BK virus :is a small DNAthat usually affect immune compromised individuals
Diseases caused by BKV:
BKV nephropathy
leucoencephalopathy by JC part
ureteric stenosis (ureteric obstruction)
transmission:
feco oral
airborn transmission
vertical and blood transfusion
Diagnosis:
BK quantitative PCR
DEcoy cells in urine
histopathology and graft biopsy with SV 40 stain
treatment:
No sufficient evidence on spescific and effective antiviral therapy
Lefluonamide,cidofivir ,IVIG may be beneficial
Decrease immunosuppression can give better outcome
Polyomaviruses are small DNA viruses that can infect humans and animals like rabbits, rodents, and birds. BK polyomavirus (BKV) is a highly prevalent forms of polyomaviruses causing infection in immuno – compromised patients.
The BK polyomavirus was isolated in 1971. Since that time no specific treatment option has been available for effective
treatment or prophylaxis.
The current consensus on management of BKV viremia
is to decrease immunosuppression, because infection is related to the degree of immunosuppression rather than the drugs used in immunosuppression. Transmission mechanism
Primary BKV infection occurs in the first decade of life, at 4 to 5 years of age.
The following are possible routes of transmission :
1- airborne transmission
2- feco-oral transmission
3- other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation)
4- blood transfusion and vertical transmission
Clinical Picture of BK virus infection :
90% of the population will become BKV seropositive during their life, it can occur after solid-organ transplant, especially in bone marrow or kidney transplant recipients. In kidney transplant
recipients, reactivation may lead to BKVN causing graft dysfunction and failure through tubulointerstitial nephritis and/or ureteral obstruction. In bone marrow transplant recipients,
BKV can lead to hemorrhagic cystitis.
It is very rare to have BKV reactivation in other immuno –
compromised patients. Definitive diagnosis of BK virus nephropathy :
-This needs a characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which is 100% specific, and pathognomonic. The diagnosis of BKV in a renal biopsy
can be missed in about 30% of cases because BKV has a focal tropism in the medulla rather than in the cortex.
-The confirmation of BKVN diagnosis, need blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed.
Urine examinations may reveal BKV-infected cells.
The most characteristic abnormality of infected cells is an enlarged nucleus with a single, large basophilic intra-nuclear inclusion which called decoy cells.
– Serology test is not helpful for anti-BKV antibodies for a definitive diagnosis of BKV infection because these antibodies can commonly be positive in the general population.
-Viral culture is rarely used as for BKV infection detection outside the research setting because this can take weeks to months; therefore, this method is not clinically applicable.
BK virus is one of the viruses that present since childhood and will be in the dormant phase in the tubule interstitial tissue. Will reactivate once the patient is immunocompromised.
This type of virus causes interstitial nephrites and picture mimic acute rejections
Risk factors and pathogenesis: The risk factors include · Factors related to recipient includes: high immunological risk like (HLA incompatibility, ABO incompatibility, and use of antilymphocyte antibodies) which reflect on degree of immunosuppression, diabetes mellitus, rejection episodes, older age, steroid use cytomegalovirus co-infection. · Factors related donor: seropositive renal donor, viruria in the donor.
Update on the Management of BK Virus Infection Its Narrative review (level of evidence v) published in Experimental and Clinical Transplantation (2020) about management of BK virus infection. Introduction: BK virus is one of polyomavirus which usually primary infection occurs early during childhood and remain latent in the tubuloepithelial cell of kidney but after solid organ transplant and immunosuppression reactivation occurs causing tubulointerstitial nephritis, ureteral stenosis andhemorrhagic cystitis. Management of BK viremia involves reduction of immunosuppression, monitoring of BK virus polymerase chain reaction (PCR), and renal function. Risk factors and pathogenesis: The risk factors include · Factors related to recipient includes: high immunological risk like (HLA incompatibility, ABO incompatibility, and use of antilymphocyte antibodies) which reflect on degree of immunosuppression, diabetes mellitus, rejection episodes, older age, steroid use cytomegalovirus co-infection. · Factors related donor: seropositive renal donor, viruria in the donor. Clinical picture: 1. Asymptomatic 2. slow progressive rise in serum creatinine 3. an unexpected finding of BK virus associated nephropathy on graft biopsy. 4. Laboratory tests include pyuria, recurrent UTI, hematuria, cellular casts, etc. Diagnosis overview: A graft biopsy is definitive for diagnosis, but can be negative due to patchy involvement and showed contain medullary specimen. Quantitative PCR diagnoses BK viremia (sensitivity 100%, specificity 88%) but there is not cutoff can be predict associated with BK nephropathy. Urinary decoy cells: it can be used only for screening but it neither sensitive nor specific (cell with enlarged nucleus and single, large basophilic intranuclear inclusion) Definitive diagnosis requires cytopathic changes on biopsy with positive immunohistochemistry (SV40 large T antigens), and positive BK viremia. BK virus nephropathy has 3 different patterns on histology, and has 3 different grades according to Banff classification. Therapeutic interventions: Immunosuppression reduction is the cornerstone of therapy, but associated with increases risk of rejection. there is no strong evidence in the form of randomized controlled trials support the use of the following agents · Cidofovir and Brincidofovir: not widely used because of nephrotoxicity. · Leflunomide: promising treatment because of its immunosuppression and antiviral effect which can replace MMF. · IVIG (intravenous immunoglobulins), and Fluoroquinolones have been used. Conclusions: BK viremia only 10% post kidney transplant recipients but BK nephropathy around 2-4%. Management involves reduction of immunosuppression.
Human polyomaviruses, which are DNA viruses, include the BK virus; BKV infections result in
Among recipients of renal transplants, tubulointerstitial nephritis and ureteral stenosis are common.On average, there are
10% of people had kidney transplants. The prevalence of BKV infection and the level of immunosuppression are directly correlated, but not the medication itself. Diabetes mellitus, older patients, male patients, delayed graft function, acute rejection episodes, and prior CMV infections are additional risk factors. Asymptomatic to frank nephropathy with distorted renal function and gradually rising blood creatinine levels are among the clinical symptoms of BKV infection. A urine assay may reveal cellular casts, pyuria, and hematuria. BKV-infected decoy cells are visible in urine microscopy.
Renal allograft biopsy with immunohistochemistry that cross-reacts with the BKV, specifically SV40, provides a conclusive diagnosis of BKVN.
Renal allograft biopsy with immunohistochemistry that cross-reacts with the BKV, specifically SV40, provides a conclusive diagnosis of BKVN.
the virus’ large-T antigen component. About one-third of individuals may not develop BK virus nephropathy, hence two core biopsies are required for confirmation, ideally involving the medulla. BKV DNA quantitative PCR is typically used to monitor renal transplant recipients. Viral replication occurs in stages, with viruria occurring around 4 weeks before viremia and nephropathy appearing 12 weeks later. The primary differential diagnosis for BKVN is acute rejection. BKV inclusions and immunohistologic tests could be used to distinguish BK virus nephropathy from other types. Correlating histologic findings with PCR evidence of viremia is also crucial.
Polyomaviruses are small DNA viruses that can infect humans and animals.
BK polyomavirus (BKV) is a prevalent form of polyomavirus that causes infection, particularly in immunocompromised patients.
BKV can lead to various complications in transplant recipients, including tubulointerstitial nephritis and ureteral stenosis in renal transplant recipients, and hemorrhagic cystitis in bone marrow transplant patients.
The management of BKV infection involves reducing immunosuppression, regular monitoring of BKV levels, and renal function assessment to prevent allograft BKV nephropathy and graft failure.
BK virus is commonly found in renal transplant recipients, and institutions have different screening policies, but most tend to reduce immunosuppression to control BKV levels.
BK virus belongs to the family Polyomaviruses and has four genotypic groups.
BKV infection primarily occurs during childhood and can be transmitted through various routes such as respiratory, feco-oral, urinary-oral, blood transfusion, and vertical transmission.
The most significant risk factor for developing BKV disease is the degree of immunosuppression, and various immunosuppressive agents can increase BKV replication.
BKV infection can lead to BK virus nephropathy (BKVN), which manifests as progressive renal damage and elevated serum creatinine levels.
Diagnosis of BKVN involves quantitative PCR to detect BKV viremia and renal biopsy for definitive diagnosis.
The presence of decoy cells in urine analysis and positive immunohistochemistry for BKV or SV40 large T antigens in renal biopsy support the diagnosis of BKVN.
BKVN can be graded into different levels based on fibrosis and viral replication.
BKVN can be differentiated from other viral infections through blood quantitative PCR and characteristic pathological findings.
Monitoring BKV infection involves quantitative PCR analysis of urine and plasma, with viruria preceding viremia.
High levels of BKV DNA in urine are associated with increased risk of viremia and BKVN.
Medical decisions should be made based on repeated BKV DNA measurements and clinical evaluation.
-Evidence level 5 (narrative review) -Risk factors include Diabetes mellitus, delayed graft function, ureteric insult, immunosuppression, CMV infection, elderly individuals and white race. -BKV infection may be asymptomatic or may cause BKVN, hemorrhagic cystitis or ureteric strictures, rarely neurological manifestations and ophthalmic complications. -The mainstay management is IS reduction, antivirals still have no good evidence. -IVIG may have a role especially in BKVN, in the setting of rejection. -Cellular immunotherapy may have future role.
BKV is an infection that affects immunocompromised patients to a large extent. BKV can lead to tubulointerstitial nephritis and ureteral stenosis in kidney transplant patients and also hemorrhagic cystitis in bone marrow transplant patients.
BKV is a double stranded DNA virus and is a member of the polyomavirus family. Transmission routes include the following :
Airborne through air droplets
feco-oral route
urinary oral route
seroconversion after solid organ transplant
blood transfusion
vertical transmission
Primary infection can occur during childhood, but is insignificant in most cases. The virus remains in the renal epithelium. In immunocompromised population, BKV replication results in asymptomatic bacteriuria.
Risk factors include the following :
Degree of immunosuppression rather than the type of immunosuppressive drug – intensive IS regimen can increase risk of BKV infection in the patient.
BKV can occur with any IS protocol, but it is seen more with tacrolimus and MMF based regimen.
Transmission of infection from the donor
Diabetes mellitus
delayed graft function
treated episodes of acute rejection
ureteral trauma
use of anti lymphocyte anitbodies
coinfection with CMV
maintenance steroid IS
older age of recipient
white race
HLA C loci
Clinical features include possible asymptomatic patient, slow increase in creatinine, progressive renal damage which is nephropathy.
Tissue biopsy is needed for diagnosis, with features such as basophilic intranuclear viral inclusions without a surrounding halo, anisonucleosis, hyper hero Asia, and chromatin clumping of infected cells.
Differential diagnosis include other viral infections such as CMV, HSV, and adenovirus,
Level of evidence
The given article is a narrative review, and thus level of evidence 5.
Introduction:
Polyomaviruses are small DNA viruses that can infect humans and animals like rabbits, rodents, and birds. Virology Properties:
BK virus is a member of the family Polyomaviruses. This family is a double-stranded DNA virus with icosahedral symmetry. BK virus has been categorized serologically and genotypically into 4 groups. Genome structure and transcription:
Polyomaviruses are small (40-50 nm in diameter), uncovered, icosahedral, with a double circular chain.
The external layer consists of structural proteins VP1, VP2, and VP3. VP1 is organized into 72 each one associated with a unique copy of smaller structure proteins (VP2 or VP3)
VP1 determines receptor specificity, whereas VP2 and VP3 are involved in viral particle stabilization.
The genomic structure encodes 6 chief proteins divided into 3 regions: early encoding region, late encoding region, and noncoding control region. Transmission mechanism:
First decade of life, on average at 4 to 5 years of age. Possible routes include the following:
(1) Airborne transmission. (2) Feco-oral transmission. (3) Urinary-oral route or seroconversion after solid-organ transplant. (4) Blood transfusion and vertical transmission.
Primary infection is asymptomatic, the virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule.
Patients with impaired cell-mediated immunity have a particularly greater risk of BKV.
Prevalence of BKVN in renal transplant recipients is 5%..
Risk factors and pathogenesis:
Degree of immunosuppression.
Tacrolimus specifically can increase BKV replication by a specific mechanism involving FK-binding protein (BP-12).
Diabetes mellitus.
Delayed graft function,
Treated episodes of acute rejection,
Ureteral trauma
Use of antilymphocyte antibodies.
Coinfection with CMV.
Maintenance steroid immunosuppression,
Older age, white race/ethnicity,
Presence of specific human leukocyte antigen (HLA) C loci.
Presence of BKV antibody titers and viruria in a potential donors.
Both HLA and ABO-incompatible transplants.
Clinical Picture of BK virus infection:
About 90% of the population will become BKV seropositive during their life; this reactivates after solid-organ transplant.
Usually 10 to 13 months post-transplant.
But may be as early as on week or late up to 5years.
(1) Asymptomatic.
(2) Slow and progressive increase of serum creatinine.
(3) An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
(4) Especially in bone marrow presents as hemorrhagic cystitis.
Laboratory findings:
(1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria.
Diagnosis Overview:
A tissue (renal) biopsy.
PCR.
decoy cells in the urine analysis increases the suspicion of BKV nephritis.
Definitive diagnosis OF BK virus nephropathy :
characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection.
presumptive diagnosis :
if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction.
In BKVN, light microscopy :
(1) viral inclusions (2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells (3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates (4) tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining; and (5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
Electron microscopy:
(1) Viral inclusions (2) tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
Banff grading of BKV:
Grade Percent Fibrosis and Viral Replication
Grade 1 Minimal viral replication in < 1% of biopsy with < 25% fibrosis
Grade 2 Any between grades 1 and 3 Grade
Grade 3 Marked virus replication in > 10% of cores with > 25% fibrosis.
Differential diagnosis:
CMV.
Herpes simplex virus.
Adenovirus.
Therefore, to confirm a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed.
Urine cytology findings for BK virus infections:
Viral replication in the urine is demonstrated by either decoy cells or BKV urine quantitative PCR.
Decoy cells are suggestive but not specific, sensitive, or definitive for BKV infection because
(1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus)
(2) Decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients.
Note, their absence does not exclude the disease.
Quantitative polymerase chain reaction:
Sustained high viral DNA levels in the plasma of renal transplant recipients who have an appropriate clinical picture can suggest BKVN.
Renal transplant recipients can be monitored with quantitative or real-time PCR for BKV infections in either the plasma or urine.
Patients with a higher viruria level are highly prone to developing BKV viremia, and patients with high sustained viremia are susceptible to BKVN.
Medical decisions, should be made on the basis of trends in quantitative DNA levels rather than on a single measurement.
Urine electron microscopy:
Polyomavirus aggregates, which are called Haufen, Haufen presence was shown to be associated with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients.
Therapeutic interventions:
Currently, there are no available antiviral medications against BKV.
Usual approach in the management of BKV viremia or BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR.
Immunosuppression reduction:
Pros: Help In viral clearance.
Cons: Risk of rejection.
Cidofovir:
Pros: Help in viral clearance.
Cons: Nephrotoxicity.
Brincidofovir
Pros: shown a lower incidence of nephrotoxicity.
Leflunomide
Pros: decrease in BKV viral load.
Cons: thrombotic microangiopathy, hepatitis, and bone marrow suppression.
Intravenous immunoglobulin:
Pros: anti-BKV immunity; the immunomodulatory.
Fluoroquinolone:
No significant role.
Role of cellular immunotherapy in the management of BKV infection.
Possible role in the future by using adoptive T-cell therapy approach.
Conclusions:
Member of human polyomaviruses, which are DNA viruses;
BKV infections lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplant population. The average incidence is about 10% of the renal transplant population.
There is a direct correlation between the incidence of BKV infection and the degree of
INTRODUCTION:
BK polyomavirus is a small DNA virus that establishes lifelong infection in the renal tubular and uroepithelial cells of most of the world’s population. In the majority, infection is quiescent and benign. but, in immunocompromised patients, it can reactivate, and in some, lead to BK polyomavirus-associated nephropathy Among kidney transplant recipients, its reactivation is common. which is frequently subclinical, although it may manifest with acute kidney injury (AKI), and is a risk factor for premature allograft loss. Route of transmission:
Primary infection is acquired during childhood, possibly via fecal-oral orrespiratory transmission after primary infection, the virus establishes lifelong infection in renal tubular and uroepithelial cells. For most individuals, both primary infection and persistent infection are clinically silent and not associated with any known adverse effects. Risk factors for replication:
· strong immunosuppression,
· elderly
· male recipients,
· prior rejection episodes,
· HLA mismatching,
· prolonged ischemia time,
· pretransplant BK virus serostatus
· Ureter stenting. Diagnosis:
Clinically and laboratory Clinical features:
BKV infection occurs 10 to 13 months posttransplant.
BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
The clinical picture can be: 1) Asymptomatic, 2) Slow and progressive increase of serum creatinine, 3) An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy. Importantly, no signs and symptoms are identified with BKV infection. Laboratory:
1) Renal biopsy: definite diagnosis
2) PCR has 100% sensitivity and 88 % specificity.
3) Urinalysis – cytology= Decoy cells – Good screen test.
