manifestations include:
1. Neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy.
2. Pulmonary diseases: such as interstitial pneumonitis
3. Ophthalmologic manifestations: single case report with bilateral atypical retinitis.
Different studies describe the relationship between BKV and some autoimmune diseases.
BK virus and malignancy:
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
BK virus and urothelial tumors:
BKV-LTAg play role in urological tumor with limited data
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. Decoy cells are abnormal BKV-infected epithelial cells that can be detected in urine and used to diagnose BKVN.
Urine electron microscopy (EM Haufen) has a higher sensitivity and specificity for detecting BKVN than urine cytology, but requires further validation.
Serology:
The BK-PCR test has high sensitivity and specificity, which identify the infection before nephritis occur.
Virus culture:
Used to isolate the virus but it grows slowly in tissue culture.
Kidney biopsy:
Allograft biopsy is the gold standard to diagnose BKVN, with a sensitivity of 94.7% for H&E and 68.4% for FISH. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival.
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.
Treatment strategy of BK virus nephropathy:
The aim of treating BKV is to eradicate the virus while saving the kidney function 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
Drugs with antiviral activities:
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug that inhibits pyrimidine synthesis and can inhibit BKV replication in vitro.
Cidofovir is a nephrotoxic drug that may cause acute kidney injury, renal tubular
acidosis, and proteinuria, and should be used carefully in kidney recipients.
MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression, and IVIG has the most potent antiviral influence. IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain.
Quinolones and statins have been found to reduce BKV proliferation, while rituximab has been associated with adverse effects. Rituximab adjuvant therapy with cidofovir had no graft failure in 9 transplant patients with BKVN.
Short-term and long-term allograft survival:
BKVN has caused permanent allograft damage in 30-60% of cases, but therapeutic approaches have improved renal allograft survival.
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
Post infection monitoring:
Post infection monitoring of BKV-PCR and renal function is essential to improve allograft outcome. Retransplantation is possible and can be done successfully.
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
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
– 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
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
note : this is the same summary in week 9 , journal club n.4
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.
Hemorrhagic 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. 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
What is BK virus?
Pathogenesis of BK infection
Clinical manifestations
Screening and diagnostic tools
Treatment
I. BK virus infection in renal transplant recipients: an overview
Please summarise this article.
BK virus (BKV) and JC virus (JCV), were discovered in 1971.
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.
BK virus and renal transplantation
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.
Abundant large cells with intranuclear inclusions were present in the urine, named later as ‘decoy cells’ for their resemblance to malignant cells.
In 1978 had defined histological changes consistent with polyomavirus nephritis in a kidney biopsy of a patient who was shedding BKV in the urine.
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, non enveloped DNA viruses.
These new group members were termed based on the site of discovery, their geographical areas.
Epidemiology of BK virus
Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world.
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:
(1) The early viral gene region: 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
Had 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.
Immunological response to BK virus
BK viral replication follows: pregnancy, diabetes, HIV infection, cancer, and post transplantation period(follow antirejection therapy).
The role of cell-mediated immunity
The major components of cellular-mediated immunity to control the BKV and play a role in BK clearance are CD4+ and CD8+ T cells .
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.
Role of alloimmune activation Anotherpossible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity. CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans.
Pathogenesis of BK infection
manifests as a mild respiratory symptom in childhood 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 ,within termittent reactivation that manifests as asymptomatic viruria.
BKV can remain latent in leukocytes, brain tissues,and lymphnodes.
Routes of transmission of primary BK virus
1.Respiratory (respiratory tract and tonsils of children)
2.fecal-oral(salivary gland cells)
3. transplacental(cross the placenta and stay dormant in fetal organs, suggesting the possibility of vertical transmission)
4. sexual transmission
4.from donor tissues (BKV infection could be from either the donor or the recipient)
Clinical manifestations
Urinary shedding of BKV was reported in 7% of healthy immune competent individuals.
1.ureteric stenosis, and late-onset hemorrhagic cystitis.
2.BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia.
3. The onset of nephritis might occur as early as 6 days after renaltransplantoraslateas5years.
4.The prevalence of ureteric stenosis is 2–6%.
5.The patients might present with bladder cramps, painful voiding,hematuria,and/or flank pain.
6.Primary central nervous system disease or reactivated central nervous system infection.
7.Reactivated acute respiratory infection leading to severe interstitial pneumonitis in association.
8. Bilateral atypical retinitis(rare).
9. Hepatitis was reported in a patient with bone marrow transplant.
10. BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis.
11. 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
Ureteral stent insertion.
Serology
BK viral loads are measured with real-time PCR.
Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successfull inidentifying early BK infection before the development of nephritis.
BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively.
Virus culture
BKV grows slowly in tissue culture, which might extend from weeks to months.
Kidney biopsy
Allograft biopsy remains the gold standard to diagnose BKVN(nephropathy), which ideally should be performed whenBKV-PCRloadinsistentlyexceedsmorethan10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction.
Treatment strategy of BK virus nephropathy
Reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection.
Withdrawal of antimetabolite drugs .
Change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide.
Reducing the dose of calcineurin inhibitor (CNI) by 25–50%.
Leflunomide
Is an immunomodulator, prodrug, and antirheumatic disease-modifying drug .
It inhibit pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects.
Cidofovir
Is a cytosine analog and viral DNApolymerase inhibitor that is used to manage other viral infections such as CMV.
mTOR inhibitors
mTOR inhibitors have shown effectiveness in in-vitro analysis in inhibiting BK replication and early gene expression. The mTOR inhibitors(sirolimus and everolimus) are thought to produce their inhibitory effect on BKV replication by restoring the down regulation of translation that occurs under cellular stress, thus delay the viral replication.
Intravenous immunoglobulin
used for BKVN for its immune modulatory effects. has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes.
Short-term and long-term allograft survival
Therapeutic approaches have revealed substantial short-term improvements, such as eliminating the circulating viremia.
The documented acute rejection rates following a reduction in immunosuppression varied from 6 to 12%.
BK nephropathy with concurrent acute rejection
More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in 10–30% of the cases.
Combination of anti rejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection.
Postinfection monitoring
To improve allograft outcome we do Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression.
BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression.
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.
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.
Level of evidence: Level V – Narrative review
Introduction
BKV infection often causes of 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.
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 gave the name ‘BK’.
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 and has a circular double-stranded DNA of ∼5000 base pairs.
Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent. Studies showed as much as 60–85% of the general population is seropositive for BKV.