EM shows presence of cast-like, three-dimensional polyomavirus aggregates, termed Haufen Treatment: 1) Reduction of Immunosuppression. 2) Cidofovir; but it is nephrotoxic. 3) IVIG 4) Fluoroquinolone: In vitro has ability to inhibit replication of BKV or SV40 polyomavirus replication. 5) cellular immunotherapy with limited data. LEVEL OF EVIDENCE IS 5
BK polyomavirus (BKPyV) is a small DNA virus that establishes lifelong infection in the renal tubular and uroepithelial cells of most of the world’s population. For the majority, infection is quiescent and benign. However, in immunocompromised patients, BKPyV can reactivate, and in some, lead to BKPyV-associated nephropathy (BKPyVAN).Among kidney transplant recipients, BKPyV reactivation is common. Reactivation is frequently subclinical, although it may manifest with acute kidney injury (AKI), and is a risk factor for premature allograft loss.
Transmission mechanism-
BK polyomavirus (BKPyV) is a ubiquitous virus with a worldwide seroprevalence of approximately 80 to 90 percent Primary infection is typically acquired during childhood, possibly via fecal-oral or respiratory transmission . Following primary infection, the virus establishes lifelong infection in renal tubular and uroepithelial cells. For most individuals, both primary infection and persistent infection are clinically silent and not associated with any known adverse effects.
Risk factors for viral replication –
The intensity of immunosuppression (particularly suppression of cellular immunity) appears to be a dominant risk factor for BKPyV replication and disease. Consistent with this, replication rates are higher in the early posttransplant period and following treatment for allograft rejection when immunosuppression intensity is highest.
No specific immunosuppressive drug or regimen has been definitively associated with clinically significant BKPyV infection. Several studies have suggested that certain drugs (particularly tacrolimus) may be associated with an increased relative risk Other important risk factors include high risk serostatus (ie, kidney transplant from a BKPyV-.seropositive donor to a seronegative recipient) impaired immune response to BKPyV and donor BKPyV viruria prior to transplant. The last two factors suggest that the donor is an important source of transmission .
Other risk factors associated with an increased risk of BKPyVAN or disease severity include older age, ureteral stent placement, ABO incompatibility ], rejection or ischemia of the transplanted kidney , delayed graft function HLA mismatch specific HLA-C alleles , BKPyV polymorphisms , and transplantation from an HCV-positive donor . In kidney transplant recipients,
Clinical Picture of BK virus infection-
BK polyomavirus (BKPyV) replication typically develops in stages: viruria followed by viremia and then, if viral replication persists, nephropathy can ensue. Asymptomatic viruria, viremia, and/or a slow progressive rise in serum creatinine are typically the only indicators of BKPyVAN. The incidence of BKPyVAN is highest in the first two to six months posttransplant. While the majority of cases occur in the first posttransplant year, BKPyVAN can occur years after transplantation. . Without resolution of infection, progressive kidney allograft dysfunction and graft loss can ensue over a period of months . Within the allograft, early infection triggers interstitial inflammation, which then progresses to fibrosis and tubular injury. Accordingly, urinalysis may reveal pyuria, hematuria, and/or cellular casts consisting of renal tubular cells and inflammatory cells, or may be normal.
Other manifestation-ureteral stenosis and In bone marrow transplant recipients, BKV can lead to hemorrhagic cystitis
SCREENING AND DIAGNOSIS-
Posttransplant screening — Screening and preemptive reduction in immunosuppression for patients with clinically significant BKPyV viremia prevent progression to BKPyVAN in the majority of patients. Screening should be done with Plasma PCR Monthly for the first six months following transplant, then every three months until two years posttransplant, and then annually until five years posttransplan and Whenever kidney allograft dysfunction occurs or when an allograft biopsy is performed for allograft dysfunction.
Diagnosis–
Kidney allograft biopsy is the gold standard for diagnosing BKPyVAN, assessing its severity, and evaluating for concomitant processes. However, because biopsy is invasive and sampling error can occur, a presumptive diagnosis is often made based upon the presence of significant viremia (plasma BKPyV viral load ≥10,000 copies/mL).
A definitive diagnosis of BKPyVAN requires the following findings on kidney biopsy
Characteristic cytopathic changes.
plus
Positive immunohistochemistry tests using antibodies directed specifically against BKPyV or against the cross-reacting SV40 large T antigen.
In BKVN, light microscopy examinations would show the following:
(1) basophilic intranuclear viral inclusions without a surrounding halo ; (2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells; (3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates (4)tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial liningand (5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium
Urine cytology in BK virus nephropathy-
Cytologic examination of the urine, which may reveal BKPyV-infected cells, Decoy cells,is infrequently used to screen for BKPyVAN. Although the presence of characteristic cytopathologic changes in infected cells (which have been called decoy cells due to their resemblance to renal carcinoma cells) is strongly suggestive of BKPyV infection .Cytological urine abnormalities (decoy cells) are suggestive but not specific, sensitive, or definitive for BKV infection because (1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus and (2) decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients..Of note, their absence does not exclude the disease
Urine electron microscopy–
Negative-staining electron microscopy of the urine of patients with BKPyVAN often reveals the presence of cast-like, three-dimensional polyomavirus aggregates, termed Haufen .Haufen form in injured tubules with BKPyV replication and a high intratubular uromodulin concentration and are excreted into the urine similar to other urinary casts. In one cohort study of >300 kidney transplant recipients, the detection of Haufen in voided urine had a sensitivity, specificity, negative predictive value, and positive predictive value for biopsy-proven BKPyVAN of greater than 95 percent , suggesting that this may be a noninvasive way to diagnose BKPyVAN. However, the urinary Haufen test requires electron microscopy.
TREATMENT-
Since there are no specific antiviral therapies for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN), the cornerstone of management is to decrease immunosuppressive medications .Several agents have been shown to have in vitro anti-BKPyV activity. However, we do not routinely use any of these agents for the treatment of BKPyV infection, given that the efficacy of these agents has not been established and use of these therapies has not been clearly shown to be superior to reduction in immunosuppression alone
Abstract
– The BK polyomavirus was isolated in 1971;
– It is risk factor for both graft lose in renal transplant recipients.
– no specific treatment or prophylaxis available .
– Ais precipitated by varisble risk factors
o heavy immunosuppression
o elderly recipients,
o prior rejection episodes,
o male sex,
o human leukocyte antigen mismatching,
o prolonged cold ischemia time,
o pretransplant BK virus serostatus,
o ureteral stenting.
Regular follow-up for BK virus infections is effective in early detection and preventing allograft loss.
The mainstay of management is reduction of immunosuppression. But cellular immunotherapy may be anew option
Introduction
BK Virus has been a significant risk factor for graft lose .
Risk factors –
· strong immunosuppression,
· elderly
· male recipients,
· prior rejection episodes,
· HLA mismatching,
· prolonged ischemia time,
· pretransplant BK virus serostatus
· Ureter stenting.
No effective and specific treatment and prophylaxis available . cellular immunotherapy may be anew treatment option.
virology
Properties
BK virus is a Polyomaviruses.ds-DNA virus. Has four types (I toIV), with each one having a different virulence.
Historical aspects
Discovered In 1971, a Sudanese renal transplant patient presented with ureteralobstruction after renal transplant.
Transmission mechanism:
Possible routes include the following:
(1) airborne transmission through air droplets
(2) a feco-oral transmission, as fecally eliminated polyomaviruses are detected in hospitalized children; (3) other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation)
(4) both through blood transfusion and vertical transmission.
Risk factors and pathogenesis:
1- degree of immunosuppression is important risk factor.
2- It is a marker of heavy immunosuppression.
3- immunosup – pressive agents can affect T cells, which can lead to increased BKV replication.
4- Tacrolimus specifically can increase BKV replication by a specific mechanism involving FK-binding protein .
5- Other risk factors include
a. diabetes mellitus,
b. delayed graft function,
c. treated episodes of acute rejection,
d. ureteral trauma,
e. use of antilymphocyte antibodies,
f. Coinfection with Cytomegalovirus (CMV),
g. maintenance steroid immunosuppression,
h. older age,
i. white race/ethnicity,
j. and presence of specific human leukocyte antigen (HLA) C loci.
k. presence of BKV antibody titers in donors, which reflects recent BKV reactivation and replication .
The viruria in a potential donor can be considered as a predictor for posttransplant BKV infection.
Recent studies have demonstrated that BKV replication in a transplant recipient is usually due to transmitted infection from the donor.
Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy, possibly due to heavy immunosuppression (whether due to induction or maintenance immunosuppression or episodes of rejection).
, ABOincompatible recipients are at a higher risk of BKVN than HLA-mismatched recipients as they may have a higher rate of rejection and need more immuno – suppression than HLA-incompatible patients.
Clinical Picture of BK virus infection:
About 90% of the population will become BKV seropositive during their life; this reactivates with immune suppression.
reactivation may lead to BKVN, by causing tubulointerstitial nephritis and/or ureteral
obstruction.
In bone marrow transplant recipients, BKV can lead to hemorrhagic cystitis.
rare to reactivate in other immuno –
compromised patients, such as AIDS , SLE other autoimmune diseases . Clinical manifestations are as follows:
(1) asymptomatic,
(2) slow and progressive increase of serum creatinine,
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Importantly, no signs and symptoms are identified with BKV infection.
BKV infection occurs 10 to 13 months posttransplant.
BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant. Laboratory findings in patients with BKV infection are as follows:
(1) elevated serum creatinine
(2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
DIAGNOSIS:
-Definitive dx need renal biopsy, but it is present in the medulla which is easily missed on biopsy.
-BK PCR has 100% sensitivity and 88 % specificity .
-Urinalysis – Decoy cells – Good screen test . BKV PCR can used .
– viremia follows viruia by 4 weeks.
-Definitive dx ; Cytopathic changes + +VE SV40 antigen- 100%Specificity .
-Presumptive diagnosis – Continuous viruria (>2 weeks) + BK PCR > 10000 Copies/ml
-Anti BKV antibodies are not sensitive for diagnosis .
-Highest risk of infection in D+/R- transplantation.
-Viral cultures usually not indicated.
–Haufen presence ( by EM) has 100% sensitivity and 99% specificity in detecting biopsy proven BKVN post KTR.
ifferential diagnosis
Other types of viral infections:
CMV, herpes simplex virus and adenovirus.
Treatment:
1. manipulation of Immunosuppression .
2. Cidofovir; but it is nephrotoxic.
3. Brincidofovir (CMX001) is a prodrug of cidofovir that is administered orally and non ephrotoxicity.
4. IVIG.
5. Fluoroquinolone: In vitro has ability to inhibit replication of BKV or SV40 polyomavirus replication.
6. cellular immunotherapy . data is limited.
Reduction in immunosuppression 25 to50% in CNI and 50% in alkylating agents, if not responding can reduce more with up-to 75% with reduction in steroid dose.
other option adjuvant treatment with CIDOFOVIR, IVIG, LEFLONAMIDE, and QUINOLONES.
However, no conclusive evidence available.
Introduction BK Virus has been a significant risk factor for graft dysfunction and failure in renal transplant recipients.
This review addresses diagnosis, screening, new diagnostic tools, and updated management of BK virus infections. Virology It is a ds-DNA virus, a member of the family Polyomaviruses, and has genotype (I to IV) with different virulence.
-Primary BKV infection occurs early in life during childhood and often clinically insignificant. -Latent infection: followed the 1ry infection) the virus stays in the renal epithelium and becomes dormant until it is reactivated – BKV replication in immunocompetent population; asymptomatic viruria, ( viral shedding 20%) – immunocompromised individuals, shedding reaches 60% and the viruria is more common.
Risk factors & pathogenesis
– Degree of immunosuppression (most important)
– Others
* DM
* Delayed graft function
* Treated episodes of acute rejection
* Ureteral trauma
* Use of antilymphocyte antibody
* Coinfection with CMV
* Older age
Clinical picture
– Asymptomatic
– Slow & progressive increase in creatinine
– On allograft biopsy progressive renal damage
Currently, there are no available antiviral medications against BKV.
– Approach in the management of BKV viremia or BKVN in renal transplant recipients is reduction of IS and continuous monitoring of BKV viremia level via PCR.
– Immunosuppression reduction; cornerstone, carries a higher risk of rejection.
Other agents used with reducing IS:
– Cidofovir; No RCT, associated with nephrotoxicity
– Brincidofovir; prodrug, less nephrotoxic, successful outcomes in renal and HSCT.
– Leflunomide; IS and antiviral properties.
– Intravenous immunoglobulin; neutralizing antibodies, used as adjunctive therapy, immunomodulatory
effects may guard against allograft rejection in the context of reducing IS.
– Fluoroquinolone; inhibit replication of BKV or SV40.
– Adoptive cellular immunotherapy; may carry potential hope
What is the level of evidence provided by this article?
BKV NEPHROPATHY IN KIDNEY TRANSPLANTS;A STATE OF THE ART REVIEW:
INTRODUCTION:
-Good post transplant outcomes from adequate immunosuppression has led to increased BKVAN with viremia being seen in up to 30% post transplant.
-We are yet to get adequate tx for BK infection.
HX OF BK VIRUS:
-Discovered in 1971 in pt with ureteral stricture post transplant.1st BKVAN proven biopsy seen in 1993.
-Initially had graft loss of 50-100%,this has decreased to < 15% in last two decades.
VIROLOGY:
-BK is a non enveloped ,icosahedral shaped double stranded DNA virus.
-Gene has an early, non coding and late region. Early has T and t antigens with the former binding to p53 and protein RB while the later codes for VP1.VP2 and VP3 viral caspid proteins.
EPIDEMIOLOGY:
-Prevalence of 90% in general population by 4 yrs.
-Stages of infection ; Viruria,viremia and nephropathy.
-After viruria,50% KTR will have viremia in 2-/ time.
-Transmission routes ; Oral, GIT and resp tract.
-Plasma VL>4 log 10 are associated with more risk of BKVAN.
RISK FACTORS:
-These include ;
Immunosuppressive meds- More incidences immediately post transplant,Tac > CYC,MTOR >CNI
Recipient xtics -Old age,DM,HLA C alleles.
Donor ; recipient interphase – D+/R+ pair, ABO incompatibility, DGF,HLA Mismatch ,Rejection or ischemia of graft, ureteral stent.
CELLULAR IMMUNE RESPONSE AND PATHOGENESIS:
-T cell mediated immunity ;CD4 and CD8 cells key in clearing BK infection. Increased interferon gamma is a good pointer yo BK specific cellular response.
-Post childhood infection, BK maintains latency in renal epithelium, prostate, testes, seminiferous tubules, cervix, vulva and lymphoid tissues ,with reduced immunity, the infection flares up and pt becomes symptomatic.
CLINICAL MANIFESTATION:
-Stepwise ; Viruria, viremia then nephropathy. Viruria occurs in up to 50% in 1st 1 yr post transplant.
-Viremia is a better marker of those at risk of BKVAN. Viremia may present as increase in creatinine +/- urinary anomalies.
-Others; Ureteral stenosis, hemorrhagic cystitis.
-Rare ; GU malignancies.
SCREENING AND DIAGNOSIS:
-BK viremia screening is the preferred modality.
Urine BK PCR – not sensitive for screeening,if +VE,confirm with plasma PCR.
Plasma BK PCR – varied genotypes may give different results. Sensitive as a screening tool, monitoring treatment and also to determine those at risk of BKVAN. High VL associated with more risk of nephropathy.
Urine cytology – Decoy cells ar a marker of polyomavirus replication but do nit necessarily indicate nephropathy. Has low PPV and high NPV. Haufen cells have both high PPV and NPV.
Donor derived cell free DNA – The higher the dd-cfDNA, the higher the VL and risk of nephropathy, Can assess progression of BKV to nephropathy.
Graft biopsy -Gold standard to dx BKVAN. biopsy core should have medulla to decrease false negative. Can be missed in up to 30%,Features ; cytopathic changes and +VE IHC- SV40 staining.
Histology -x2 biopsy cores with cortex + medulla recommended to increase diagnostic yield. All histology should be stained for SV40 where features of nephropathy are absent.C4d staining is more sensitive for acute rejection than nephropathy.
Presumptive dx ;VL > 10000 Copies/ml.
TREATMENT:
RIS is mainstay of treatment.
Decrease antimetabolite by 50% and maintain CNI + Steroid dose while monitoring graft function and BK PCR every fortnight.
Stop antimetabolite if no change in VL.
Decrease CNI and aim for 4-6ng/ml for Tac AND 50-100ng/l for CYC if no change in VL despite stopping the antimetabolite.
2.Other therapies;
IVIG – Has BK neutralizing antibodies and can be used if no change with RIS.
Quinolones – No efficacy seen post transplant despite having antiviral properties.
Cidofovir – Has high nephrotoxicity SE with little efficacy being reported from studies. Also associated with proteinuria and proximal tubular dysfunction.
Leflunomide -No outright benefit in BK infected pts when compared to RIS.
3.Future therapeutic trials.
Human IgG1
Adoptive transferred posoleuccel
KIDNEY RE-TRANSPLANTATION:
-Successful post graft dysfunction from BKVAN.
-Graft/Native nephrectomy not recommended.
-Careful dosing of immunosuppression to avert rejection to be adhered to.
-Graft survival post transplant 98% and 94% at 1 yr and 3 yrs respectively.
· BKV infection is associated with graft dysfunction and loss.
· It is named after the initials of Sudanese patient with ureteric stenosis with discovered viral particle in the epithelial lining.
· Mode of transmission:
feco-oral, respiratory, transplacental and organ transplantation
· Primary infection in childhood usually asymptomatic viuria , while the virus remains dormant in uroepithelial cells then become activated in immunocompromised patients (as renal transplant recipients) with increasing viruria up to 60%..
· Risk factors for infection:
high immunological risk, increased HLA mismatch, ABO and HLA incompatible transplantation, strong induction as ATG, TAC and MMF containing IS therapy, repeated treatment of rejection episodes, so the most important is the net immunosuppression state, D+/R- serological status prior to transplantation, old age and diabetes in the recipient, DGF and prolonged cold ischemia time.
· No specific antiviral to be used in prophylaxis or ttt of BKV cases.
· BKN clinical manifestations in kidney transplantation:
o Interstitial nephritis and ureteral stenosis commonly occur at 10-13 months post-transplant.
o Rising creatinine, hematuria and pyuria and cellular casts.
o Definitive BKN is diagnosed by allograft biopsy which has interstitial nephritis that turn chronic and cause allograft dysfunction and loss.
o Biopsy may be false -ve (patchy affection and mainly in medulla), so 2 core biopsies are needed including renal medulla.
o Biopsy shows 3 patterns (A, B, C) with early cytopathic changes then acute interstitial nephritis then chronic tubulointerstitial nephritis.
o Special staining fir IHC (SV 40) simian virus 40, stains large T antigen present in polyoma virus, is diagnostic for polyoma virus (SV, BK and JC). Specificity is 100 % and sensitivity is 77.7 %
o Blood BKV PCR indicates viremia whether has BKN or not,
o BKV PCR can be done in urine sample.
o Decoy cells (cells with large inclusion bodies replacing the normal chromatid) in urine increases suspicion of BKN. But definitive diagnosis is biopsy.
o Decoy cells=infected tubular and urothelial cells (only epithelial) with large basophilic nucleus (looks like high grade urothelial atypia),
o DD from owl eye appearance of CMV inclusion bodies (that is surrounded by complete halo around it )
o Decoy cells in urine (infected urothelial cells), with :
§ Sensitivity 100 % of BKN.
§ Specificity 84%.
§ NPV is 100%.
§ PPV is 6%.
o Presumptive BKN means sustained (>2 weeks) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction
o Hemorrhagic cystitis occurs in bone marrow transplantation.
· BKN Differential diagnosis:
o Other viral infections as CMV and adenovirus.
o Acute rejection (DD by presence of viral inclusion bodies, and positive PCR (viremia))
· The main line of ttt is reduction of immunosuppressive therapy, but the problem is increasing risk of rejection and graft loss (so achieving the balance between both conditions is difficult.
· Reduction of MMF dose by 50 %, reduction of CNI by 25-50 % is started, then FU PCR if not decreasing stop MMF.
· Still not proved, to shift from tacrolimus to cyclosporin or to shift from MMF to mTORi.
· Adoptive specific T cell immunotherapy may be future therapy for refractory cases.
· Follow up PCR every 2 weeks and FU graft function every week.
· NO RCT to demonstrate specific therapy, but additional use of cidofovir, leflunamide, quinolones and IVIG in refractory cases (not decrease in viral load with reduction of IS).
1. Summary of the article: Introduction BK Virus has been a significant risk factor for graft dysfunction and failure in renal transplant recipients. Risk factors – strong immunosuppression, elderly male recipients, prior rejection episodes, HLA mismatching, prolonged ischemia time, pretransplant BK virus serostatus and Ureter stenting. No effective and specific treatment as such – main stay of treatment is immunosuppression reduction; cellular immunotherapy provides new insight. This review addresses diagnosis, screening, new diagnostic tools, and updated management of BK virus infections. Virology Polyomavirus family – small double-stranded DNA virus 4 genotypes with different virulence – Type 1 most prevalent 80%, type IV 15% Transmission (1) airborne transmission (droplet) (2) feco-oral transmission – community (3) urinary-oral route (children to care giver) or seroconversion post-transplant (4) blood transfusion and vertical transmission (mother à foetus) pathogenesis
· Viral inoculation in childhood (respiratory / oral routes) – asymptomatic
· Primary viremia à dissemination through blood to different tissues
· Virus stays latent in kidney, urothelial lining
· BKV replication and urinary shedding – asymptomatic viruria – 20% in immunocompetent hosts,
· Reactivation and increased Viral replication in immunocompromised and transplant patients – secondary viremia, urinary shedding (viruria 60%)
· Patients with impaired cell-mediated immunity have a particularly greater risk of BKV Nephropathy (mean prevalence 5%) and ureter stenosis (rare). Risk factors
The most important risk factor is intense immunosuppression especially Tac + MMF
Other risk factors – diabetes, prolonged cold ischemia, DGF, treated Acute Rejection episodes, use of ATG, CMV- coinfection, high dose steroid, ABO-incompatible and HLA-mismatched transplant, high BKV antibody in donor (recent transmission from donor), older age, white race/ethnicity and presence of specific HLA-C loci, ureteral trauma (stenting).
Clinical Picture of BK virus infection
may present with asymptomatic viruria
slow and progressive renal dysfunction (rising Creatinine)
progressive renal damage (BKVN) with or without symptoms – detected on surveillance renal allograft biopsy
Progressive BKVN, tubulointerstitial nephritis and ureteral obstruction may lead to renal allograft failure.
Decoy cells in urinalysis increases suspicion, but not specific of BKVN
Quantitative PCR in blood (preferable to urine) – detect viremia and active proliferation
· A presumptive diagnosis can be made with sustained viruria (>2weeks) and significant viremia (plasma DNA PCR load > 10,000 copies/mL) with or without kidney dysfunction
Renal biopsy is definitive diagnostic test for BKVN
– Characteristic cytopathic changes* (large intranuclear inclusion) + positive IHC against BKV or SV40 large T antigens is pathognomonic of BKV infection with 100% specificity. – Medullary tropism – viropathic lesions may be missed
2 cores including medullary tissue can increase detection
*Light microscopy (Cytopathic changes):
anisonucleosis, hyperchromasia, and chromatin clumping of infected cells with basophilic intranuclear viral inclusions without surrounding halo.
interstitial infiltration of mononuclear or polymorphonuclear cells
tubulitis – lymphocyte invasion in basement membrane of tubular epithelium
Urine electron microscopy (with negative staining) shows – – Cast-like 3-D polyomavirus aggregates, called “Haufen” non-invasive method for BKVN diagnosis in renal transplant recipients – differentiates between BKVN and asymptomatic BKV infection Management:
Currently, there are no effective antiviral medications against BKV available.
· Few controlled studies available on management of BKV infection in renal transplant recipients.
Reduction of immunosuppression is mainstay of treatment with regular monitoring of BKV viremia levels using quantitative PCR
Various Medications used successfully in case series / case reports Cidofovir and Brincidofovir along with IS reduction
few single-center studies and case series have described the benefits
no RCT to support efficacy
Leflunomide – immunosuppressant + antiviral properties o replacing MMF, have shown control of BKV in in few case-series Intravenous immunoglobulin (IVIg) o contains neutralizing antibodies against BKV – good choice in the management of BKVN o used as adjunctive therapy for BKVN in multiple case reports and case series, but no RCT o may also guard against allograft rejection Adoptive T cell transfer –
· BKV reactivation occurs due to failure of BKV-reactive T cells to control viral replication. Transfer of primed BKV-reactive T cells can help in controlling the BKV-associated disease.
· CMV- or EBV- or BKV-specific T cells are produced by various techniques using immunodominant epitopes / peptides /overlapping peptide, using MHC-multimers or interferon-capture technology or in-vitro expansion of T cells. · Adoptive T- cells were used successfully in HSCT patients for prophylaxis as well as treatment of resistant viral infections. o Few participants had active BKV infection, which improved after adoptive T-cell transfer. CONCLUSIONS: · BKV infection in SOT recipients flares up due to heavy immunosuppression (Tac + MMF + high steroid), manifests from asymptomatic to frank nephropathy, with progressive renal dysfunction and graft failure.
· Abnormal Urinalysis with Decoy cells indicates shedding of BKV, and suggests for Quantitative PCR in blood.
v Definitive diagnosis of BKVN is made by renal allograft biopsy with IHC with SV40 large-T antigen.
– BKVN could be missed in 30% patients – 2 core biopsies preferably including the medulla are needed for confirmation.
– Acute rejection is the main differential diagnosis of BKVN, which also gets precipitated after IS reduction.
Ø There are no effective antiviral medications for BKV infections. Concomitant administration of various agents with IS reduction has been reported in only uncontrolled case series or retrospective observational studies – lack firm conclusions on their therapeutic efficacy.
Ø The common approach for BKV infection management is active screening (quarterly for 2 years post-transplant) – by serum and urine quantitative PCR for BKV DNA.
o Viral replication goes in stages – viruria preceding viremia by about 4 weeks and nephropathy by 12 weeks.
o With any level of rising BKV viremia – IS reduction and then continuous monitoring viral load (quantitative PCR in blood) and RFT should be performed.
Ø Newer treatment, including cellular immunotherapy, may carry potential hope. 2. Level of evidence: Level V (Narrative review)
1. Please summarise this article; BK virus belongs to a family of polyomavirus family, small double-stranded DNA virus, categorized into four groups with different virulence. It has been a significant risk factor for both graft dysfunction and failure in allograft. It was observe that the strong immunosuppression has been the risk factor for BKV infection and reactivation. Other risk factor are BKV serostatus, AMR, elderly recipient, male gender, and prolong cold ischemia time. It is no such effective and specific treatment, although, the main stay of treatment is immunosuppression modification, other newer options are cellular immunotherapy. Transmission; . Primery infection–à first decade. . Possible routes-à droplets (airborne), feco-oral, urinary-oral rout, blood born, during renal transmission, trans-placental. . Remain dormant state in EPITHELIAL cells of tubular, parietal, transitional structure, and bowman’s capsules. The incidence of shedding in immunocompetent patient is around 20%. The incidence of shedding of viruria in immunocompromissed recipient is around 60%. In pregnant women the shedding disappear two weeks after delivery. The prevalence of BKVN in renal transplant recipient is 5%. Risk factors and pathogenesis; There is increased risk of 1. Degree of immunosuppression, ( Tacrolimus has associated with increased replication by involving FK-binding protein( BP-12). 2. Diabetes mellitus, DGF, AMR episodes, older age. 3. Co-infection with CMV. 4. White race and specific HLA C locus. 5. Donor seropositivity, antibodies. 6. ABO miss-match. Clinical Picture of BK virus infection;
The prevalence of infection is around 90% in first decade of life, however, there is risk of reactivation in immonocompromissed patients.
They can present with hemorrhagic cystitis in bone marrow recipients,
BKVN in renal transplant.
Usually BKV infection occurs in first year post-transplantation, but could be as soon as first week and as late after 5 years.
Diagnosis;
For definitive diagnosis needs biopsy histopathological evaluation.
Steps are,
1. Primery infection present with no or mild symptoms.
2. Latent infection asymptomatic inactive infection and virus infection is detected with molecular technique.
3. Serologic evidence of infection à almost all healthy children and 60-90% of adults.
4. Viral activation à viruria, decoy cells detection,
5. Viral disease à histological evidence of viral replication and associated with clinical symptoms.
However, can miss the diagnosis because the BKV tropism focally in medulla not in cortex.
But can do diagnosis if persistent viruria and PCR copies >10000/ml.
Its difficult to differentiate between rejection and BKVN, except IF, and to differentiat between other viral infection need PCR showing >60-100 copies+ histological result. Viral culture; Not applicable, Urinalysis; using negative staining electron microscopy show cast like 3-dimentional polyomavirus aggregates Haufen with sensitivity of 100% and specificity of 99%. Treatment; There is such randomized control trails and guidelines in management of BKVN, however, the Immunosuppression reduction up-to 30 to 50% is the main stay of treatment. No specific antiviral medication, however, Cidofovir, prodrug of cidofovir the Brincidofovir, leflonemaide, quinolones in addition to IS modification can have additive effects 2. What is the level of evidence provided by this article; Level V
BK virus is a member of the family Polyomaviruses.
This family is a double-stranded DNA virus with icosahedral symmetry.
Transmission:
(1) airborne transmission
(2) a feco-oral transmission
(3) urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation
(4) both through blood transfusion and vertical transmission;
Primary infections are often clinically insignificant, but the virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule
In the immunocompetent population, BKV replication is manifested by asymptomatic viruria, and the incidence of shedding is 20%.
However, in immunocompromised individuals, the risk of shedding reaches 60% and the viruria is more common
The mean prevalence of BKVN in renal transplant recipients is 5%, whereas the prevalence of ureteral stenosis is less
Risk factors and pathogenesis
The most important risk factor for developing BKV disease is the degree of immunosuppression, most commonly tacrolimus and mycophenolate mofetil.
Tacrolimus specifically can increase BKV replication by a specific mechanism involving FK-binding protein (BP-12)
Other risk factors – diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci.
Clinical Picture of BK virus infection
In kidney transplant recipients, reactivation may lead to BKVN, which may end with graft dysfunction and failure by causing tubulointerstitial nephritis and/or ureteral obstruction.
The various presentations would be:
(1) asymptomatic,
(2) slow and progressive increase of serum creatinine, and
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy. no signs and symptoms are identified with BKV infection.
Lab findings:
(1) elevated serum creatinine and
(2) urine analysis with pyuria, hematuria, and findings consistent with interstitial
nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
Diagnosis:
A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN.
Tropism is medulla, not the cortex, which may increase the risk of missing the viropathic lesions
Quantitative PCR is used to diagnose BKV viremia
The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis, which should be followed by quantitative PCR of blood preferable to urine
Definitive diagnosis of BK virus nephropathy
A definitive diagnosis of BKVN requires characteristic cytopathic changes on the
renal biopsy plus positive immunohistochemistry (against BKV or against
SV40 large T antigens), which has a specificity of 100%, and pathognomonic results
for BKV infection.
A presumptive diagnosis can be done if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction
Light microscopy examinations would show the following:
(1) basophilic intranuclear viral inclusions without a surrounding halo
(2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells
(3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates
(4) tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining and
(5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
Urine electron microscopy
Urine examinations using negative-staining electron microscopy for patients with BKV infection will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen.
Urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis in renal transplant recipients. This diagnostic technique is of a great utility, especially in differentiating between BKVN and asymptomatic BKV infection
Management:
The usual approach in the management of BKV viremia or BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR.
Introduction
● The BK polyomavirus is a risk factor for both graft dysfunction and failure in renal transplant recipients.
● BKV infections lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplants and hemorrhagic cystitis in bone marrow transplant patients
● The average incidence is about 10% of the renal transplant population.
● Viruria preceding viremia by 4 weeks and nephropathy by 12 weeks.
● Acute rejection is the main differential diagnosis of BKVN.
● The challenging management of BKV infection is the balance between the fear of rejection due to reduction of IS drugs and the maintenance of IS at the same level, which could cause more BKV viremia and consequently BKVN
virology
● Primary BKV infection occurs in the first decade of life
● Transmission
(1) airborne transmission
(2) a feco-oral transmission
(3) other as urinary-oral route or seroconversion after solid-organ transplant
(4) both blood transfusion and vertical transmission
● The virus stays in the renal epithelium, tubular, parietal, and transitional structures and in Bowman’s capsule
The risk factors for BK virus infection :
☆ Heavy immunosuppression
☆ Elderly recipients
☆ Prior rejection episodes
☆ Male sex
☆ HLA mismatching, ABO-incompatible
☆ Prolonged cold ischemia time and DGF
☆ Pretransplant BK virus serostatus
☆ Ureteral stenting and trauma
☆ Diabetes mellitus
☆ Previous CMV infections
☆ Immunosuppressive agents affect T-cells and antilymphocyte antibodie
☆ Maintenance steroid
☆ white race/ethnicity
☆ Presence of BKV antibody titers in donor
Clinical Picture of BK virus infection
(1) asymptomatic
(2) slow and progressive increase of Sc
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
● BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant
● Urine show hematuria, pyuria, cellular casts and decoy cells
● Monitoring in kidney recipients is by serum and urine quantitative PCR for BKV
Definitive diagnosis of BK virus nephropathy
● A positive SV40 in renal allograft biopsy is a definitive diagnosis of BKVN with 2 core biopsies are needed for confirmation preferably including the medulla because viropathic lesions are patchy in the medulla rather than in the cortex
● Renal biopsy plus positive immunohistochemistry has a specificity of 100%
● A presumptive diagnosis if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL) with or without kidney dysfunction
● Electron microscopy show the following
(1) viral inclusions
(2) tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
Differential diagnosis
● Other viral infections (CMV, HSV, adenovirus).
● To confirm a diagnosis of BKVN, a blood PCR showing > 60 to 100 copies plus characteristically pathologic morphology
Urine cytology findings for BK virus infections
● Enlarged nucleus with a single, large basophilic intranuclear inclusion in urin
● The presence of decoy cells which can be present in CMV or adenovirus infection
● BKV urine quantitative PCR with sensitivity and specificity of 100% and 88%
● Higher viruria levels are prone to BKV viremia, and high viremia are susceptible to BKVN.