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 is the main
BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1, Genotype I 80% worldwide, genotype IV 15% and genotypes II and III are relatively rare
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 transplantation period. 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. T cells react against both nonstructural and BK capsid proteins and can be measured by the enzyme-linked immunosorbent spot (ELISPOT) and tetramer staining. The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels.
Role of alloimmune activation
Awadalla et al. had linked the higher degree of HLA mismatches with an increase in the incidences of BKVN, which hypothesizes the role of alloimmune activation wereas Drachenberg et al. 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 BKVN. Therefore, 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
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.
Routes of transmission of primary BK virus
Respiratory route, Gastrointestinal transmission, Vertical transmission, Sexual transmission, Donor-derived infection, urine and blood
Clinical manifestations
Ureteric stenosis, late-onset hemorrhagic cystitis (HC), BKpolyomavirus-associated nephropathy (BKVN)(onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years)
Others manifestation
Meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy, acute respiratory infection leading to severe interstitial pneumonitis, bilateral atypical retinitis (rarely), hepatitis.
Association with autoimmune disease and malignancy has been proposed.
Risk factors
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.
Timing of screening
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.
Monitoring of the urine
Monitoring of the urine 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
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.
BK virus mRNA levels in urine-This method is considered as 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, other test includes 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 log10 genome (copies/ml)) 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.
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.
Banff working proposal.
Class 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
Allograft rejection
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 some BKV cases and is linked with more aggressive disease.
IHC staining of renal tissues or urinary sediments with anti-HLA DR, which has been related to acute rejection. 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
Decreasing immunosuppression is the only validated therapy to treat BKVN
Treatment of presumptive BK virus nephropathy
Switching a drug within the same class or to a different class and steroid avoidance these 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
Treatment of BK virus nephropathy in the setting of allograft dysfunction
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: Pyrimidine depletion and tyrosine kinase inhibition: A/E Hemolytic anemia thrombocytopenia, and thrombotic microangiopathy
Cidofovir: Inhibits viral replication; mechanism unknown: A/E Potentially nephrotoxic and severe anterior uveitis.
IVIG: Contain neutralizing antibodies against BKV and are immunomodulatory, A/E May led 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, A/E Hyperlipidemia, bone marrow toxicity, mucositis and oral ulcerations, and lymphedema.
Fluoroquinolones: Inhibit BKV replication in vitro and inhibit the large T antigen helicase activity, A/E 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, A/E Anorexia, dizziness, nausea, and diarrhea.
Pravastatin: Prevent caveolae-mediated endocytosis, A/E Adverse muscle events and hepatic dysfunction
Short-term and long-term allograft survival
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.
BK nephropathy with concurrent acute rejection
Hirsch et al. suggested a combination of antirejection therapy with a subsequent reduction in immunosuppression.
Post infection monitoring.
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 achieve
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 consider changing to sirolimus or adding leflunomide. Inability to clear BKV can lead to worse allograft outcomes.
Re-Transplantation
Generally, pretransplant clearance of BK viremia is essential. Allograft nephrectomy is not necessary before re-transplantation.
BKV viruria, viremia, and BK nephropathy can recur and cause allograft loss
Introduction :
BKV infection 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 virus and renal transplantation: historical perception:
Gardner et al. is the first to detect BK virus (BKV) in 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.
Polyomaviridae variants :
The Polyomaviridae (PyV) are a family of small, nonenveloped DNA viruses includes (BKV,JCV, and simian virus 40 (SV40) ) which is having 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, with primary infection occurring in early childhood and remaining dormant throughout life.
BK virus structure:
The BK virus genome is divided into three parts: the early viral gene region, the noncoding control region (NCCR), and the late viral gene region (LVGR). The NCCR regulates the expression of the virus early and late genes, while the LVGR encodes the capsid proteins VP-1, VP-2, and VP-3
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 and genotypes II and III. 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, IV/b-3, IV/c-1, and I/c-2). These subgroups may reflect different geographical and migration patterns of the human population. The clinical and immunological consequences of these genotypes on clinical aspects and the course of the disease are still unknown.
Immunological response to BK virus:
The immune system plays an essential role in controlling BKV replication and resolution of BKVN due to defective immune surveillance, lack of humoral immunity, alloimmune activation, and viral variation. Humoral immunity, antibody mediated immunity, and allo-human leukocyte activation may all play a role 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 primary BKV transmission include respiratory, fecal-oral, transplacental, or from donor tissues.
Clinical manifestations:
BKV does not cause disease in healthy individuals, but is associated with different clinical features in immunocompromised patients, such as BKVN,ureteric stenosis, and late-onset hemorrhagic cystitis (HC).
Outside renal transplantation, BKV is commonly encountered in patients with HSCT. BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
The onset of nephritis can occur as early as 6 days after transplant or as late as 5 years. 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 and ureteral dilatation.
BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection, but has been linked to neurological manifestations such as meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy in patients with HSCT or HIV infection.
Pulmonary diseases such as reactivated acute respiratory infection and severe interstitial pneumonitis have been reported in HIV-infected patients, and ophthalmologic manifestations such as bilateral atypical retinitis and retinal necrosis have been reported. However, further data are needed before labeling BKV to cause an ophthalmological manifestation.
BK virus and autoimmune diseases have been linked in the literature, with a prevalence of 16% in patients with systemic lupus erythematosus and an increase in the prevalence of persistence/or recurrent BK viruria in patients with lupus. However, there is no article that describes BKV activation in patients at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference.
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.
BK virus and urothelial tumors:
BKV-LTAg may play a role in the pathogenesis of urothelial tumors, but evidence is limited.
Risk factors:
Risk factors for BKVN include overall immunosuppression, male sex, older recipient age, previous rejection episodes, HLA mismatching, cold ischemia, BK serostatus, and ureteral stent insertion.
Screening and diagnostic tools:
Serology:
Quantitative BKV-PCR has been successful in identifying early BK infection before nephritis, but not all recipients will develop nephritis. The BK-PCR test has high sensitivity and specificity, but is interlaboratory dependent and should be interpreted in light of clinical condition.
Virus culture:
Virus culture can be used to isolate BKV, but it grows slowly in tissue culture.
kidney biopsy :
Allograft biopsy is the gold standard to diagnose BKVN, with a sensitivity of 94.7% for H&E and 68.4% for FISH. BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis, and reduced allograft survival.
Differential diagnosis:
BKVN can be distinguished from acute rejection by presence of BKV inclusion bodies, immunohistology, and IHC staining.
Treatment strategy of BK virus nephropathy:
Reducing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response, but should be balanced against risk of rejection.