● A strong correlation was shown between the negativity of urine BKV PCR and blood BKV PCR
Serology
● Anti-BKV antibody does not seem to be protective
● Previous BKV seropositivity in the recipient can affect progression of BKV infection, from viruria to viremia then BKVN
● The risk of developing a clinically BKV
infection is high when D+/R-
● Viral culture take weeks to months so it is not applicable
● Urine electron microscopy show cast-like 3-dimensional polyomavirus aggregates which are called Haufen which has 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients
● Haufen associated with high-level BKV viremia and acute kidney injury and BKVN. So it is of a great utility, in differentiating between BKVN and asymptomatic BKV infection.
● It’s limitations are :
☆ Depends on a sophisticated analysis
☆ Requires a meticulous interpretation
☆ It cannot discriminate between rejection and BKVN.
● So high load of Haufen support BKVN rather than rejection as a cause of allograft dysfunction
Therapeutic interventions
● Reduction of immunosuppression
● Monitoring of BKV viremia using PCR
● Cidofovir but nephrotoxicity limit it
● Brincidofovir (CMX001) is a prodrug of cidofovir administered orally with a lower incidence of nephrotoxicity
● Leflunomide is an immunosuppressant and has antiviral properties against BKV
● Side effects of leflunomide include TMA , hepatitis, and bone marrow suppression.
● Intravenous immunoglobulin (IVIG)
however it may guard against allograft rejection in the context of reduced IS
● Fluoroquinolone considered as
potential agents for controlling BKV infection in renal transplant recipients.
● fluoroquinolones reduce large T antigen
expression and inhibit of large T antigen helicase activity.
Role of cellular immunotherapy in the management of BKv infection
● Performed by use of overlapping peptide pools that included antigens from Epstein-Barr virus, CMV, adenovirus, BKV, and human herpesvirus
● Cell products using either prophylactically or in response to single or
multiple viral infections.
I. Introduction
– polyomaviruses are small DNA viruses which infect humans, rodents, birds, rabbits
– BK virus (BKV) causes infection in immunocompromised patients
– BKV causes tubulointerstitial nephritis and ureteral stenosis in kidney transplant recipients
– BKV causes hemorrhagic cystitis in bone marrow transplant recipients
– mainstay of management is reduction in immunosuppression and close monitoring of BKV PCR and kidney function to prevent BKVAN which can increase the risk of graft failure and loss
– the main challenge is balancing between rejection (with reduction of immunosuppression) and progression to BKVAN (with maintenance of immunosuppression)
II. Virology
o Transmission mechanism
airborne through air droplets
fecal-oral route
urinary-oral route
seroconversion following SOT e.g., kidney transplantation
blood transfusion and vertical transmission
– primary infections occur during childhood through respiratory or fecal route, the virus remains dormant in the renal epithelium (tubular, parietal, transitional structures and in the bowman’s capsule)
– the risk of viral shedding is 60% in immunocompromised patients making viruria more common than in the immunocompetent population (20%)
o Risk factors and pathogenesis
immunosuppression burden (rather than the type of immunosuppression)
diabetes mellitus
delayed graft function
previous treated episodes of acute rejection
ureteral trauma
use of antithymocyte depleting agents
CMV coinfection
maintenance steroid immunosuppression
prior rejection episodes
elderly recipients
male sex
white race
HLA mismatch
ABO incompatibility
prolonged cold ischemia time
pre-transplant BK virus serostatus
ureteral stenting
III. Clinical picture and BK virus infection
– asymptomatic
– slow progressive increase in serum creatinine
– unsuspected finding of BKVAN on surveillance graft biopsy
– there are no specific signs and symptoms identified with BKV infection
– BKVAN can occur as early as week 1 post-transplant or as late as 5years following transplant
– Laboratory findings in BKV infection: –
elevated serum creatinine
urinalysis – pyuria, hematuria, features of interstitial nephritis (cellular casts composed of renal tubular cells, inflammatory cells)
the tests may also be normal
IV. Diagnosis overview
– kidney biopsy is required for a definitive diagnosis of BKVAN
– the viropathic lesions are patchy and the tropism in BKV is the medulla (not cortex) hence a diagnosis can be missed
– quantitative BKV PCR demonstrates BKV replication whether there is renal involvement or not hence can be used to diagnose BKV viremia
– presence of decoy cells in urine increases the suspicion for BKV nephritis but should be followed by a blood quantitative PCR rather than urine
o Definitive diagnosis of BKVAN
– characteristic cytopathic changes on kidney biopsy plus
– positive IHC (against BKV or SV40 large T antigens)
– specificity 100% and is pathognomonic for BKV infection
– BKV has a focal tropism in the medulla rather than in the cortex hence BKV diagnosis can be missed on kidney biopsy in 30% of the cases
– presumptive diagnosis of BKVAN can be made when there is
sustained (i.e., >2week duration) urinary viral shedding and
significant BKV replication (plasma BKV DNA PCR load >10,000 copies/mL)
± kidney dysfunction
– it can be difficult to differentiate between BKVAN and rejection
o Differential diagnosis
– other viral infections e.g., CMV, HSV, adenovirus
– confirmed BKVAN diagnosis requires characteristic pathologic findings plus a blood BKV quantitative PCR of >60 to 100 BKV copies
o Urine cytology findings for BKV infections
– BKV infected cells on urine examination are characterized by an enlarged nucleus with a single, large basophilic intranuclear inclusion
– decoy cells (characteristic cytopathologic changes in infected cells) are strongly suggestive of polyomavirus infections
– decoy cells are cytological urine abnormalities which resemble renal carcinoma cells
– decoy cells and BKV urine quantitative PCR are indicators of viral replication in urine
– decoy cells are not specific, sensitive or definitive for the diagnosis of BKV infection
– decoy cells can be present in other renal viral infections e.g., CMV, adenovirus
– decoy cells correlate poorly with biopsy-proven BKVAN
– absence of decoy cells does not exclude BKV disease
o Quantitative PCR
– sensitivity and specificity of quantitative BKV PCR for BKVAN is about 100% and 88% respectively
– useful in monitoring for BKV infections
– viruria precedes viremia by 4 weeks
– patients with a higher viruria level are likely to develop BKV viremia
– patients with a high sustained BKV viremia are susceptible to BKVAN
– alterations in immunosuppressive drugs should be based on BKV quantitative PCR trends rather than a single reading
o Serology
– examining serum for anti-BKV antibodies is not useful since these antibodies can be present even in the general population
– the utility of assessing anti-BKV Ab levels before and after surgery remains unclear
o Viral culture
– not clinically applicable since it takes weeks to months to isolate the virus from a clinical specimen hence it is rarely used to detect BKV infection unless in research settings
o Urine electron microscopy
– can detect haufen i.e., polyoma aggregates using negative-staining electron microscopy
– detection of urine haufen bodies is a noninvasive method for the diagnosis of BKVAN
– there is a relationship between haufen, high-level BKV viremia and occurrence of AKI and BKVAN
– this technique requires expertise and it is not known whether it can differentiate between BKVAN and rejection
V. Therapeutic interventions
– there are no antiviral medications against BKV
– mainstay of management of BKVAN or BKV viremia remains immunosuppression reduction and continuous monitoring of BKV viremia using quantitative PCR
o Immunosuppression reduction
– carries a high risk for rejection
– at times differentiating rejection from BKVAN is a histologic challenge
o Cidofovir
– there are no RCTs to support its use in BKVAN
– cidofovir is also nephrotoxic making it unfavourable
o Brincidofovir
– this is a prodrug of cidofovir, administered orally, less nephrotoxic
– larger clinical trials are needed to establish its safety and efficacy in management of BKVAN
o Leflunomide
– an immunosuppressant with antiviral properties against BKV in vitro
– side effects include bone marrow suppression, hepatitis, TMA
– prospective controlled studies are needed to confirm its efficacy and safety in BKV infection
o Intravenous immunoglobulin (IVIG)
– contains neutralizing antibodies against BKV making it a good alternative in BKVAN management
– no RCTs have been reported
– IVIG helps guard against rejection in the context of reduced immunosuppression
o Fluoroquinolone
– inhibit BKV and SV40 replication in vitro
– the data available indicates that fluoroquinolones do not play a significant role in management of BKV diseases
o Role of cellular immunotherapy
– involves adoptive transfer of primed BKV-reactive T cells to help control BKV disease in patients
VI. Conclusion
– BKV is a polyomavirus, DNA virus which causes tubulointerstitial nephritis and ureteral stenosis in kidney transplant recipients
– there are established risk factors and clinical manifestations
– definitive diagnosis is dependent on kidney biopsy and IHC findings, 2 cores are needed including the medulla t reduce the chances of a missed diagnosis
– patients require regular monitoring with BKV serum or urine BKV DNA PCR (preferably serum)
– viruria precedes viremia by 4 weeks and BKVAN by 12 weeks
– acute rejection is a key differential diagnosis of BKVAN, the latter is characterized by specific cytopathic changes and IHC analysis correlated with PCR evidence of viremia
– currently, there are no antiviral medications targeting BKV infections
– so far, there are no RCTs to support use of the other therapeutic interventions
– the mainstay of management remains reduction of immunosuppression, continuous follow up with quantitative PCR and kidney function tests
– cellular immunotherapy is the newer option which is still being explored
Polyomaviruses are small DNA viruses that can infect humans and animals .
BK polyomavirus (BKV) is
the most prevalent forms of polyomaviruses infecting humans, especially in
immunocompromised patients as renal
transplant recipients, BKV can lead to tubulointerstitial nephritis and
ureteral stenosis; it can also lead to hemorrhagic cystitis in bone marrow
transplant patients.
The cornerstone in management of BKV viremia is to decrease immunosuppression, which will be challenging due to fear of rejection.
BK virus is one of the most common infections in renal transplant recipients.
Reports showed reduction of immunosuppression has been effective in preserving allograft function and management of BKVN.
*Virolo
Properties
Polyomaviruses is a double-stranded DNA virus with icosahedral symmetry. BK categorized serologically and genotypically into 4
groups
Polyomaviruses are small (40-50 nm in diameter),heat stable , their
genome is about 5000 base pairs, contained in the histones derived from host cells.
*Transmission mechanism
Primary BKV infection occurs early in life at 4 to 5 years of age.
routes of transmission include:
(1) airborne.
(2) a feco-oral
(3) urinary-oral.
(4)seroconversion after solid-organ transplant(such as renal transplantation).
(5)blood transfusion and vertical transmission.
Primary infections are often clinically insignificant;
however, the virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule.
*Risk factors and pathogenesis:
Heavy immunosuppression is the most important risk factor , Transplant
physicians consider BKV infection as a marker of heavy immunosuppression.
BKV disease can occur with any immunosuppression medication,
.But more common with tacrolimus and
mycophenolate mofetil.
Tacrolimus specifically can increase BKV replication by a specific mechanism involving FK-binding protein (BP-12).
*Other risk factors Include:diabetes mellitus, DGF, treated
episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies,
coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression,
older age, white race/ethnicity, and presence of specific human leukocyte
antigen (HLA) C loci, and presence of BKV antibody titers in donors.
*Clinical Picture of BK Virus Infection
Reactivation of bk virus occurs in bone marrow or kidney transplant recipients.
Clinical manifestations range from asymptomatic infection to slow and
progressive increase of serum creatinine, and an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
*Diagnosis Overview
-Quantitative PCR is used to diagnose BKV viremia.
-The presence of decoy cells in the urine analysis which is infected cells with enlarged
nucleus with a single, large basophilic intranuclear inclusion these cells are suggestive
but not specific, sensitive, or definitive and their absence does not exclude
the disease.
Viruria precede viremia by 4 weeks, Patients with a higher viruria level are more prone to develope BKV viremia, and patients with high
sustained viremia are susceptible to BKVN.
-renal biopsy needed for a definitive diagnosis of BKVN and it should be at least 2 cores containing medulla to Minimis the chance of missing the pathology .
-Definitive diagnosis of BKVN requires
characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry
(against BKV or against SV40 large T antigens), which has a specificity of 100%.
By light microscopy Biopsy shows tubulointerstitial nephritis
which is sometimes difficult to differentiate between BKVN and allograft rejection.
-Presumptive diagnosis can be done if there
is sustained (more than 2-week duration) urinary viral shedding and significant
BKV replication (plasma DNA PCR load > 10 000 copies/mL),
-Urine electron microscopy using negative-staining electronmicroscopy for patients with BKV infection will show cast-like 3-dimensional
polyomavirus aggregates, which are called Haufen
Presence of a high load of Haufen with equivocal biopsy would highly support the possibility of BKVN rather than rejection as a cause of allograft dysfunction.
-Examine serum for anti-BKV antibodies is
not helpful for a definitive diagnosis of BKV infection.
-Viral culture is not clinically applicable.
*Therapeutic Interventions
-Reduction of immunosuppression is
the cornerstone in the management of BKV infection, but it carries a higher
risk of rejection.
-Modification of immunosuppression to treat BKV infection
carries a higher incidence of long-term chronic rejection.
One study suggested
that patients with persistent sustained BKV viremia are prone to the development of de novo donor-specific anti-HLA antibodies.
– Currently, there are no available
antiviral medications against BKV
Potential anti-BKV agents have been suggested by several reports to be beneficial together with immunosuppression reduction.
*These agents includes:
-Cidofovir but nephrotoxicity
is a main limitation.
– Brincidofovir (CMX001):prodrug of cidofovir that is administered orally. Phase 3 clinical trials have shown a lower incidence of
nephrotoxicity with brincidofovir.
Successful outcomes in renal and hematopoietic transplant have been described but larger-scale clinical trials are needed.
-Leflunomide
used to replace MMF and its not clear whether its effective against BKV or its
effect related to reduction of immunosuppression.
-Intravenous immunoglobulin contains neutralizing antibodies against BKV,
which makes it a good choice in the management of BKVN.
The immunomodulatory effects
of IVIG may guard against allograft rejection in the context of reduced
immunosuppression.
-Fluoroquinolone In
vitro studies have shown that fluoroquinolone antibiotics can inhibit
replication of BKV or SV40,but data suggest that fluoroquinolones do not
currently have a clinically significant role in the management of BKV-related
diseases.
-Role of cellular immunotherapy in the management of BKV infectio
Idea of this approach depends
on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
Researches are still in the early stages, and data on immunodominant BKV epitopes for T-cell priming are limited.
*Conclusion
-BKV infections lead to
tubulointerstitial nephritis and ureteral stenosis in the renal transplant population.
-The average incidence is about 10% of the renal transplant population.
‘Direct correlation exists between
the incidence of BKV infection and the degree of immunosuppression, but not the drug itself.
-Definitive diagnosis of BKVN
is made by renal allograft biopsy using immunohistochemistry, which cross-react
with the BKV, specifically SV40 large-T antigen part of the virus.
-Acute rejection is the main differential diagnosis of BKVN.
-Immunosuppression reduction is cornerstone in management.
–Polyomavirus infect both humans and animals .Amongst the immunosuppressed, BK is one of the most common infections. Post KTR, it can cause tubulointerstitial nephritis, ureteral stenosis and hemorrhagic cystitis(In BMT).
-BKV current management is via monitoring with BKV PCR,RIS and careful attention to the graft function.
TRANSMISSION.
-Primary infection occurs in 1st decade of life via ; airborne spread, fecal oral route, urinary oral route, seroconversion post SOT and vertical route.
-Primary infections are latent but get reactivated in immunosuppressed in real epithelium with above mentioned manifestations.
-Viruria is at % in immunocompetent vs 60% in immunosuppressed.
RISK FACTORS AND PATHOGENESIS.
-This include;
Immunosuppression – Considered a marker of over immunosuppression, Tac +MMF protocols have been associated with increased incidences of dx. Tac causes BK infection via an FK binding protein.
DM
DGF
Previous acute rejection tx.
Ureteral trauma.
Steroid maintenance tx.
CO infection with CMV.
Use of antilymphocyte ABs.
Older age, White race
ABO incompatibility.
High BK donor antibody titres.
CLINICAL PRESENTATION.
-Mostly reactivated post transplant -BMT & SOT.
-BKVN – Graft dysfunction could occur from interstitial nephritis +/- ureteral stenosis.
-Hemorrhagic cystitis in BMT.
-Could be asymptomatic or present with ;
Slow and gradual increase in creatinine.
Progressive kidney dysfunction.
Lab- Increase in creatinine, pyuria, + hematuria and cellular casts on urinalysis.
DIAGNOSIS.
-Definitive dx established by renal biopsy, it resides in the medulla and thus can be easily missed on biopsy.
-BK PCR is 100% sensitive and 88 % specific to access infection.
-Urinalysis – Decoy cells – Good screen test followed by BKV PCR as a follow up test. BKV urine PCR can also be done.
-Viruria precedes viremia by 4 weeks.
-Definitive dx ; Cytopathic changes + +VE SV40 large T antigen- 100%Specific.
-Presumptive diagnosis – Continuous viruria (>2 weeks) + BK PCR > 10000 Copies/ml
-Anti BKV antibodies are not protective and lag in the circulation and thus are not sensitive in diagnosing infection. They peak 1st 6 weeks of infection or 2 years post primary infection.
-Highest risk of infection in D+/R- pair.
-Viral cultures take long to get results and is thus not indicated.
-On urine electron microscopy, Haufen presence has 100% sensitivity and 99% specificity in detecting biopsy proven BKVN post KTR. It cn be use for dx minus biopsy.
TREATMENT.
-RIS – This is done in a stepwise fashion involving CNIs, Steroids and anti metabolites while monitoring the graft function.
-Cidofovir – Main SE is nephrotoxicity but can be combined with RIS.
-Brincidofovir – PO prodrug of cidofovir with less nephrotoxicity but still needs more studies before adoption in clinical use.
-Leflunomide – Has antiviral properties against BK and has been used as a substitute to MMF with good results in limited studies. It is associated with TMA, hepatitis and BM Suppression. More studies needed to establish efficacy against BKV.
-IVIG -Has neutralizing antibodies against BKV and can be used as an adjunctive.
-Fluoroquinolones – Some studies have shown their inhibitory effects on BKV replication by decreasing expression of large T antigen and equally inhibition of Large T antigen Helicase activity. We have mixed results with their use and thus not adopted in use yet.
-Cellular immunotherapy- looks Promising but more studies needed on it.
· BKV infection is associated with graft dysfunction and loss.
· It is named after the initials of Sudanese patient with ureteric stenosis with discovered viral particle in the epithelial lining.
· Mode of transmission: feco-oral, respiratory, transplacental and organ transplantation
· Primary infection in childhood usually asymptomatic viuria , while the virus remains dormant in uroepithelial cells then become activated in immunocompromised patients (as renal transplant recipients) with increasing viruria up to 60%..
· Risk factors for infection: high immunological risk, increased HLA mismatch, ABO and HLA incompatible transplantation, strong induction as ATG, TAC and MMF containing IS therapy, repeated treatment of rejection episodes, so the most important is the net immunosuppression state, D+/R- serological status prior to transplantation, old age and diabetes in the recipient, DGF and prolonged cold ischemia time.
· No specific antiviral to be used in prophylaxis or ttt of BKV cases.
· BKN clinical manifestations in kidney transplantation:
o Interstitial nephritis and ureteral stenosis commonly occur at 10-13 months post-transplant.
o Rising creatinine, hematuria and pyuria and cellular casts.
o Definitive BKN is diagnosed by allograft biopsy which has interstitial nephritis that turn chronic and cause allograft dysfunction and loss.
o Biopsy may be false -ve (patchy affection and mainly in medulla), so 2 core biopsies are needed including renal medulla.
o Biopsy shows 3 patterns (A, B, C) with early cytopathic changes then acute interstitial nephritis then chronic tubulointerstitial nephritis.
o Special staining fir IHC (SV 40) simian virus 40, stains large T antigen present in polyoma virus, is diagnostic for polyoma virus (SV, BK and JC). Specificity is 100 % and sensitivity is 77.7 %
o Blood BKV PCR indicates viremia whether has BKN or not, o BKV PCR can be done in urine sample.
o Decoy cells (cells with large inclusion bodies replacing the normal chromatid) in urine increases suspicion of BKN. But definitive diagnosis is biopsy.
o Decoy cells=infected tubular and urothelial cells (only epithelial) with large basophilic nucleus (looks like high grade urothelial atypia),
o DD from owl eye appearance of CMV inclusion bodies (that is surrounded by complete halo around it )
o Decoy cells in urine (infected urothelial cells), with :
§ Sensitivity 100 % of BKN.
§ Specificity 84%.
§ NPV is 100%.
§ PPV is 6%.
o Presumptive BKN means sustained (>2 weeks) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction
o Hemorrhagic cystitis occurs in bone marrow transplantation. · BKN Differential diagnosis:
o Other viral infections as CMV and adenovirus.
o Acute rejection (DD by presence of viral inclusion bodies, and positive PCR (viremia))
· The main line of ttt is reduction of immunosuppressive therapy, but the problem is increasing risk of rejection and graft loss (so achieving the balance between both conditions is difficult.
· Reduction of MMF dose by 50 %, reduction of CNI by 25-50 % is started, then FU PCR if not decreasing stop MMF.
· Still not proved, to shift from tacrolimus to cyclosporin or to shift from MMF to mTORi.
· Adoptive specific T cell immunotherapy may be future therapy for refractory cases.
· Follow up PCR every 2 weeks and FU graft function every week.
· NO RCT to demonstrate specific therapy, but additional use of cidofovir, leflunamide, quinolones and IVIG in refractory cases (not decrease in viral load with reduction of IS).
Summary of the article Update on the Management of BK Virus Infection
BK polyomavirus (BKV) is considered one of the highly prevalent forms of polyomaviruses.
BKV is a double-stranded DNA virus with icosahedral symmetry, has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence.
In KTR can cause TIN and ureteral stenosis while causing hemorrhagic cystitis in bone marrow transplant patients.
Transmission mechanism 1. Airborne transmission through air droplets. 2. A feco-oral transmission, as fecally eliminated polyomaviruses are detected in hospitalized children. 3. Other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation). 4. Blood transfusion. 5. Vertical transmission
Risk factors for BKV infection
1. The degree of immunosuppression(BKV infection is a marker of heavy immunosuppression).
2. Diabetes mellitus.
3. Delayed graft function.
4. Treated episodes of acute rejection.
5. Ureteral trauma.
6. Use of antilymphocyte antibodies.
7. Coinfection with Cytomegalovirus (CMV).
8. Maintenance steroid immunosuppression.
9. Older age.
10.White race/ethnicity.
11.Presence of specific human leukocyte antigen (HLA) C loci.
12.The presence of BKV antibody titers in donors.
Steps of BK Virus Infection in Renal Transplant Recipients
1. Primary infection: Initial infection of the host including viremic spread to susceptible tissues with mild or no clinical symptoms
2. Latent infection: Asymptomatic inactive infection of susceptible cells after primary infection. Virus detection is perfomed only by molecular techniques.
3. Serologic evidence of infection: Variation in antibody titers occurs in almost all healthy children and 60% – 90% of asymptomatic adults. No correlation with intrarenal latent viral load. Presents a weak correlation with viral disease.
4. Viral activation: Evidence of replication can be detected by observing “decoy cells” or free urine virions. Viral detection by a polymerase chain reaction in urine, serum, or cerebrospinal fluid, can be considered to be a transient and asymptomatic event or as part of a viral disease.
5. Viral disease: Histologic evidence of viral replication in organs (cytopathic signs and/or positive immunohistochemistry or in situ hybridization) and virus-induced tissue damage is often associated with clinical symptoms.
BKVN; light microscopy examinations
1. Basophilic intranuclear viral inclusions without a surrounding halo.
2. Anisonucleosis, hyperchromasia, and chromatin clumping of infected cells.
3. Areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates.
4. Tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining.
5. Tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
6. When extensive, it is difficult to differentiate between BKVN and allograft rejection.
BKVN; electron microscopy examinations
a) Viral inclusions with diameter size ranging from 30 to 50 nm.
b) Tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
Clinical Picture of BK virus infection
1. Asymptomatic.
2. Slow and progressive increase of serum creatinine.
3. An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
4. Usually, BKV infection occurs 10 to 13 months posttransplant.
5. BKVN may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
Diagnosis of BKV
1. Laboratory findings;elevated serum creatinine and urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis.
2. The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis.
3. Quantitative PCR is used to diagnose BKV viremia(a blood quantitative PCR showing > 60 to 100 BKV copies).
4. A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN(may be missed in the tissue obtained because viropathic lesions are patchy.)
Definitive diagnosis of BK virus nephropathy
A definitive diagnosis of BKVN requires:
a) Characteristic cytopathic changes on the renal biopsy. plus
b) positive immunohistochemistry (against BKV or against SV40 large T antigens). It has a specificity of 100%, and pathognomonic results for BKV infection. A presumptive diagnosis of BKV can be done if there is:
a) Sustained (more than 2-week duration) urinary viral shedding.
b) Significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction. Differential diagnosis
Other types of viral infections:
CMV, herpes simplex virus and adenovirus.
BKV infection; therapeutic interventions
1. Immunosuppression reduction.
2. Cidofovir; nephrotoxicity is a limitation.
3. Brincidofovir (CMX001)is a prodrug of cidofovir that is administered orally and nonephrotoxicity.
4. IVIG.
5. Fluoroquinolone:In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication.
6. Role of cellular immunotherapy in the management of BKV infection: data on immunodominant BKV epitopes for T-cell priming are limited.
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
The article deals with management of BK virus infection.
Introduction: BK virus, one of the most common infections in renal transplant recipients, is a form of polyomavirus which causes tubulointerstitial nephritis and ureteral stenosis if renal transplant recipients, andhemorrhagic cystitis in bone marrow transplant recipients. Management of BK viremia involves reduction of immunosuppression, monitoring of BK virus polymerase chain reaction (PCR), and renal function.
Virology: BK virus was first diagnosed in 1971 in a Sudanese renal transplant recipient with ureteral stenosis. It is a small virus with 5000 base pair genome, encoding 6 chief proteins divided into 3 regions (early encoding, noncoding, and late encoding regions).
Transmission: Primary BK virus infection occurs in first decade of life, through feco-oral route, airborne transmission, and through solid organ transplant (10-13 months post-transplant), blood transfusion, and vertical transmission. Post-primary infection, the virus remains latent in renal epithelium, and multiplies when the immunity of the person decreases.
Risk factors and pathogenesis: The risk factors include degree of immunosuppression, diabetes mellitus, ft function, ureteral trauma, acute rejection treatment, older age, steroid use, seropositive renal donor, viruria in the donor, cytomegalovirus co-infection, white race, HLA C loci, HLA incompatibility, ABO incompatibility, and use of antilymphocyte antibodies.
Clinical picture: Clinically BK virus infection can be asymptomatic, or can present as slow progressive rise in serum creatinine, or as an unexpected finding of BK virus associated nephropathy on graft biopsy. Laboratory tests show elevated serum creatinine, pyuria, hematuria, cellular casts, etc.
Diagnosis overview: A graft biopsy is definitive for diagnosis, but can be negative due to patchy involvement, more so in the medulla. Quantitative PCR diagnoses BK viremia (sensitivity 100%, specificity 88%). Urinary decoy cells (cell with enlarged nucleus and single, large basophilic intranuclear inclusion) point towards BKV nephritis, and should be followed by blood or urine quantitative PCR. Definitive diagnosis requires cytopathic changes on biopsy with positive immunohistochemistry (SV40 large T antigens), and positive BK viremia. Presumptive diagnosis requires sustained viruria with plasma DNA PCR >10000 copies/ml. BK virus nephropathy has 3 different patterns on histology, and has 3 different grades according to Banff classification. Serology (serum anti BK virus antibody) is not helpful in diagnosis. Viral culture is used oly in research setting. Urine electron microscopy can show Haufen (3-dimentional polyomavirus aggregates).
Differential diagnosis: It includes other viral infections like cytomegalovirus, herpes simplex virus, adenovirus etc.
Therapeutic interventions: Immunosuppression reduction is the cornerstone of therapy, but increases risk of rejection. Other medications including Cidofovir, Brincidofovir, Leflunomide, IVIG (intravenous immunoglobulins), and Fluoroquinolones have been used, but there are no randomized controlled trials with respect to use of these agents. Use of adoptive transfer of BK virus reactive T cells is a potential therapeutic way of managing BK virus associated nephropathy.
Conclusions: 10% of renal transplant recipients get affected by BK virus infections, with direct correlation with the degree of immunosuppression. Management involves reduction of immunosuppression, and antiviral use has been shown to be effective in uncontrolled retrospective studies, with no randomized controlled trial. Active screening for the BK virus levels, and continuous follow-up using BK virus PCR levels and renal function is imperative for optimal management.
2. What is the level of evidence provided by this article?
Introduction : Polyomaviruses are small DNA viruses and one of the common infections in kidney transplant patients that can lead to tubulointerstitial nephritis and ureteral stenosis in kidney transplant patients also lead to hemorrhagic cystitis in bone marrow transplant patients. The mainstay of treatment is reduction of immunosuppression. The balance between the fear of rejection due to reduction of immunosuppression and the maintenance of immunosuppression at the same level,is challenging . virology Properties:
BK virus is a member of the family Polyomaviruses which is a double-stranded DNA virus with icosahedral symmetry first discovered in 1971, in a Sudanese renal transplant patient who presents with ureteric stenosis . BK virus has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence. Transmission mechanism :
Primary BKV infection occurs during childhood and is often clinically insignificant. Possible routes of transmission include the following: (1) Airborne transmission through air droplets . (2) Afeco-oral transmission, as fecally eliminated polyomaviruses are detected in hospitalized children. (3) Urinary-oral route or seroconversion after solid-organ transplant (4) Blood transfusion and vertical transmission. After transmission the virus stays dormant in the renal epithelium and reactivated in a state of immunosuppression . Risk factors and pathogenesis :
1. The degree of immunosuppression is the most important risk factor for developing BKV disease. 2. Immunosuppression protocols especially tacrolimus and mycophenolate mofetil based regimen. 3. Other risk factors include treated episodes of acute rejection ,use of antilymphocyte antibodies, the presence of BKV antibody titers in donors, DM , DGF, ureteral trauma,, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci.30-32 ,
Clinical Picture of BK virus infection :
Patients can either be asymptomatic or show slow and progressive increase of serum creatinine, or an unsuspected finding of renal allograft biopsy in patients with progressive renal damage (BKVN). Laboratory findings will be (1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
Diagnosis :
Renal allograft biopsy : will give definitive diagnosis of BKVN but viropathic lesions are patchy and the BKV tropism is medulla, not the cortex, so diagnosis may be missed in the tissue obtained . Findings will be characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection.
Quantitative plasma PCR : for diagnosing BKV viremia if plasma DNA PCR load > 10 000 copies/mL) Urine cytology: The presence of decoy cells in the urine analysis are suggestive but not specific, sensitive, or definitive for BKV infection , it should be followed by quantitative PCR of blood preferable to urine. Differential diagnosis BK virus infection
Monitoring of renal transplant recipients : can be with quantitative or real-time PCR for BKV infections in either the plasma or urine. The sensitivity, specificity, positive predictive value, and negative predictive values of urine levels were 70%, 70%, 53%, and 83% for any viremia and 91%, 66%, 33%, and 98% for sustained viremia, respectively. Serology : Anti-BKV antibody levels before transplant will predict the risk of developing a clinically significant BKV infection which is high when transplant is performed between a positive BKV donor and a negative recipient.
Haufen: is a polyomavirus aggregate associated with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients . Thus, urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis in renal transplant recipients , it is a sophisticated analysis and requires a meticulous interpretation by pathologists.
Therapeutic interventions: -The mainstay of treatment is reduction of immunosuppression although it is challenging because it carries higher risk of rejection.
– Currently, there are no available antiviral medications against BKV. – Follow up with continuous monitoring of BKV viremia levels using quantitative PCR.
– Cidofovir: Is nephrotoxic and has no strong evidence beyond its use.
-Brincidofovir (CMX001) : Is a prodrug of cidofovir that is administered orally less nephrotoxic .
– Leflunomide: is an immunosuppressant agent with antiviral properties against BKV in vitro . also no strong evidence to support its use. Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression. Intravenous immunoglobulin : (IVIG) contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKVN. Again no strong evidence to support its use. – Fluoroquinolone : Is an antibiotic which can inhibit replication of BKV or SV40 polyomavirus replication in vitro; but the clinical data suggest that fluoroquinolones do not currently have a clinically significant role in the management of BKV-related diseases.
Cellular immunotherapy : adoptive transfer of BKV-reactive T cells which may help in controlling the BKV-associated disease it is promising anyhow , but needs also stronger evidence .
What is the level of evidence provided by this article?
This article is systematic review level V of evidence
Please summarise this article. Introduction
-Polyomaviruses are small DNA viruses . BK polyomavirus (BKV) is highly prevalent forms of polyomaviruses causing infection in immuno -compromised patients.
– In renal transplant recipients, BKV can lead to tubulointerstitial nephritis and ureteral stenosis; it can also lead to hemorrhagic
cystitis in bone marrow transplant patients. virology Properties
-BK virus has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence. Genome structure and transcription
-Polyomaviruses genome is about 5000 base pairs, contained in the histones derived from host cells.
-The external layer consists of structural proteins VP1, VP2, and VP3.
-VP1 determines receptor specificity, whereas VP2 and VP3 are
involved in viral particle stabilization outside the host cell and transport within it. Transmission mechanism
– Possible routes of transmission include the following: (1) airborne transmission through air droplets (2) a feco-oral transmission. (3) other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant , and (4) both through blood transfusion and vertical
Transmission.
-Primary polyomavirus infections usually occur during childhood through respiratory or oral routes and often clinically insignificant.
-The virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule.
-In the immunocompetent population, BKV replication is manifested by asymptomatic viruria, and the incidence of shedding is 20%. However, in immunocompromised individuals, the risk of shedding reaches 60% and the viruria is more common.
-The mean prevalence of BKVN in renal transplant recipients is 5%, whereas the prevalence of ureteral stenosis is less. Risk factors and pathogenesis
-The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used.
-Active BKV disease is thae most commonly associates with tacrolimus and MMF.
– Immunosup – pressive agents can affect T cells, which can lead to increased BKV replication.
-Other risk factors include diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with CMV, maintenance steroid immunosuppression, older age, white race/ethnicity, presence of HLA C loci and the presence of BKV antibody titers in donors.
-Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy . Clinical Picture of BK virus infection
-About 90% of the population will become BKV seropositive which reactivates after solid-organ transplant, especially in bone marrow or
kidney transplant recipients.