Drugs with antiviral activities:
Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug that inhibits pyrimidine synthesis and can inhibit BKV replication in vitro.
Cidofovir is a nephrotoxic drug that may cause acute kidney injury, renal tubular acidosis, and proteinuria, and should be used carefully in kidney recipients.
MTOR inhibitors have shown effectiveness in inhibiting BK replication and early gene expression, and IVIG has the most potent antiviral influence. IVIG has been successful in treating BKVN with concurrent acute rejection, but its efficiency is uncertain.
Quinolones and statins have been found to reduce BKV proliferation, while rituximab has been associated with adverse effects. Rituximab adjuvant therapy with cidofovir had no graft failure in 9 transplant patients with BKVN.
Short-term and long-term allograft survival:
BKVN has caused permanent allograft damage in 30-60% of cases, but therapeutic approaches have improved renal allograft survival.
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. Treatment should be tailored for each patient individually.
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.
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
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 the 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.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Monitoring BKVN using quantitative plasma BKV-PCR is
important to improve allograft outcomes.’
Thanks a lot, dear professor.
so nice of you Dr saiwan
BK virus infection in renal transplant recipients: an overview
BKV-DNA genome composed of 3 parts:
1.early viral gene region
2.late viral gene region
3.capsid protein VP1 in the LVGR
BKV subdivided into 4 genotypes:
Route of transmission:
1.respiratory
2.GIT
3.vertical
4.sexual
5.donor-derived
6.urine
7.blood
The clinical presentation varies from asymptomatic to BKVN, ureteric stenosis and late onset hemorrhagic cystitis…
when the viral within the uroepithelium starting replication and shedding of virus into urine (viruria),then after several weeks (~ 4 weeks) virus seen within blood (viremia),then around 12 weeks BKVN
BKV viruria …..30-40%
BKV viremia ….10-15%
BKVN ………….2-15%
ureteric stenosis…2-6%
BKVHC …..rare after kidney transplantation while more common among hematopoietic stem cell transplanataion
BKV may involve brain, respiratory tract, eye ,liver and causing autoimmune diseases
BKV seen or associated with some malignancies such as urothelial carcinoma
Diagnosis:
A.Urine
1.urine cytology ( decoy cells) large cells with intranuclear inclusion of virus make resemble of malignant cells ,which is not diagnostic 100% and absence dose not exclude BKV infection
2.urine electromicroscopy EM (haufen)
3.urine PCR : Quantitative viral load and BKVmRNA
B.Serology:
1.BKV-PCR
2.serum Ab
C.viral culture (require weeks-months)
D. renal biopsy (three patterns /classes which are resemble of rejection)
different screening program available, the one most popular is screening PCR at 1st month post transplantation ,then monthly up to 6 months, then every 3 months up to 2 year and in some centers annually
there is no definitive antiviral or vaccination …..the main treatment is reduction of immunosuppressive medications
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate, ‘there is no definitive antiviral or vaccination …..the main treatment is reduction of immunosuppressive medications’.
BK virus infection in renal transplant recipients: an overview
Summary of this article:
What is BK virus?
Human Polyomavirus: multi-bodies
Small (30 to 45 nm) double-stranded DNA viruses, non-enveloped DNA group of viruses.
Immunosuppressed population
Group include:
BK: Nephropathy
JC: progressive multifocal leukoencephalopathy
Merkel cell: Merkel cell carcinoma
A Touch of History;
What does BK stand for?
Discovered In 1970 from a Sudanese kidney transplantation recipient with a ureteric stricture(Gardner et al. were the first to detect BK polyomavirus (BKV) in urine
BKV nephropathy was diagnosed by a needle biopsy in a renal transplant recipient suspected of having acute rejection. This case was diagnosed in 1993 at Pittsburgh.
Epidemic of BKVN in the 1990s may be resulted from using more potent
immunosuppressive drugs such as tacrolimus, mycophenolate mofetil and sirolimus.
BKV infection is a significant cause of interstitial nephritis and allograft failure in renal transplant recipients, presenting as an asymptomatic rise in creatinine.
Primary Infection is usually acquired in childhood, through either feco-oral, respiratory route or during transplantation with the graft, other forms of transmission may happen including vertical and sexual transmission.
Virus likely persists in the renal epithelium; it infects renal tubules and uroepithelium of most people (around 60-85% of people are infected) and infection remain lifelong.
Replication in immunosuppression status, in immunocompetent individuals the infection is usually benign and asymptomatic.
In immune-compromised renal transplant recipients, infection can be acquired either due to reactivation of latent infection or newly transmitted from the donor kidney, infection is either subclinical or it may become symptomatic causing BK nephropathy with subsequent graft dysfunction and probable graft loss.
BK infection has a stereotypical pattern, starting by viruria, then viremia and lastly nephropathy (occurring in 2-15 % of transplant recipients)
Pathogenesis of BKVN is a combination of defective T cell or humoral response to BKV, alloimmune activation, or viral variation in molecular sequences.
BK virus can cause graft loss by the following mechanisms:
BK virus infects tubular epithelium causing interstitial inflammation, tubular injury with subsequent fibrosis.
Secondary immunological response cause further allograft damage.
Epidemiology:
Approx. 80% of the general population has a detectable antibody to BKV, which appears early in life and remains elevated throughout life.
The prevalence of this virus in the ESRD population, kidney donors, and transplant recipients has not been well defined.
The prevalence of BK viruria, viremia, and nephritis after renal Tx has been estimated at 30, 13, and 8%, respectively.
BKV-induced nephropathy occurs in up to 10% among kidney allograft recipients.
Overall, the reported incidence of allograft failure ranges from 15-50%.
It is also seen in other Solid organ transplants but at a much lower rate.
also observed in patients with HIV infection, other immunodeficiency states and rarely also in SLE.
How does the recipient get it:
Donor Derived: latent infections in the Allograft epithelial cells.
Recipients who had BKV infection and received a kidney from the same donor have been shown to have identical BKV genotypes, supporting donor transmission.
Recipients whose donors had higher BKV antibody titers were more likely to develop BKV infection than those with lower titers, also supporting donor transmission.
Recipient: Reactivation of previously acquired infection.
feco-oral and respiratory routes have been suggested.
Other routes include blood transfusion, trans placentally, through semen, &organ transplantation
Risk factors for BK viremia
A- The intensity of immunosuppression
It is more common in HLA mismatched transplantation due to aggressive immunosuppression used.
It is more common also in patients with frequent rejection episodes.
No specific drug is linked to infection, but tacrolimus may be associated with more infection than cyclosporine, and m TOR may be associated with lower incidence of infection.
B- Donor factors
BKV serostatus, such as transplanting kidney from BK + donor to BK – recipient
The presence of donor viruria before transplantation
C- Recipient factors
Older age
Male sex
The use of ureteric stent as a prophylaxis of ureteric leak
Damage of transplanted kidney related to Ischemia or rejection.
The role of cell-mediated immunity
Cell-mediated immunity is essential for controlling the BKV and preventing its spread. CD4+ and CD8+ T cells react against capsid proteins and CTL kill BK-infected cells after recognition of damaged segments of viral DNA.
Without proper immunological regulation, progressive lytic infection can lead to viral leakage, necrosis, and allograft dysfunction.
The role of humoral immunity
Humoral immunity and antibody-mediated immunity are important in the pathogenesis of BKVN, as kidney recipients from a seropositive donor are more likely to develop viremia.
Role of alloimmune activation
Alloimmune activation is a possible immunological factor involved in the development of BKVN, as it involves T cells that cross-react to both BKV and allo-antigens, allowing BKV to escape immunological surveillance.
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:
BKV infection is usually subclinical or mild respiratory symptom in childhood but 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.
Immunosuppression => viral replication
Ascending infection via cell-to-cell spread => progressive lytic infection.
This results in large nuclear and peri-nuclear virus-containing inclusions in the tubule cells.
Lysis of these infected cells results in viral seepage into=>
a. the tubule lumen and urine but also
b. the interstitial and to surrounding cells.
Subsequent tubular cell necrosis leads to cast formation and denudation of the basement membrane.
Destruction of tubular capillary walls results in vascular spread of the virus.
heterogeneous interstitial infiltration of inflammatory cells as well as tubulitis
Clinical Manifestation of BK virus:
Most of cases are asymptomatic.
Timing:
85% of those who develop viremia do so by month 3-4 post transplantation.
95% of BKVN in the first 2 years.
Asymptomatic:
Asymptomatic Viruria 30-40%, 2-3 months
Asymptomatic Vireamia 10-20%, 3-6 months
Asymptomatic raise of Creatinine, BKVN 2%-5%
Symptomatic:
BK virus and renal disease:
BK virus infection causes viruria, which can progress to viremia and eventually to BKVN/PyVAN.
Incidence of BKVN varies depending on immunosuppressive regimens and screening strategies.
BK virus-associated nephropathy
BKV-associated nephropathy causes irreversible injury and allograft failure(Tubulointerstitial nephritis )
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6%.
Treatment of ureteric stenosis involves percutaneous nephrostomy and dilatation.
Hemorrhagic cystitis
Hemorrhagic cystitis (BKV-HC) is rare in renal transplant and can present with bladder cramps, painful voiding, hematuria, and/or flank pain.
Management involves vigorous intravenous hydration and Cidofovir given locally through bladder installation for remission.
Less common manifestations include:
BKV can cause neurological manifestations, pulmonary diseases, and ophthalmologic manifestations.
vasculopathy, meningoencephalopathy, retinitis, pneumonitis, hepatitis, GBS and variety of neoplasms.
Graft dysfunction (BK nephropathy) in the form of increase in the serum creatinine associated with pyuria, hematuria and/or cellular casts.
Ureteritis and ureteric stenosis secondary to BKV infection is uncommon but some studies reported association.
Debatable and unclear association with genitourinary malignancies
Other rare manifestations including CNS infection, pulmonary, hepatic disease, and ophthalmic manifestations (bilateral atypical retinitis)
BK virus and malignancy: thoughts on viral oncogenesis
BKV-DNA has been identified in tissue samples of different neoplasms, including brain tumors, 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 due to expression of early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive cells into a neoplastic transformation.
Additionally, BKV-LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products.
Regardless of whether BKV has a causative part in human cancer development, it will remain a topic of debate.
BK virus and urothelial tumors
BKV has been linked to urothelial malignancies, particularly bladder carcinoma, as evidenced by Geetha et al. and Alexiev et al., who found high levels of BKV-LTAg in the nucleus of almost every tumor cell and none in the non-neoplastic urothelium.
However, no evidence of BKV-LTAg in urothelial malignancies has been reported to date.
Screening of BK virus
Screening is recommended monthly in the first 6 months then /3 months for 2 years post transplantation and then annually till 5 years after transplantation.
Urine PCR has high sensitivity but low specificity for BK nephropathy and is not used frequently in screening.
Decoy cells have high sensitivity (100% in one study), but low specificity for BK nephropathy (71%) and it can be mistaken with other viruses such as CMV and adenovirus.
Blood PCR is the best method for screening since it correlates well with BK nephropathy, it is sensitive (sensitivity 100%) and more specific (specificity 88%) than urinary PCR, but it is less sensitive in detection of strains other than serotype 1
Protocol biopsies may be done to detect hidden BK nephropathy.
The best method is to screen using decoy cells and reserve blood test (PCR) in the setting of graft dysfunction or if decoy cells were detected
Diagnosis
A- Viruria (urine PCR, urine decoy cells)
Sensitive but nonspecific (most of patients are asymptomatic and do not progress to BK nephropathy)
May be replaced by decoy cells which represents renal tubular or uroepithelial cells containing intranuclear viral inclusions and reflects higher urinary viral load. But it can be present in other viral infections including CMV.
Both have low positive predictive value for progression to nephropathy.
Detection of viruria is an indication for doing PCR blood.
B- Viremia (PCR)
Sensitive (sensitivity 100%) and more specific (specificity 88%) than urinary PCR
Level > 10000 copies/ml have a very high positive predictive value of nephropathy if associated with sustained viruria > 2 weeks and some recommend settling the diagnosis of BK nephropathy at this level of viremia without biopsy.
The presence of viremia is an indication for reduction of immunosuppression.
C- BK nephropathy
Occur mostly in the first year after transplantation but can occur from 6 days after transplantation up to 5 years’ .
Presents by graft dysfunction (increase in serum creatinine associated with pyuria, hematuria and/or cellular casts), the diagnosis is confirmed by renal biopsy.
Renal biopsy for BK nephropathy
At least 2 biopsy cores should be taken since the injury is usually focal, and medulla should be included since BK virus is more likely to be present in the medulla and around 1/3 of cases are missed with one core.
The diagnosis requires the presence of the following:
A- Characteristic cytopathy (not specific) including.
Intranuclear basophilic viral inclusions without surrounding hallo, Interstitial mononuclear and PNL infiltration, tubulitis and tubular injury.
BK nephropathy is classified into 3 grades.