– In kidney transplant recipients, reactivation may lead to BKVN, which
may end with graft dysfunction and failure .
Clinical manifestations are as follows: (1) asymptomatic, (2) slow and progressive increase of serum creatinine, and (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance
renal allograft biopsy.
-No signs and symptoms are identified with BKV infection.
-BKV infection occurs 10 to 13 months posttransplant. BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
-Laboratory findings in patients with BKV infection are as follows:
(1) elevated serum creatinine and
(2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. However, these results could be normal. Diagnosis Overview
-A Renal biopsy is needed for a definitive diagnosis of BKVN; however, a diagnosis may be missed in the tissue obtained because viropathic
lesions are patchy and locates in medulla, not the cortex, which may increase the risk of missing the viropathic lesions.
-Quantitative PCR is used to diagnose BKV viremia.
-BK virus nephritis is suspected when the clinical diagnosis of tubulointerstitial nephritis is suspected; however, there are no clinical
features of tubulointerstitial nephritis that are unique to BKVN.
– Decoy cells in the urine increases the suspicion of BKV nephritis,
which should be followed by quantitative PCR of blood preferable to urine . Definitive diagnosis of BK virus nephropathy
-A definitive diagnosis of BKVN requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity ofm100%, and pathognomonic results for BKV infection.
-In the absence of definitive criteria for BKVN diagnosis , a presumptive diagnosis can be done if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction; these characteristics have been proposed to define presumptive BKVN. Differential diagnosis
-BK virus infection can be similar to other types of viral infections (CMV, herpes simplex virus, adenovirus).
– Confirmation of a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic
morphology results are needed. Urine cytology findings for BK virus infections
-Urine examinations may reveal BKV-infected cells( Decoy Cells) that
strongly suggestive of polyomavirus infections.
-Viral replication in the urine is demonstrated by either decoy cells or BKV urine quantitative PCR.
-Decoy cells are suggestive but not specific, sensitive, or definitive for
BKV infection because (1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus42) and (2) decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients. Quantitative polymerase chain reaction
-Sustained high viral DNA levels in the plasma of renal transplant recipients who have an appropriate clinical picture can suggest BKVN.
-Renal transplant recipients can be monitored with quantitative or real-time PCR for BKV infections in either the plasma or urine.
-Multiple retrospective and prospective studies have agreed that viruria
precede viremia by 4 weeks.
-Viral replication in the urine as detected by either analysis of urine
cytology or demonstration of the virus by quantitative PCR has been shown to be present in 20% to 60% of renal transplant recipients, depending on the method of detection.
-It is recommended that medical decisions, especially those with regard to alterations of immunosuppression, be made on the basis of trends in
quantitative DNA levels rather than on a single measurement. Serology
-It is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection because positivity for these antibodies is quite common in the general population.
– During BKV infection, there are high levels of BKV IgG titers during the first 6 weeks of infection or 2 years after primary infection. Anti-BKV
antibody does not seem to be protective.
– Previous BKV seropositivity in the recipient can affect progression of BKV infection, especially progression from viruria to viremia. viral culture
-It is rarely used as a method for BKV infection detection outside the research setting. It can take weeks to months . Urine electron microscopy
-Urine examinations using negative-staining electron microscopy for patients with BKV infection will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen .
-Urine analyses in patients with a low viremia (median of
26 959 copies/mL) did not show Haufen bodies.
-Urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis in renal transplant recipients.
-The presence of a high load of Haufen with equivocal biopsy would
highly support the possibility of BKVN rather than rejection as a cause of allograft dysfunction. Therapeutic interventions
-Currently, there are no available antiviral medications against BKV.
-The usual approach in the management of BKV viremia of BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR. Immunosuppression reduction
– it carries a higher risk of rejection, making this decision challenging. Cidofovir
-One of the limitations of this approach is nephrotoxicity, thus making the decision to use cidofovir unlikely. Brincidofovir (CMX001)
-It is prodrug of cidofovir that is administered orally. Phase 3 clinical trials have shown a lower incidence of nephrotoxicity with brincidofovir. Leflunomide
-Leflunomide is an immunosuppressant agent that also has antiviral properties against BKV in vitro.
-Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression. intravenous immunoglobulin
-Intravenous immunoglobulin (IVIG) contains neu – tralizing antibodies against BKV, which makes it a good choice in the management of BKVN. Fluoroquinolone
-In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication in vitro. Role of cellular immunotherapy in the management of BKV infection
-Identifying viral immunogenic antigens is necessary for successful generation of virus-specific T cells. What is the level of evidence provided by this article?
Level 5
Update on the Management of BK Virus InfectionIntroduction
Ø The main treatment of BK viremia is to decrease immunosuppression.
Ø The challenging part in the management of BKV infection is the balance between the fear of rejection due to the reduction of immunosuppression.
Ø Primary BKV infection occurs in the first decade of life on average at 4 to 5 years of age.
Ø Possible routes of infection include: airborne,feco-oral transmission, and others such as post-solid organ transplantation Risk factors and pathogenesis:
Ø The degree of immunosuppression medication.
Ø Diabetes mellitus
Ø Delay graft function .
Ø A treated episode of acute rejection.
Ø Ureteral trauma.
Ø Use of ATG as induction therapy.
Ø Co-infection with CMV,.
Ø Maintenance steroid immunosuppression.
Ø Older age.
Ø White race /ethnicity.
Ø Post graft C loci.
Ø HLA and ABO incompatible transplants. The clinical picture of BKV infection:
Ø 90% of BKV seropositive reactivate after solid organ transplant, especially in bone marrow or kidney transplant recipients.
Ø BKVN leads to tubulointerstitial nephritis and or ureteral obstruction which results in graft dysfunction.
Ø A definite diagnosis by kidney biopsy, however, quantitive PCR is used to diagnose BKV viremia
Ø Urine cytology for BKV infection:
Ø Urine examination reveals BKV infection cells is enlarged nuclear with single large basophilic internuclear inclusion. Threptic intervention:
Ø A few controlled studies are available to guide us in the management of BKV infection in renal transplantation.
Ø No available antiviral mechanism against BKV. Immunosuppression reduction:
Ø Reduction of immunosuppression therapy carries a higher risk of rejection (acute or chronic). Cidofovir
Ø No randomized controlled trials are available to support its use
Cidofovir nephrotoxicity is limit its use. Brin cidofovir
Ø Pro. drug of cidofovir has a lower incidence of nephrotoxicity.
Ø Need large studies to prove the safety and efficacy of brin cidofovir. Leflunomide
Ø The immunosuppressant agent that has antiviral properties against BKV.
Ø It decreases viral load, however, this does not reflect the cause of BKV viral load .
Ø Side effect:TMA.hepatitis,B.M suppression.
Ø But still, more controlled trials are needed for leflunomide to confirm the efficacy and safety of this drug against BKV infection IVIG
Ø Contain neutralizing antibodies against BKV which makes it a good choice in the management of BKVN.
Ø In hypogammaglobinaemia, IVIG therapy was beneficial with regard to anti BKV immunity.
Ø The immunomodulate effects of IVIG may guard against allograft rejection in the context of reduced immunosuppression. Fluoroquinolone :
Ø Inhibit replication of BKV or SV40 polyomavirus replication in vitro.
Ø Data suggest that fluoroquinolone does not currently have a clinically significant role in the management of BKV-related disease. Cellular immunotherapy in the management of BKV infection:
Ø Cellular therapy using T-cells to restore antiviral immunity.
Ø There are few controlled studies available on the management of BKV infection in a renal transplant recipient.
Ø Newer options including cellular immunity may carry potential hope for the treatment of BKV infection
level 5
I agree with your analysis, summary and level of evidence this article provides.I note that you consider adoptive cellular immunotherapy as a future potential
BKV can cause tubulointerstitial nephritis, ureteral stenosis hemorrhagic cystitis in renal transplant recipients.
The current consensus on BKV viremia management is to reduce immunosuppression.
Thereafter we have to perform BKV polymerase chain reaction (PCR) on regular follow-up, to prevent allograft BKV nephropathy (BKVN), in order to reduce the risk of graft failure.
Transmission mechanism
BKV infection occurs first in life at very early age.
Routes of entry include oral (feco-oral or urinary-oral), via solid-organ transplants, blood transfusion and vertical transmission.
Primary infections are clinically not significant. The virus remains in the renal epithelium and replicates when immunity declines.
Clinical Picture of BK virus infection
No Signs or Symptoms are diagnostic of BKV infection
Mostly asymptomatic
Slowly progressive increase of serum creatinine
Progressive kidney damage (BKVN) on Renal Allograft Biopsy
Urine exam may show pyuria, hematuria, and cellular casts (interstitial nephritis)
Diagnosis Overview
Graft biopsy is mandatory for confirmatory diagnosis of BKVN (patchy lesions are often missed)
Quantitative PCR of blood is necessary to diagnose BKV viremia (BKV replication) in cases with tubulointerstitial nephritis
Urinary decoy cells are suggestive of BKVN
BK Viruria by PCR is not enough for a diagnosis
Definitive diagnosis of BK virus nephropathy (BKVN)
Renal biopsy with characteristic cytopathic changes
and
Positive immunohistochemistry (against BKV or SV40 large T antigens)
plus
Blood quantitative PCR with more than 60 to 100 BKV copies
Since BK virus infection can be similar to renal viral infections like CMV, HSV and adenovirus, characteristically cytopathologic morphology on biopsy as well as PCR are necessary.
Serology
Serum anti-BKV antibodies for a diagnosis of BKV infection is not helpful because these antibodies are quite commonly positive in the general population.
Viral culture & Urine electron microscopy
BKV infection detection via viral culture urine electron microscopy is not feasible outside of the research setting and thus cannot be used in clinical settings because of cost & duration.
Therapeutic interventions
Reducing immunosuppression is the cornerstone but it also raises risk of rejection
Cidofovir is beneficial but no RCTs are available as proof and it is nephrotoxic
Brincidofovir (prodrug of cidofovir) displayed low nephrotoxicity in phase 3 clinical trials
Leflunomide used instead of mycophenolate results in reduction of BKV load but may cause thrombotic microangiopathy, hepatitis, and bone marrow suppression
IVIG antibodies neutralize BKV, and is a good choice in the management of BKVN
Fluoroquinolones do not have a clinically significant role in management of BKV
Conclusions
In 10% of renal transplants BKV infections lead to tubulointerstitial nephritis and ureteral stenosis.
The common approach for BKV infection management is active screening using quantitative PCR every 3 months post transplant.
If there is BK viremia, immunosuppression is to be reduced and there should be continuous follow-up of BKV viremia levels and renal function tests.
BK virus infection can be as early as the first decade of life but usually asymptomatic. The virus was isolated from many tissues shedding light on its variable modes of transmission, blood, fecal oral, urine-oral etc. Air-borne infection can happen as well. It belongs to polyomavirus family and have 4 subtypes that are different in terms of virulence. Viruria is detected early, and BK named from the first case in whom the virus was isolated when presented by ureteral obstruction. We can see BKVN or ureteral stenosis in Renal tx patients while hemorragic cystitis is more common in BM transplant patients.
90% of the population mostly become positive for BK during their life. In transplant patient average of infection is through 10th-13th months but can occur as early as 1st week and late in 5th year. association is mostly related to degree of immunosuppression.
BK viral infection can be asymptomatic, seen on biopsy or manifetsed as interstisial infection with deterorating renal function. Definitive BKAN is done with renal biopsy . infection can be patchy or confined to medulla, so 2 core biopsy is needed. around 30% of cases can be missed. screening can be by checking for decoy cells in the urine. Our aim is to prevent nephropathy by checking for vuria and viremia earlier on followup; usually done by PCR. Prevention , early manipulation is essential to prevent renal impairment. The main challenge is the balance between risk of rejection and BK nephropathy.
screening before transplant is not recommended but one suggested screening is to check for BK virus monthly till 9th month then every 3 months till the end of second year.
treatment is mainly be reduction of immunosuppression by %30-50. Leflomide, cidofovir, brincidofovir, IVIG are utilized. Quinilones are thought to have some benifit.
Primary BKV infection occurs in the first decade of life, on average at 4 to 5 years of age.
The virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule.
The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used .
Active BKV disease has been associated with various immunosuppression protocols, most commonly tacrolimus and mycophe- nolate mofetil based .
Tacrolimus specifically can increase BKV replication by a specific mechanism involving FK-binding protein (BP-12) .
Other risk factors that could be involved, although not commonly, include diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci
BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant .
Clinical manifestations are as follows: asymptomatic, slow and progressive increase of serum creatinine, and an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy .
A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN .
On the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection .
I wish you could type headings and sub-headings as underline or in bold.I agree with your analysis, summary and level of evidence this article provides.
BK polyoma virus BKPyv is a main pathogen encountered during post transplant period. associated with variable presentations as its infecting different organs and and features variable presentations .
Its usually showcasing reactivation of of dormant BKPyv who used to be attracted early in life via air born, droplet born and feco-oral rout.
It might present as tubulo-interstitial disease as its infecting tubular epithelial and interstitial cells , ureteric epithelial cells resulting in ureteric obstructive uropathy.Hemorrhagic cystitis was frequently reported with Bone marrow transplantation. Risk factors:
Main risk factors in patients with kidney transplantation is over immunsuppression, particularly with Tacrolimus and Mycophnolic acid or Azathioprim .Suppression of cell mediated immunity ,which is keeping the virus in quarantine , might flourish the virus growth , proliferation and disease propagation. Tacrolimus might enhance BKPyv growth via FK binding protein.
Other less common factors include:
Older age of recipient.
Diabetes mellitus.
Corticosteroid based maintenance medicine.
Treatment for acute CMR.
Co-infection with CMV.
HLA C locus.
The presence of BKPyv antibody titer in donors which reflect recent infection confer higher risk of attracting infection.
HLAi and ABOi transplantation carry higher risk of BKPyv infection , attributed to intense immune suppression and anti-rejection administration.
Its rarely reported in other immune deficient conditions like HIV , SLE and Diagnosis of BKPN:
biopsy is the slandered modality for diagnosing BKPN. Its usually showcases characteristic features including:
1] Tubular epithelial cells with intra-nuclear inclusions which is distinctively without peripheral halo, to differentiate it from CMV infection.
2] Interstitial fibrosis.
3] Tubular infiltration with lymphocytes mimicking ACMR.
4]Infitration of interstitium with mononuclear and polynuclear Cells.
Introduction Polyomaviruses are one of the highly prevalent forms of small DNA viruses that can cause infection in humans, especially in immunocompromised patients. Management of BKV viremia is to decrease immunosuppression, follow PCR, and monitor renal functions to prevent graft failure. Virology Properties BK virus is a double-stranded DNA virus with icosahedral symmetry, categorized into 4 groups with different virulence. Historical aspects Viral particles were found in the ureters of a Sudanese renal transplant patient and high serum BKV antibody titer was seen at the same time. Transmission mechanism (1) Airborne transmission. (2) A feco-oral transmission, (3) Urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation) (4) Blood transfusion and vertical transmission Risk factors and pathogenesis · The degree of immunosuppression · Diabetes mellitus, · Delayed graft function, · Treated episodes of acute rejection, ureteral trauma, · Use of anti-lymphocyte antibodies, · Coinfection with Cytomegalovirus (CMV), · Maintenance of steroid immunosuppression, · Older age, white race/ethnicity, · Presence of specific human leukocyte antigen (HLA) C loci. · The presence of BKV antibody titers in donors
Clinical Picture of BK virus infection (1) asymptomatic, (2) slow and progressive increase of serum creatinine, (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy. Laboratory findings: (1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. Diagnosis Overview For a certain diagnosis of BKVN, a tissue (renal) biopsy is required, however patchy viropathic lesions could be overlooked. Tubulointerstitial nephritis and BKV viremia are identified by quantitative PCR.
Definitive diagnosis of BK virus nephropathy Diagnosis of BKVN requires cytopathic changes and positive immunohistochemistry with 100% specificity.
Steps of BK Virus Infection in Renal Transplant Recipients ·Primary infection. ·Latent infection. ·Serologic evidence of infection. ·Virus detection. ·Viral disease. Urine cytology findings for BK virus infections
· Urine examinations may reveal BKV-infected cells. BKV-infected cells have an enlarged nucleus with a single, large basophilic intranuclear inclusion. Differential diagnosis
·CMV
·Herpes simplex virus,
·Adenovirus Serology Viral culture is not suitable for BKV detection outside the research setting as viral isolation from the clinical specimen can take weeks to months Therapeutic interventions ·Immunosuppression reduction ·Cidofovir ·Brincidofovir (CMX001) ·Leflunomide ·Intravenous immunoglobulin ·Fluoroquinolone
Role of immunotherapy in the management of BKV infection The idea of this approach depends on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
Conclusion: ·BK virus is a member of human polyomaviruses, which are DNA viruses; ·BKV infections lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplant population. ·There is a direct correlation between the incidence of BKV infection and the degree of immunosuppression, but not the drug itself. ·Other risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection episodes, and previous CMV infections. ·Clinical manifestations of BKV infection range from being asymptomatic to frank nephropathy with disturbed renal function and progressive increase of serum creatinine levels. ·Acute rejection is the main differential diagnosis of BKVN. ·Concomitant administration of agents with immunosuppression reduction is difficult to assess. ·Active screening every 3 months after renal transplant should reduce immunosuppression and follow-up with quantitative PCR and renal function tests. ·Newer options, including cellular immunotherapy, may carry potential hope for the treatment of BKV infection. ============================================= What is the level of evidence provided by this article?