Grade 1 – pvl 1, ci ≤1
Grade 2 – pvl 1, ci ≥2 or pvl 2, any ci score or pvl 3, ci ≤1
Grade 3 – pvl 3, ci ≥2
NB: pvl 1 (tubulitis <1%), pvl 2( tubulitis 1-10%), pvl 3 (tubulitis > 10%)
And
B– Positive IHC test for SV40 which includes using of antibodies directed against the cross-reacting SV40 large T antigen. Specificity of the test is 100%, but it does not differentiate between BK and JC virus associated nephropathy. Sensitivity may be lower due to focal injury since BK virus is more likely to be present in the medulla so at least 2 biopsy cores should be taken, and the medulla should be included.
Treatment;
Reduction of immunosuppression which represents the main line of therapy with monitoring of viral load by plasma PCR.
No single protocol is available, but options include reduction of MMF by 50%, stop MMF, reduce CNI dose, shift from tacrolimus to cyclosporine, shift from MMF to azathioprine.
Monitor viral load (plasma PCR) /2-4 weeks, clearance of viremia precedes viruria by weeks to months so monitoring of viruria has no clinical implication in follow up.
Monitor renal functions/2-4 weeks (especially in patients with graft dysfunction)
Several agents were tried in the treatment of BK nephropathy due to their in vitro anti-BKPyV activity, including IVIG, leflunomide, cidofovir, and quinolone. All these are not routinely recommended as there is no clear evidence of their superiority on reduction of immunosuppression alone.
If there is concurrent BK nephropathy and AR the treatment is debatable some recommend given pulse steroids without reduction of immunosuppression then reduce immunosuppression after treating rejection, others reduce immunosuppression and do not treat AR even with pulse steroids.
If patient develop AR after reduction of immunosuppression it is generally not recommended to augment immunosuppression again if there is biopsy proven BK nephropathy
Re-transplantation after graft failure due to BK nephropathy;
Kidney Re-Transplantation with an excellent graft survival at 1(98%) and 3 years (94%) after transplantation.
Viral clearance should be confirmed before transplantation.
Recommend HLA and ABO compatible transplantation, to avoid aggressive immunosuppression.
There is no evidence to support allograft nephrectomy is necessary before retransplantation.
Recurring BKV might reflect a previous BK variant or DeNovo infection.
No a specific treatment and early diagnosis of BKVN has significantly improved allograft outcome.
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘there is no evidence to support allograft nephrectomy is necessary before retransplantation’.
Thank you prof.
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.
–Reduction in immunosuppression 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.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘Allograft nephrectomy though a possibility must not be done in all pts’.
Noted Prof.
🎯It is a repeated article from week 9: 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).
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘Early diagnosis through screening protocols and surveillance biopsy is associated with better graft outcome’.
1.Please summarise this article.
Virology
The human BKV is a member of the Polyomaviridae (PyV) virions, a subclass of papovaviruses that includes the JCV, SV40, & BKV.
BKV is a small (40–45nm capsid), non-enveloped DNA virus.
BKV tolerates heating (50°C for 30 min) without effect on infectivity.
The term “polyoma” refers to the ability of viruses to produce many tumors.
BKV is a common virus that affects the majority of people worldwide. Children are first infected & the virus remains latent for the rest of their lives.
60–85% of the general population is seropositive for BKV.
BKV-DNA genome is divided into 3 parts:
The NCCR which regulates the expression of the virus early & late genes that control differentiation & activation of the host cell.
Immunological response to BK virus
Because of the severe immunosuppression, BKV replication typically starts early in the post-TX period & may occur after anti-rejection medication.
The role of cell-mediated immunity
The main elements of cellular-mediated immunity that control the BKV and participate in BK clearance are CD4+ and CD8+ T cells.
The role of humoral immunity
Humoral immunity may play a part in the pathogenesis of BKVN since patients with a H/O immunity to the virus may not manifest symptoms, regardless of the viral load.
Role of allo-HLA alloimmune activation & heterologous
immunity.
T cells cross-react to both BKV & allo-antigens. Because the allo-HLA molecules that represent BKV-peptides cannot be recognized by the host BKV-specific effector memory T cells, BKV is able to evade immunological monitoring.
==================
Pathogenesis
Primary BKV infection is usually subclinical.
BKV enters the circulation via infected tonsils, infects the PBMN cells, & then spread to secondary locations, such as the kidneys.
The virus become latent, uroepithelium & renal tubular cells after resolution of primary infection.
IS therapy causes the virus to become active, multiply in the interstitium, cross into the PTCs & lead to tubular cell lysis & viruria. The degree of injury, inflammation, & fibrosis determines the outcome.
Routes of transmission of primary BK virus
==================
Clinical features
After infection, the first multiplies in the uroepithelial cells, appears in the urine (viruria), progressing a few weeks later to the blood (viremia), & ultimately causing BKVN (PyVAN).
BK viruria occurs in 30–40% of KTX recipients & 10–15% of recipients develop BK viremia.
BKVN is seen in 2 to 15% of KTX recipients.
BKVN can occur as early as 6 days after KTX or as late as 5 years.
Ureteric stenosis occurs in 2–6% & it can rarely lead to allograft dysfunction necessating intervention (
percutaneous nephrostomy & percutaneous ureteral dilatation, with concurrent reduction of IS medications).
BKV-associated HC or non-HC is typically observed in HSCT recipients, however it can also be seen in KTX recipients.
BKVN can occur in native kidneys of HSCT, heart & lung transplant recipients, & in immunocompromised HIV-infected patients. It presents with AKI & significant proteinuria, & characteristic kidney biopsy features.
Rare manifestations of BKV
Risk factors
==================
Screening and diagnostic tools
Timing of screening
BKV screening started at 1stmonth post-TX, then monthly for the 1st6 months, & then every 3 months for up to 2 years (AST Infectious Diseases Guidelines & KDIGO guidelines).
Common screening methods for BK virus
Allograft biopsy:
It is the gold standard to diagnose BKVN.
Ideally should be done when BKV-PCR load insistently exceeds > 10 000 copies/ml (4 log 10 genome (copies/ml)) with or without allograft dysfunction.
Macroscopy: streaky fibrosis of the medulla with cortical scars.
Microscopy: sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis & mononuclear cell infiltrates.
BK viral inclusions within tubular epithelium can be seen (H&E & PAS staining).
Alternatively BKV can be identified via in-situ hybridization.
Differential diagnosis
AR: treating the presumed AR with increased IS drugs may aggravate BKVN. BKVN may co-exist with AR.
The presence of BKV inclusion bodies & immunohistology findings of positive immunoperoxidase staining for SV40, which emphasize the virally infected cells, allow BKVN to be distinguished from AR.
Other differential diagnosis includes any disease associated with early (1–12 weeks post-TX) & late (≥3 months) renal allograft dysfunction.
==================
Available therapeutic options for BK virus
1.Immunosuppression reduction:
May rebuild the immune responses against BKV.
Can induce AR.
There is no standard strategy for IS modification; however, different regimens have been tried upon recognition of viremia.
Approaches include withdrawal of antimetabolite drugs or change from MMF to azathioprine, sirolimus, or leflunomide, reducing the dose of CNI by 25–50% (target lower level of cyclosporine 50–100 ng/ml & tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI.
2.Leflunomide:
Acts by pyrimidine depletion & tyrosine kinase inhibition
Hemolytic anemia thrombocytopenia, & TMA are recognized adverse effects.
3.Cidofovir:
Inhibits viral replication, mechanism unknown.
Potentially nephrotoxic & cause severe anterior uveitis.
4.IVIG:
Contain neutralizing ant-BKV antibodies & are immuno-modulatory.
May cause paradoxical rise in viral load.
5.mTOR inhibitors:
Inhibit the proliferation of BKV-specific T-cell & controls the differentiation of memory CD8 T cell’,
A/E: Hyperlipidemia, bone marrow toxicity, mucositis &
oral ulcerations, & lymphedema.
6.Fluoroquinolones:
Inhibit BKV replication in vitro & inhibit the large T antigen helicase activity.
A/E: gastritis, C difficile, hepatoxicity, neurological adverse effects, & altered mental status.
7.Artesunate:
Inhibit BK viral proliferation in a primary human renal cell culture.
A/E: Anorexia, dizziness, nausea, & diarrhea.
8.Statins:
Prevent caveolae-mediated endocytosis.
A/E: muscle damage & hepatic dysfunction.
==================
Short-term and long-term renal allograft survival
The KTX survival for recipients with BKVN has significantly increased in recent years.
Treatment techniques have produced notable short-term improvements, such as removing the circulating viremia, but greater research is required to fully understand the long-term effects, such as late acute & chronic rejections.
AR rates following a reduction in IS range from 6 to 12%.
BKVN with concurrent AR
More than half of biopsies can show tubulitis, & any decrease in immunosuppression can precipitate rejection in 10–30% of the cases.
Celik et al. found a reduction in IS load is more than capable in reducing viral load than steroid pulses in biopsies with BKVN & tubulitis.
Hirsch et al. suggested a combination of antirejection therapy with a subsequent IS reduction in once BKVN is diagnosed concurrent with AR.
Generally, an initial IS reduction without steroid pulses should be considered upon detection of BKVN.
Postinfection monitoring
Improved allograft prognosis requires careful monitoring of BKV-PCR & renal function throughout any course of therapy, especially after AR has been treated or IS has been reduced.
Retransplantation following graft loss due to BKVN
Successful retransplantations are reported (Ramos et al, USA-OPTN registry data).
Pretransplant clearance of BK viremia is essential after minimizing immunosuppression.
Although allograft nephrectomy is not required prior to re-TX, it sounds logical to remove the infected graft in the presence of active viral replication.
BKV viruria, viremia, & BK nephropathy can recur & cause allograft loss.
Conclusion
Despite the lack of a specific treatment, an early diagnosis of BKVN has significantly improved allograft results.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Early diagnosis of BKVN has resulted in substantial improvement in allograft outcomes’.
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.
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.
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.
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.
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your list of comments in relation to renal re-transplantation.
Your comment on graft nephrectomy is confusing to me
Thanks; our Prof. sorry, I meant
After failed graft due to BKvN, and planning for retransplantation; allograft nephrectomy is not necessary before re-transplantation and no evidence support this approach.
BK virus in kidney transplant recipients
Summary of the Article
Introduction
BK infection is considered a possible cause of graft dysfunction and its presents as a gradual asymptomatic rise in serum creatinine.
Polyomaviridae variants
Epidemiology
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 BKVN with concomitant acute rejection
Post-infection monitoring include
Conclusion
Level of evidence
Level ((V))
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation that 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.
However, you have typed that the following possible options: leflunomide, quinolone, artesunate, pravastatin, IVIG, rituximab. I would state that there is no robust evidence supporting using these drugs.
Summary BKV
Introduction
BKV belongs to the Polyomaviridae family that comprises of JCV, BKV and SV40.
Additional 12 human polyomaviridae viruses have been identified.
BKV primary infections usually occurs in childhood then 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: genotype 1 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:
1. Defective immune clearance by the host T cells
2. Absent humoral immunity
3. Alloimmune activation
4. Viral variation of molecular sequences
Pathogenesis of BKV infection
Primary infection is 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 in interstitial and spreads to the peri-tubular capillaries leading tubular cell lysis and viruria.
Reaction between the BKV and immune system leads to various 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
Common 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:
1. Asymptomatic hematuria
2. Symptomatic hematuria
3. Hematuria with clots
4. 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:
1. Neurological-encephalitis, meningitis, GBS
2. Pulmonary disease- Interstitial pneumonitis
3. Ophthalmic- Only one case of bilateral atypical retinitis has been reported to date.
4. Hepatic-hepatitis
5. Autoimmune-persist 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 they 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
Haufen are 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 genotypes.
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% for polyomavirus nephropathy; though it does not differentiate between BKV and JCV.
FISH has higher sensitivity and specificity than IHC and H&E staining, however its use is limited in clinical setting.
Suggested algorithm for screening
Recipients should be screened for decoy cells every 3 months, when decoy cells are detected, additional test should be carried out that include urine and plasma PCR with the possibility of doing kidney biopsy in the setting of deteriorating 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.
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
Decreasing immunosuppression is the inly validated therapy, and should be balanced against the risk of rejection.
MMF are first withdrawn however some studies have shown that CNI may inhibit the anti-BKV T cell reaction thus challenging this approach.
Leflunomide
It is a pyrimidine synthesis inhibitor, hence cannot be combined with other anti-proliferative drugs.
Thus, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage (withdrawal of antimetabolite and reduction of CNI).
Adverse effects include hemolysis, aplastic anaemia, 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 target of cidofovir.
It’s exclusively excreted through urine, resulting in high renal tubular cell concentrations.
It’s 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 neutralising antibodies and is able to neutralise 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.
Other drugs:Quinolones/artesunate/statins/rituximab
Further prospective randomised studies are required to validate the use of this drugs.