Level V.
I agree with your analysis, summary and level of evidence this article provides.I note that you consider adoptive cellular immunotherapy as a future potential.
Introduction:
BK virus belongs to the family of polyoma viridae. It is icosahedral double stranded DNA virus that causes disease in humans. The BK virus is a very ubiquitous virus that infects majority of the people at a very young age – 4-5 years. It was first discovered in a Sudanese transplant who had ureteric stenosis and was named after the patients initials. It mainly causes tubulointerstitial disease and ureteric obstruction in solid organ transplant patients and hemorrhagic cystitis in HSCT patients. It can lead to kidney graft failure in kidney transplant patients. The main risk factor is the degree of immunosuppression. There are 4 subtypes with subtype I being the most prevalent followed by subtype IV
Genome Structure:
It is a small – 40-50nm in diameter -, uncovered, icosahedral shaped virus with a double circular chain. The genome is about 5000 base pairs, contained in the histones derived from host cells. The genomic structure encodes 6 chief proteins divided into 3 regions: early encoding region, late encoding region and non-coding region
Transmission:
Primary BK viral infection occurs in early childhood, on average at 4-5 years. Posible routes of transmission include:
Airborne transmission
Feco-oral route
Urinary-oral route
Organ transplantation
Through transfusion of blood
Maternal to child transmission
Primary infections are often clinically insignificant. The virus has a tropism for the renal tubular cells, parietal cells, transitional structures and Bowmans capsule. In the immunocompetent individuals, the BK virus does not cause any infection. It can lead to asymptomatic viral shedding in the urine in up to 20% of the immunocompetent individuals. The viruria incidence increase up to 60% in immunocompromised individuals.
Risk Factors and Pathogenesis:
The risk factors include:
The degree of immunosuppression
Use of tacrolimus and mycophenolate
Diabetes mellitus
Delayed graft function
Episodes of acute rejection
Concomitant CMV infection
Ureteral trauma
Use of anti lymphocyte antibodies
Maintenance steroid use
White race
Older age
Presence of specific HLA C loci
Presence of high BK virus antibodies
ABO incompatible transplants – They have a higher risk of of BK virus nephropathy as compared to HLA mismatched transplants
Clinical Picture:
Majority of individuals (90%) will have had a BK virus infection. The BK virus enters into a latent phase and reactivates after SOT or HSCT. In SOT, it can cause BKVAN or ureteric stenosis while in HSCT patients, it can cause hemorrhagic cystitis.
Clinical manifestations are as follows:
Asymptomatic
Slow and progressive increase of serum creatinine
Unsuspected finding of progressive renal damage on surveillance biopsy
Usually BK virus infection occurs 10 – 13 moths post transplant but can occur up to 5 years after transplant.
Steps in BK viral infection:
Primary infection
Latent infection
Serologic evidence of infection
Viral activation – evidence of replication by detecting decoy cells, or by quantitative viral PCR in urine or blood
Viral disease – histologic evidence of viral replication and virus-induced tissue damage
BK virus does not cause symptoms
Laboratory findings in patients with BK virus infection include:
Elevated serum creatinine
Urine may show pyuria, hematuria and findings consistent with interstitial nephritis as cellular casts and inflammatory cells
Diagnosis Overview:
A tissue (renal) biopsy is needed for the definitive diagnosis of BKVN. However, as the virus affects patch areas of the kidney and has a predilection for the medulla, the diagnosis may be missed.
Quantitative PCR is used to diagnose viremia, which demonstrates BK viral replication whether there is renal involvement or not.
A definitive diagnosis of BKVN requires characteristic cytopathic changes on the renal biopsy plus positive IHC which has a specificity of 100%. A diagnosis of BKV in a renal biopsy can be missed in 30% of cases because BK virus has a focal tropism for the medulla than the cortex.
In the absence of definitive criteria for BKVN diagnosis, a presumptive diagnosis can be made if there is sustained (> 2 week duration) urinary viral shedding and significant BK viral replication (plasma DNA PCR load > 10,000 copies/ml)
BKVN can be graded histologically into 3 subtypes based on the degree of fibrosis and viral replication
In BKVN, LM would show the following feature:
Basophilic intranuclear inclusion bodies without a surrounding halo
Anisonucleosis, hyperchromasia and chromatin clumping of infected cells
Areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates
Tubular injury in the form of tubular cell apoptosis, desquamation and flattened epithelial lining
Tubulitis with lymphocyte invasion to the BM of the tubular epithelium
In BKVN, EM examination would show the following features:
Viral inclusion bodies with diameter size ranging from: 30-50 nm
Tubular damage including tubular cell necrosis, prominent lysosomal inclusions and luminal proteins and cellular casts
Serology is not helpful in the diagnosis as because majority of the population have been infected by the BK virus and will have positive antibodies
Viral culture is rarely used as a method for BK viral infection outside the research setting
The differential diagnosis includes:
ACR
CMV nephritis
HSV
Adenovirus
Therapeutic Intervention:
Immunosuppression reduction:
This is the mainstay of treatment of BKVN although it carries a high risk of developing rejection. Cidofovir:
There have been case reports and single center studies showing efficacy of the use of cidofovir. However, there have been no RCTs and its use is limited by its nephrotoxicity profile Brincidofovir:
This is a prodrug of cidofovir and has a lower incidence of nephrotoxicity than cidofovir. However, there have only been case reports of the use of brincidofovir. Large multi center RCTs are needed Leflunamide:
This is an immunosuppressive drug that also has in vitro antiviral properties against BK virus. It is normally used in the place of mycophendlate. Several studies have shown beneficial effects when it replaces mycophendlate. However, it is not clear whether the beneficial effects are due to its antiviral effects or the reduced immunosuppression IVIG:
IVIG contains neutralizing antibodies against BKV which would theoretically make it a good therapeutic intervention. However, there have only been case reports and no multi center RCTs Fluoroquinolones:
These drugs can inhibit the replication of BKV and SV40 virus replication in vitro and have been used for treatment of BKVN and as prophylaxis. This is the only group of drugs that has had randomized trials which showed no benefit in renal transplant patients Role of Adoptive cellular therapy:
There has been interest in developing T lymphocytes with activity against BKV and transfusing them into recipients with BKVN. Several techniques have been established to manufacture these T cells and one study showed beneficial effects in HSCT
Conclusion
BK virus is a member of the ubiquitous polyoma virus family. Majority of the human population are infected by the BK virus at a young age. It mainly affects SOT and HSCT and can lead to BKVN, ureteric stenosis and hemorrhagic cystitis. The main risk factor for BKVN is the degree of immunosuppression. A definitive diagnosis of BKVN is made by renal allograft biopsy using IHC and demonstrating characteristic cytopathic changes. In up to 30% of cases, the diagnosis can be missed due to the focal tropism for the medulla. ACR is the main differential diagnosis. The mainstay of treatment includes immunosuppression reduction. Newer option include cellular immunotherapy.
I note that you consider adoptive cellular immunotherapy as a future potential. I agree with your analysis, summary and level of evidence this article provides.
# The objective:
To cover the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.
# Introduction:
*BKV is regarded as one of highly prevalent forms of polyomaviruses leading to infection particularly in immuno – compromised patients.
*In renal transplant recipients can lead to tubulointerstitial nephritis, ureteral stenosis and hemorrhagic cystitis in BMT patients.
* BKV viremia is mainly treated by reduction of immunosuppression (IS), regular follow-up of BKV (PCR) and renal functions to prevent BKV nephropathy that may result in graft failure, so there is challenging between avoiding the rejection which need to keep the IS at adequate level and at the same time it is lead to more BKV viremia and consequently BKVN.
# virology:
*BK virus is a member of the family Polyomaviruses
*Double-stranded DNA virus with icosahedral symmetry.
*It is detected serologically and genotypically into 4 groups with different virulence.
# Genome structure and transcription:
The genomic structure encodes 6 chief proteins divided into 3 regions:
1)Early encoding region
2)Late encoding region,
3)Non coding control region.
# Transmission mechanism:
*Primary BKV infection occurs at 4 to 5 years of age.
*The routes of transmission by:
1) Airborne route through air droplets.
2) A feco-oral route.
3) Urinary-oral route or seroconversion after SOT.
4) Blood transfusion and vertical transmission; as BKV DNA has been found in the placenta, brain, and renal tissue of aborted fetuses.
*Primary polyomavirus infections usually occur during childhood through respiratory or oral routes, it is insignificant; but the virus remains in the renal epithelium.
* In the immunocompetent population, BKV replication is manifested by asymptomatic viruria, and the incidence of shedding is 20%.
*In immunocompromised individuals, the risk of
shedding reaches 60% and the viruria is more common.
* Patients with impaired cell-mediated immunity have a particularly greater risk of BKV infection.
# Risk factors and pathogenesis:
The degree of (IS) mainly with heavy (IS).
*The type of (IS) protocols, more frequent with tacrolimus and MMF.
* Other risk factors but uncommon, DM, delayed graft function, treated episodes of AR, ureteral trauma, use of antilymphocyte antibodies, co-infection with CMV, maintenance steroid IS, older age, white race/ethnicity, and presence of specific HLA- C loci and presences of BKV antibody titers in donors.
*Both HLA and ABO-incompatible transplants have a higher risk of BKV nephropathy, and ABO incompatible are at a higher risk than HLA-mismatched due to higher rate of rejection and need more IS.
#The clinical Picture:
*90% of the people will become BKV seropositive during their life; which reactivates following SOT (BMT&KT).
*Clinical manifestations are:
1) asymptomatic
2) Slow and progressive increase of serum creatinine
3) An unsuspected finding of progressive renal damage (BKVN) on renal biopsy.
*No signs and symptoms are detected with BKV infection. (BKV infection occurs 10 to 13 months after transplant.
BKVN may occur earlier at week 1 or as late as 5 years after transplant).
# Laboratory findings :
1) Elevated serum creatinine.
2) Urine cytology (the presence of decoy cells increases the suspicion of BKV nephritis, the infected cells is an enlarged nucleus with a single, large basophilic intranuclear inclusion.
3)Urine electron microscopy: will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen
4) Quantitative PCR of blood preferable to urine.
5) Biopsy is needed for a definitive diagnosis of BKVN which requires characteristic cytopathic changes and positive IHC (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic.
# Differential diagnosis:
BK virus infection can be similar to other types of viral infections.
# Therapeutic interventions: *Immunosuppression reduction:
Reduction of IS considered as keystone in the management of BKV infection, but it has a high risk of rejection that making this decision challenging.
*Cidofovir:
Assocated with nephrotoxicity, thus making the decision to use cidofovir unlikely.
*Brincidofovir (CMX001):
It is a prodrug of cidofovir that is administered orally.
Larger-scale clinical trials are needed to establish it is safety and efficacy.
*Leflunomide:
Studies showed association between leflunomide and decrease in BKV viral load; but, this does not reflect whether it is a result of IS reduction or antiviral properties of leflunomide.
Side effects of leflunomide include TMA, hepatitis, and BM suppression.
*Intravenous immunoglobulin:
It contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKV; however, no controlled studies have been reported.
*Fluoroquinolone:
In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV, but overall, the data suggest that fluoroquinolones do not currently have a clinically significant role in the management of BKV-related diseases.
*Cellular immunotherapy in the management:
Newer options, including cellular immunotherapy, may carry potential hope for treatment of BKV infection.
# What is the level of evidence provided by this article?
I agree with your analysis, summary and level of evidence this article provides. I note that you consider adoptive cellular immunotherapy as a future potential
BK polyomavirus is a significant risk factor for graft dysfunction and failure in renal transplant recipients, and no specific treatment or prophylaxis is available.
Risk factors include elderly recipients, prior rejection episodes, male sex, human leukocyte antigen mismatching, prolonged coldischemia time, pretransplant BK virus serostatus, andureteral stenting.
Regular follow-up is effective in detecting patients with BK virus and preventing allograft loss.
BKV reactivation after solid-organ transplant can lead to tubulointerstitial nephritis and/or ureteral obstruction in bone marrow or kidney transplant recipients, as well as hemorrhagic cystitis in other immuno-compromised patients.
BK virus nephropathy can occur 10-13 months posttransplant, with elevated serum creatinine, pyuria, hematuria, and findings of interstitial nephritis.
Diagnosis Overview
A tissue biopsy is needed to diagnose BKVN, but patchy viropathic lesions may lead to missed diagnosis.
Quantitative PCR of blood is preferable to urine.
Definitive diagnosis of BK virus nephropathy
A definitive diagnosis of BK virus nephropathy requires characteristic cytopathic changes, immunohistochemistry, and pathognomonic results, and can be done if there is sustained urinary viral shedding and significant BKV replication.
BKVN is characterized by basophilic intranuclear viral inclusions, anisonucleosis, hyperchromasia, chromatin clumping, tubular damage, tubular injury, lymphocyte invasion, and allograft rejection.
Differential diagnosis of BKVN requires blood quantitative PCR and characteristically pathologic morphology results.
BKV-infected cells have an enlarged nucleus with a single basophilic intranuclear inclusion and cytopathologic changes suggestive of polyomavirus infection.
Decoy cells are not definitive for BKV infection, but their absence does not exclude the disease.
Quantitative polymerase chain reaction detected BKV DNA in 78 transplant patients, but only 2 of 41 without Nephropathy and 0 of 17 nontransplant patients with advanced human immunodeficiency virus infection.
Renal transplant recipients can be monitored with quantitative or real-time PCR for BKV infections in plasma or urine, and viruria precedes viremia by 4 weeks.
Viral replication is present in 20-60% of renal transplant recipients, with 10-30% showing levels of BKV viremia in the first 6 months.
Medical decisions should be made based on trends in quantitative DNA levels, rather than on a single measure.
Serology is not necessary to diagnose BKV infection, but the risk of developing higher levels of BKV IgG is directly correlated with donor anti-BKV antibody positivity.
Antibody levels before and after transplant are not clear, and it is not entirely clear which antibodies are neutralizing.
viral culture
Viral culture is not suitable for BKV detection outside the research setting.
Urine electron microscopy can be used to diagnose BKVN in kidney transplant recipients, but it depends on a sophisticated analysis and interpretation by pathologists.
The presence of a high load of Haufen with equivocal biopsy could support medical decisions of reduction of mimmunosuppression rather than augmentation.
Therapeutic interventions are needed to manage BKV infection in renal transplantation, with the usual approach being reduction of immunosuppression and continuous monitoring using quantitative PCR.
Immunosuppression reduction
Immunosuppression reduction has been the cornerstone of BKV infection management, but it carries a higher risk of rejection due to the presence of viral inclusions and SV40 immunohistochemistry.
Cidofovir
Cidofovir has potential for immunosuppression reduction, but nephrotoxicity makes its use unlikely.
Brincidofovir
Has shown a lower incidence of nephrotoxicity and successful outcomes in renal and hematopoietic transplant, but larger-scale clinical trials are needed to confirm safety and efficacy.
Leflunomide
Leflunomide is an immunosuppressant agent that has antiviral properties against BKV in vitro.
Studies have shown a significant association between it and decrease in BKV viral load, but this does not reflect the cause.
Side effects include thrombotic microangiopathy, hepatitis, and bone marrow suppression.
Intravenous immunoglobulin
IVIG is a good choice for BKVN management, but no controlled studies have been reported.
Fluoroquinolone
Fluoroquinolones have an inhibitory effect on BKV replication in vitro, and may have a role in preventing replication in renal transplant recipients.
However, they do not currently have a clinically significant role in the management of BKV-related diseases.
Role of cellular immunotherapy in the management of BKv infection
Cellular immunotherapy has been used to treat BKV-associated diseases since the early 1990s, using T cells to restore antiviral immunity in immunocompromised patients.
Identifying viral immunogenic antigens is necessary for successful generation of virus-specific T cells, and data on immunodominant BKV epitopes for T-cell priming are limited.
Blyth and associates recently reported the use of overlapping peptide pools derived from all 5 BKV antigens to expand T-cell populations.
BK virus (BKV) is a member of human polyomaviruses, which can lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplant population.
There is a direct correlation between the incidence of BKV infection and the degree of immunosup-pression, but not the drug itself. Risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection episodes, and previous CMV infections.
Clinical manifestations range from asymptomatic to frank nephropathy with disturbed renal function and progressive increase of serum creatinine levels.
Diagnosis is made by immunohistochemistry and serum and urine quantitative PCR.
There are no available antiviral medications for BKV infections, and there are few controlled studies on management.
==================================================================== What is the level of evidence provided by this article?
The level of evidence provided by this article is V
Please summarise this article. BK virus is an important risk factor for graft dysfunction and renal failure. Currently prophylaxis and treatment for BK virus infection is not established. The main risk factors include immunosuppression , elderly recipients, prior rejection episodes, male sex, human leukocyte antigen mismatching, prolonged cold ischemia time, pretransplant BK virus serostatus, and ureteral stenting. Newer management options are being developed. The management options have been reduction of immune suppression, regular follow up and monitoring.
Virology BK virus is double-stranded DNA virus with icosahedral symmetry divided into four groups.
Risk factors and pathogenesis The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used. Other risk factors are diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci.