Post infectious monitoring
Scr should be monitored every 1–2 weeks and plasma BKV-PCR level every 2–4-week for 8 weeks. Then monthly until clearance of BK viremia or at viral burden falls below threshold value and stabilisation of renal function is 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
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.
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your list of comments in relation to renal re-transplantation.
Your comment on graft nephrectomy is confusing to me
Thank you prof.
Graft nephrectomy is not recommended prior to re-transplantation.
However in a case of active BKV infection during time of re-transplantation then nephrectomy can be done though there is no evidence to support this approach.
Summary:
Introduction:
Three decades after its discovery in 1971, BK virus (BKV) and JC virus (JCV) were shown to induce interstitial nephritis and allograft failure in renal transplant patients. BKV infection is one of many possible causes of renal dysfunction in kidney transplant recipients, often within the first year. Asymptomatic creatinine increases with tubulointerstitial nephritis may resemble acute rejection, creating a diagnostic and management conundrum.
Epidemiology of BK virus:
Polyomavirus hominins-1, better known as BKV, is a ubiquitous virus that infects most people around the globe. Initial infection typically takes place during early infancy, and thereafter, the virus stays latent throughout life in immune-competent people. 60–85% of the general population is BKV-positive. However, there is a paucity of data related to BKV prevalence in Middle Eastern countries and in Africa, and a single study discovered was from Iran, with a seroprevalence of 41.8%.
Pathogenesis of BK infection:
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.
Clinical manifestations:
Graft dysfunction, also known as BK nephropathy, manifests itself in the majority of patients as asymptomatic elevations in blood creatinine levels, which are often accompanied by pyuria, hematuria, and/or cellular casts.
While ureteritis and ureteric stenosis as a result of BKV infection are rather rare, certain studies have indicated a link between the two.
It rarely manifests itself as hemorrhagic cystitis.
A relationship with genitourinary cancers that is both debatable and uncertain exists.
Additional, far less common signs include infections of the central nervous system, lung illness, liver disease, and eye disease.
Oncogenesis and BK virus:
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, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, and Ewing sarcoma.
Common screening methods for BK virus:
The objective is to detect early signs of viruria or viremia before graft dysfunction manifests itself.
Screening should begin one month after the transplant, continue once per month for the first six months, and then move to once every three months for the next two years.
Urine: Urine cytology (Decoy cells), Urine electron microscopy (EM Haufen), Quantitative assessment of the levels of BK virus and viral load in the urine, BK virus mRNA levels in urine
Serology: Serum BK-PCR, Serum antibodies
Virus culture: o has a sluggish growth rate in tissue culture
Kidney biopsy serves as the gold standard for diagnosing BKVN.
BK virus nephropathy treatment:
Immunosuppressive therapy, with or without antivirals, was the initial BKV treatment. Modifying immunosuppressive treatment is not conventional.
Such approaches can include withdrawing antimetabolite drugs, changing 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.
Medications that inhibit the activity of viruses
· Leflunomide. · Cidofovir.\s· mTOR inhibitors.\s· Intravenous immunoglobulin
Other therapeutic approaches for the treatment of nephropathy caused by the BK virus
Quinolones; artesunate
statins; rituximab.
I appreciate your comments on BKV in renal transplantation. However, in the heading ‘Treatment; your have typed that the following possible options: leflunomide, quinolone, artesunate, pravastatin, IVIG, rituximab.
I would state that there is no robust evidence supporting using these drugs.
It is first identified early in 1971 as a cause of ureteric stricture post transplantation
Human polyomaviruses (HPyVs) are small, double-stranded, non-enveloped DNA group of viruses
12 types exist till 2007, the most common and important types that are involved in diseases in immunocompromised patients are:
BK polyomavirus is a small, double stranded, non-enveloped DNA virus. 4 serotypes exsists, the most common is genotype 1 (80%), followed by genotype 4 (15%). Its genome encodes for 6 viral proteins, 2 early, 1 none coding and 3 late proteins. The early proteins include large (T) and small tumor antigen (t).
Infection is usually acquired in childhood, through either feco-oral, respiratory route or during transplantation with the graft, other forms of transmission may happen including vertical and sexual transmission
It infects renal tubules and uroepithelium of most of people (around 60-85% of people are infected) and infection remain lifelong
BK infection has a stereotypical pattern, starting by viruria, then viremia and lastly nephropathy (occurring in 2-15 % of transplant recipients)
Pathogenesis of BKVN is a combination of defective T cell or humoral response to BKV, alloimmune activation, or viral variation in molecular sequences
so BK virus can cause graft loss by the following mechanisms:
Risk factors for BK viremia
A- The intensity of immunosuppression
B- Donor factors
C- Recipient factors
Clinical presentation of BK virus
Screening of BK virus
Diagnosis
A- Viruria (urine PCR, urine decoy cells)
B- Viremia (PCR )
C- BK nephropathy
Renal biopsy for BK nephropathy
The diagnosis requires the presence of the following:
A- Characteristic cytopathy (not specific) including
Intranuclear basophilic viral inclusions without surrounding hallo, Interstitial mononuclear and PNL infiltration, tubulitis and tubular injury
BK nephropathy is classified into 3 grades
NB : pvl 1 (tubulitis <1%), pvl 2( tubulitis 1-10%), pvl 3 (tubulitis > 10%)
And
B– Positive IHC test for SV40 which includes using of antibodies directed against the cross-reacting SV40 large T antigen. Specificity of the test is 100%, but it does not differentiate between BK and JC virus associated nephropathy. Sensitivity may be lower due to focal injury since BK virus is more likely to be present in the medulla so at least 2 biopsy cores should be taken and the medulla should be included
Treatment
Re-transplantation after graft failure due to BK nephropathy
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments in regards to retransplantation, “Consider HLA and ABO compatible transplantation, in order to avoid aggressive immunosuppression.”
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.
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.
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.
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.
. I appreciate your comments on BKV in renal transplantation. However, in the heading ‘Treatment; your have typed that the following possible options: Quinolone, artesunate, pravastatin, IVIG, rituximab.
I would state that there is no robust evidence supporting using these drugs.
Summary
Introduction
This article is focussed on BKV infection in kidney transplant recipients. An overview of the different aspects related to this infection in the transplant population has been discussed. The various headings that have been discussed in this study include BKV virology, pathogenesis, clinical features, diagnosis, treatment, screening, and how this infection can impact short term and long term renal graft survival. This article is based on recent evidence.
Discussion
Virus structure and family
The human BKV belongs to the family Polyomaviridae, which is a subgroup of papovaviruses. The other viruses in this family include SV40 and JCV. These viruses are non enveloped and have a diameter of 40-45 nm, bearing heat upto 50 deg celsius without its infectivity getting affected. It has double stranded DNA.
BKV DNA genome has three parts, namely:
Epidemiology
BKV infects humans all over the world. It predominantly affects children, and then stays dormant throughout life in immunocompetent people. It is possible that 85% of the population are seropositive for BKV in the UK.
Variants
There are four genotypes or subtypes which have been categorized according to the DNA sequence variations in VP-1.
Continuous duplication of BK genome during activation can lead to rearranged variant viruses being generated. This is because of the deletion and duplication that occurs in the NCCR sequence.
Immunological response to BK virus
BKV replicates in immunosuppressed individuals, thus seen in states such as pregnancy, diabetes, cancer, HIV, and in the post transplant period. In the post transplant period, replication can occur early and can follow anti rejection therapy due to the intense immunosuppression. This is because the immune system plays a vital role in the elimination of the virus, especially in preventing viral replication, and thus when the immune system is suppressed with medication, it can lead to potent and widespread BK viral replication. Defective immune surveillance by T cells and absence of humoral immunity to BKV can lead to BKV pathogenesis in the host.
Transmission routes
Clinical features
Risk factors
Screening
The goal of screening is to identify viruria or viremia early so that treatment can be done before graft dysfunction is seen. KDIGO guidelines recommend screening for BKV at first month post transplant, then monthly for the first 6 months, and then every 3 months for unto 2 years.
Viral replication can start in the early post transplant period, with a pattern of viruria followed by viremia and then nephropathy.
Monitoring in urine includes detection of BKV infected epithelial cells named as ‘decoy cells’ or aggregates of BKV virions. This can be done through quantification of urinary BKV viral load by BKV DNA OCR or reverse transcriptase PCR for BKV RNA.
Biopsy
Histological features include macroscopic appearance of streaky fibrosis of the medulla with circumscribed cortical scars and microscopic appearance of sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis. Mononuclear cell infiltrates can be seen. H&E staining can identify BK viral inclusions within the tubular epithelium.
Differential diagnosis
Treatment
The aim of treatment is to eradicate virus while saving kidney function. Treatment options include :
Post infection monitoring
Serum creatinine is tested every week and plasma BK PCR level checked every 2 weeks for 8 weeks. Following this, monthly checks are done until clearance of BK viremia and stabilization of renal function.
Conclusion
Early diagnosis of BKV can give a possible good outcome for both the patient and the graft. This can be done through molecular techniques and tissue analysis. A variety of options are involved in treatment, but individualized treatment plans for each patient are recommended. The different options of treatment include reduction in immunosuppression dosage or switching IS drugs to help the immune system eliminate virus. Graft function is to be monitored to reduce risk of allograft rejection. In addition, antiviral medications such as leflunomide can help in achieving faster and more effective results. Post infection monitoring for 2 months followed by regular checks every month until full clearance of BKV is crucial.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Early diagnosis of BKVN has resulted in substantial improvement in allograft outcomes’.
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.
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Early diagnosis of BKVN has resulted in substantial improvement in allograft outcomes’.
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
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘ Early diagnosis of BKVN (by molecular techniques and tissue analysis) has resulted in substantial improvement in allograft outcomes’.
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 the 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
Unfortunately non of the above medication has had an effective outcome in the treatment of the BKVN.
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 the 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 a period of undetected BKV
I like your well-structured detailed summary, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation. I agree that ‘In spite of three decades of research in the field of BKV, there still remain some unanswered question’.
BK virus infection in renal transplant recipients: an overview
Please summarise this article.
Introduction
BK virus and renal transplantation: historical perception
Polyomaviridae variants
Epidemiology of BK virus
BK virus structure
BK virus variants
The role of cell-mediated immunity
The role of humoral immunity
Role of alloimmune activation
The role of other factors
Pathogenesis of BK infection
Routes of transmission of primary BK virus
====================================================================
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:
BK virus and malignancy: thoughts on viral oncogenesis
BK virus and urothelial tumors
===================================================================
Risk factors
=================================================================
Screening and diagnostic tools
Quantitative measurements of urinary BK virus-viral loads
Virus culture
===================================================================
Kidney biopsy
—=================================================================
Suggested algorithm for screening
===================================================================
Differential diagnosis
Allograft rejection
Another differential diagnosis
====================================================================
Treatment strategy of BK virus nephropathy
Treatment of BK virus nephropathy in the setting of allograft dysfunction
Drugs with antiviral activities
Leflunomide
mTOR inhibitors
Intravenous immunoglobulin
Other therapeutic options for treating BK virus nephropathy
====================================================================
Short-term and long-term allograft survival
BK nephropathy with concurrent acute rejection
Postinfection monitoring
Retransplantation
====================================================================
Conclusion
I like your well-structured rather extensive summary, analysis and take home messages typed as conclusion.
Typing whole sentence in bold amounts to shouting.
Thanks alot for you Prof.Sharma
So nice of you, Dr Wadi
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.
Epidemiology of BK virus
-Primary infection occurs mainly during childhood, and the virus remain dormant in immunocompetent individuals.
– 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: 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 yet 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 like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion. I appreciate your comments on BKV in renal transplantation that transplant nephrectomy is not necessary for retransplantation.
Introduction:
BKV & renal transplantation:
Immunological response of BKV:
Pathogenesis of BKV infection:
Route of transmission:
Clinical manifestation:
BVK & malignancy:
Risk factors of BKVN:
Screening & diagnosis:
Treatment:
Short & long term graft survival:
BKVN with concurrent rejection:
Re-transplantation:
I appreciate your comments on BKV in renal transplantation. However, in the heading ‘Treatment; your have typed that the following possible options: antivirals e.g. leflonumide, cidofovir, mTOR-inhibitors inhibit BKV replication, Quinolone, artesunate, pravastatin, IVIG, rituximab.
I would state that there is no robust evidence supporting using these drugs.
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 immune suppression, 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 not that 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
I like your well-structured detailed summary, analysis and take home messages typed as conclusion.
I appreciate your comments on BKV in renal transplantation. I agree that ‘Evidence is not that robust for using these drugs and some are nephrotoxic: Leflunomide, cidofovir, and Quinolones
Thnxs, prof
So nice of you, Ben
welcom prof
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 protein
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 HSCTrecipients present with hemorrhagic and non-hemorrhagic cystitis
· For HIV infected 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,
-ophthalmological 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 polyomavirus 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 like your well-structured detailed summary, analysis and take home messages typed as conclusion.
I appreciate your comments on BKV in renal transplantation.