Clinical Picture · Graft dysfunction and failure · Asymptomatic · Slow and progressive increase of serum creatinine · An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy
Diagnosis Renal Biopsy Quantitative PCR Decoy cells in urine Suspect BK virus in tubulointerstitial nephritis Definitive diagnosis of BK virus nephropathy It requires cytopathic changes on the renal biopsy plus positive immunohistochemistry against BKV or against SV40 large T antigens. Differential diagnosis Differential diagnosis BK virus infection can be similar to other types of viral infections (CMV, herpes simplex virus, adenovirus) Urine cytology findings for BK virus infections The infected cells is an enlarged nucleus with a single, large basophilic intranuclear inclusion- Decoy Cells Other test Quantitative polymerase chain reaction Viral serology It is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection because positivity for these antibodies is quite common in the general population Urine electron microscopy It will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen Therapeutic interventions immunosuppression reduction The reduction of immunosuppression has been the cornerstone in the management of BKV infection, it also carries a higher risk of rejection, making this decision challenging. Cidofovir Limitations of this approach is nephrotoxicity, thus making the decision to use cidofovir unlikely Brincidofovir (CMX001) Larger-scale clinical trials are needed to establish the safety and efficacy of brincidofovir in the management of BKVN p Leflunomide intravenous immunoglobulin In patients with hypogam – maglobulinemia, IVIG therapy was beneficial with regard to anti-BKV immunity; the immunomod ulatory effects of IVIG may guard against allograft rejection. Fluoroquinolone Data suggest that fluoroquinolones do not currently have a clinically significant role in the management of BKV-related diseases Conclusions · There is a direct correlation between the incidence of BKV infection and the degree of immunosup – pression, but not the drug itself · The risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection episodes, and previous CMV infections. · Clinical manifestations of BKV infection range from being asymptomatic to frank nephropathy with disturbed renal function and progressive increase of serum creatinine levels · Acute rejection is the main differential diagnosis of BKVN · There are no available antiviral medications for BKV infections · The common approach for BKV infection management is active screening every 3 months after renal transplant; with any levels of BKV viremia, immunosuppression should be reduced · Newer options, including cellular immunotherapy, may carry potential hope for treatment of BKV infection What is the level of evidence provided by this article? Level V
Human Polyomavirus HPvY has been associated with development of malignancies. HPyY has been associated with skin cancer and , Merkel cell carcinoma (MCC). This review is about the BK virus BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
Tropism and epidemiology
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old.
Following primary infection, BKPyV persists in the kidneys. If the host becomes immunosuppressed, the virus causes significant morbidity.
Transmission can be feco oral, trnasplacental or by vertical route.
Currently there no significant evidence of association with BKPyV and malignancy.
Role in development of malignancy
The oncogenic properties of BKPyV are welldemonstrated in in vitro and in vivo
Two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg)
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase
Transforming ability of BKPyV is welldocumented in experimental rodent models, definitive transforming activity is not always observed in human
Inactivation of tumour suppressor gene has a role .
Alteration in chromosomal activity
Main association with bladder and prostate cancer.
Conclusion
· At the moment there is no conclusive evidence of role of BKPyV in the development of cancer
· The investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumours are required
Update on the Management of BK Virus Infection Introduction ▪︎BK polyomavirus (BKV) is one of the highly prevalent forms of polyomaviruses
causing infection in immuno -compromised patients. It can lead to tubulointerstitial nephritis and ureteral stenosis in renal transplant recipients.
▪︎The current consensus on management of BKV viremia is: 1. Decrease immunosuppression (IS) 2. Regular follow-up of BKV polymerase chain reaction (PCR), 3. Continuous monitoring of renal functions ▪︎The challenging part in the management of BKV infection is the balance between the fear of rejection due to reduction of IS and the maintenance of IS at the same level, which can lead to BKV viremia and so BKVN. Virology BK virus is a member a double-stranded DNA Polyomaviruses Transmission mechanism ▪︎Primary BKV infection occurs on average at 4 to 5 years of age. ▪︎Possible routes include the following: (1) airborne transmission through air droplets (2) a feco-oral transmission (3) urinary-oral route or seroconversion after solid-organ transplant. (4) blood transfusion and vertical transmission. Risk factors and pathogenesis The degree of immunosuppression rather than the type of immunosuppression used. Immunosuppressive agents can affect T cells, which can lead to increased BKV replication. Clinical Picture of BK virus infection In kidney transplant recipients, reactivation may lead to BKVN, which may end with graft dysfunction and failure by causing tubulointerstitial nephritis and/or ureteral obstruction. ▪︎Clinical manifestations: (1) asymptomatic, (2) slow and progressive increase of serum creatinine, and (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy. Importantly, no signs and symptoms are identified with BKV infection. ▪︎Laboratory findings: (1) elevated serum creatinine. (2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts. However, these results could be normal. Diagnosis Overview 1. A renal biopsy for a definitive diagnosis. 2. Quantitative PCR to diagnose BKV viremia ▪︎BK virus nephritis is suspected when the clinical diagnosis of tubulointerstitial nephritis is suspected. ▪︎The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis, which should be followed by quantitative PCR of blood preferable to urine. Definitive diagnosis of BK virus nephropathy ▪︎Requires: Characteristic cytopathic changes on the renal biopsy pluse positive IHC. ▪︎In the absence of definitive criteria, a presumptive diagnosis can be done if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction. ▪︎BKVN can be graded into 3 grades using Banff criteria according to the percentage of fibrosis and the amount of viral replication. ▪︎Light microscopy and electron microscopy examinations; which will show features of BKV nephropathy. Differential diagnosis Other types of viral infections (CMV, herpes simplex virus, adenovirus). ▪︎ To confirm a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed. Urine cytology findings for BK virus infections ▪︎Urine examinations may reveal BKV-infected cells (an enlarged nucleus with a single, large basophilic intranuclear inclusion which have been called decoy
cells) ▪︎Viral replication in the urine is demonstrated by either decoy cells or BKV urine quantitative PCR. ▪︎Quantitative PCR analyses ▪︎Serology is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection
▪︎Viral culture is rarely used ▪︎Urine electron M will show Haufen
◇ Therapeutic interventions ▪︎The usual approach in the management of BKV viremia or BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR. ▪︎Other therapeutic options: – Cidofovir: one of the limitations is nephrotoxicity, thus making the decision to use cidofovir unlikely.
– Leflunomide & Brincidofovir larger-scale clinical trials are needed to establish their safety and efficacy. – Intravenous immunoglobulin: contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKVN. – Fluoroquinolone (immunosuppression rather than augmentation as in cases of rejection.
-There is a possibility of management of BKV infection using the adoptive transfer of BKV-reactive T cells.
◇ Conclusions ▪︎There is a direct correlation between the incidence of BKV infection and the degree of immunosuppression, but not the drug itself. Other risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection
episodes, and previous CMV infections.
▪︎Clinical manifestations of BKV infection range from being asymptomatic to frank nephropathy. ▪︎ A definitive diagnosis of BKVN is made by renal allograft biopsy using immunohistochemistry, which cross-react with the BKV, specifically SV40 large-T antigen part of the virus. ▪︎BK virus nephropathy could be missed in about one-third of patients; therefore, 2 core biopsies are needed for confirmation, preferably including the medulla. ▪︎ Renal transplant recipients are usually monitored by serum and urine quantitative PCR for BKV DNA. ▪︎Acute rejection is the main differential diagnosis of BKVN. ▪︎There are no available antiviral medications for BKV infections. ▪︎The common approach for BKV infection management is active screening every 3 months after renal transplant; with any levels of BKV viremia, IS should be reduced and there should be continuous follow-up of BKV viremia levels using quantitative PCR and RFTs. ▪︎ Newer options, including cellular immunotherapy, may carry potential hope for treatment of BKV infection
2. What is the level of evidence provided by this article? Level V
Polyoma- viruses Are Small DNA Viruses That Can Infect Humans And Animals Like Rabbits, Rodents, And Birds. BK Polyomavirus (BKV) Is Considered One Of The Highly Prevalent Forms Of Polyomaviruses Especially Immunocompromised, BKV In Renal Transplant Recipients Can Cause Tubular Interstitial Nephritis, Ureteric Stenosis & Hemorrhagic Cystitis In Bone Marrow Transplant Recipients.
Virology:
BKV four Gene-typically Gps.
Double-Strand DNA( Polyoma- viruses )
Structure: External Layer Of The Virus Consist Of 3 Structural Protein: VP1(Determine Receptor Specificity), VP2 & VP3 ( Involved In Viral Particle Stabilization Outside Host Cell)
Transmission Mechanisms:
Airborne Transmission Through Air Droplets
A Feco-Oral Transmission.
Urinary-Oral.
Blood Transfusion And Vertical Transmission; As BKV DNA Has Been Found In The Placenta, Brain, And Renal Tissue Of Aborted Fetuses
· Primary Polyomavirus Infections Usually Occur During Childhood Through
Respiratory Or Oral Routes.
It Is Usually Asymptomatic And The Virus Remain In Renal Epithelium (Tubules)
· It Becomes Reactivated In Immunocompromised Patients
Risk Factors:
The Intensity Of Immunosuppression.
Most Common With Tacrolimus And Mycophenolate Mofetil Based IS.
Immunosuppressive Agents Can Affect T Cells, Which Can Lead To Increased BKV Replication.
Other Risk Factors: DM, Delayed Graft Function, Treated Episodes Of Acute Rejection, Ureteral Trauma, Coinfection With CMV, Maintenance Steroid Use, Older Age And White Race/Ethnicity.
Transmitted Infection From The Donor (The Risk Is High With D+ And R-)
ABO And HLA Incompatible Transplantation, Presence Of BKV Antibodies In Donor.
Clinical Features:
About 90% of the population will become BKV seropositive during their life => It reactivates after bone marrow and renal transplantation => In kidney transplant recipients => reactivation may lead to BKVN, which may end with graft dysfunction and failure by causing tubule-interstitial nephritis and/or ureteral obstruction => In bone marrow transplant recipients, BKV can lead to hemorrhagic cystitis, Usually, BKV infection occurs 10 to 13 months post-transplant. BK virus nephropathy may occur earlier at week 1 post-transplant or as late as 5 years post-transplant
Asymptomatic Infection
Slow Raising in Serum Creatinine.
Finding Of Unsuspected Progressive Renal Damage on Renal Biopsy.
BKV Infection Usually Occur Between 10–13-Month Post Transplantation.
Early BKV Infection Can Occur 1 Week Post-Transplant and Late Infection Can Be Occurred After 5 Years.
Elevated serum creatinine
Urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
Diagnosis:
Renal Biopsy Needed for Definitive Diagnosis, But It May Be Missed Due to Patchy Lesion & BKV Involvement Restricted to Medulla.
Presence Of Decoy Cells in Urine Increase Suspicion of BKV Nephritis.
PCR In Blood Indicate Viremia.
Cytopathic Changes in Renal Biopsy with Positive SV40 Staining Has 100% Specificity for BKV Infection.
Presumptive BKVN: Sustained (2weeks) Urinary Viral Shedding & PCR >10000 Copies/ mL with Or Without Renal Dysfunction.
Histologically BKVN Graded Into 3 Grade.
BKVN Microscopical Finding Include:
Basophilic Intranuclear Viral Inclusion Without Complete Halo.
Anisonucleosis, Hyperchromatosis and Chromatin Clumping of Infected Cell.
Tubular Damage with Mononuclear or Polymorphonuclear Cell Infiltrate.
Tubular Injury
Tubulitis With Lymphocyte Invade Tubular Basement Membrane.
Detection Of Decoys Cells in Urine Suggestive of BKV Infection with Low Sensitivity & Specificity, Presence of urine decoy cells (infected cells with an enlarged nucleus with a single, large basophilic intranuclear inclusion) and viral shedding.
N. B: decoy cells is not specific to BKV infection (can be present with CMV or other polyoma viruses) and poorly correlated with BKVN.
BKV PCR Has Sensitivity 100% and Specificity 88%, Confirmed by quantitative PCR (in blood is preferred) > 10000 copies/ml, both can diagnose infection in case with normal biopsy.
Monitoring Of BKV Infection by Blood or Urine PCR.
Viruria Can Precede Viremia By 4 Weeks.
Anti-BKV Antibodies Are Not Useful BKV Infection Diagnosis & It Is Not Protective.
Viral Culture Rarely Used for Diagnosis of Infection Outside Research Setting.
Presence Of Haufen Bodies in Urine Has 100% Sensitivity and 99% Specificity for Biopsy-Verified BKVN, So It Can Be Non-Invasive Method for BKVN Diagnosis in Renal Transplant Recipients.
Differential Diagnosis of BKV Infection Include CMV, Adenovirus & Herpes Simplex Virus.
Serology:
Not recommended to test for BK virus antibodies.
DD: CMV infection, adenovirus and HSV.
Treatment:
There are no available antiviral medications against BKV.
The usual approach in the management of BKV viraemia or BKVN in renal transplant recipients is the IS Reduction and monitoring of BKV viremia levels using quantitative PCR.
Cidofovir: Multiple single-center studies and case series have described the benefits of adding cidofovir with immunosuppression reduction. It is associated with nephrotoxicity.
Brincidofovir: a pro-drug of cidofovir administered orally to avoid the nephrotoxic effect. Some reported successful outcomes in small scale studies.
Leflunomide: IS agent with antiviral properties. No available RCT to prove its effect.
IV Immunoglobulin: the available Ig contains neutralizing antibodies against BK virus. Till now, not recommended as a treatment.
Flouroquinolone: In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV. However, RCT did not prove it.
Cellular Immunotherapy Can Be Effective in Treatment of BKV Infection.
Introduction
It is a polyomavirus with latency mainly in renal tubules that can be reactivated with immunosuppression mainly in kidney and bone marrow transplants
Risk factors
– D+/R-
– Combined CNI and MMF immunosuppression
– Use of rATG for induction
– Coinfection with CMV
– Advanced age
– acute rejection
– HLA mismatch
– Caucasians
Clinical presentations
– Asymptomatic
– Slow progression of creatinine levels
– Occasional biopsy finding of nephropathy
– Investigation of kidney damage (nephropathy)
Diagnosis
– Biopsy is the most appropriate, including graduations in A, B or C
– Viruria and viremia.
– Presence of decoy cells in the urine
Treatment
There is no specific treatment and adequate studies are lacking to establish an effective treatment. Decreasing current immunosuppression is still the most effective way to treat the patient.
New models of immunotherapy with positive donor blood using CART cells may be a more effective answer in the future, but studies need to be carried out.
Summary review Update on the Management of BK Virus Infection 2020
This article address, the diagnosis, screening, diagnostic tools, and updated management of BK virus infections. Introduction:
Polyomaviruses are small DNA viruses that can infect humans and animals.
BK virus has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence.
BKV is considered one of the highly prevalent forms of polyomaviruses causing infection in humans, especially in immunocompromised patients including pregnant women.
Transmission:
Primary BKV infection occurs in the first decade of life (4 to 5 years of age).
Routes of transmission include, airborne transmission, a feco-oral transmission, including urinary-oral route or after solid-organ transplant and through blood transfusion and vertical transmission.
Risk factors:
Tacrolimus and MMF based immunosuppression protocols.
Others include, DM, DGF, treated episodes of AR, ureteral trauma, use of antilymphocyte antibodies, coinfection with CMV, and older age.
Viruria in a potential donor is considered as a risk factor.
HLA and ABO-incompatible transplants.
Clinical Picture of BK virus infection
About 90% of the population will become BKV seropositive during their life.
This reactivates after solid-organ transplant, especially in bone marrow or kidney transplant recipients.
In kidney transplant recipients, reactivation may lead to BKVN, which cause tubulointerstitial nephritis and/or ureteral obstruction, which can lead to graft dysfunction or failure.
No signs and symptoms are identified with BKV infection.
It can present as slow and progressive increase of serum creatinine, or BKVN on surveillance renal allograft biopsy.
BKV infection occurs 10 to 13 months post-transplant, but can occur as early as week 1 post-transplant or as late as 5 years post-transplant.
Diagnosis Overview
Can presented with elevated serum creatinine and urine analysis with pyuria, hematuria, cellular casts, and note that this may be normal.
The presence of decoy cells in the urine analysis increases the suspicion of BKVN
Quantitative PCR of blood preferable to urine.
Acute rejection is the main differential diagnosis of BKVN. BK virus nephropathy could be differentiated from AR with BKV inclusions and immunohistologic analyses. In addition, it is important to correlate histologic findings with PCR evidence of viremia.
Definitive diagnosis of BK virus nephropathy
A definitive diagnosis of BKVN requires characteristic cytopathic changes and positive immunohistochemistry (against BKV or SV40 large T antigens), which has a specificity of 100% and 88%, specifity.
A diagnosis of BKV in a renal biopsy could be missed in about 30% of cases because BKV has a focal tropism in the medulla rather than in the cortex. 2 core biopsies are needed for confirmation, preferably including the medulla.
Specific histologic patterns of BKVN include Cytopathic/cytolytic changes with or without patchy or diffuse tubulointerstitial inflammation and atrophy.
Presumptive diagnosis: In the absence of the specific histologic pattern, presumptive diagnosis can be made if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL).
It is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection.
Viral culture takes weeks to months so is not clinically applicable.
Recommendations for BK Virus Screening:
Pre-transplant screening currently not established.
Post-transplant screening: monthly till 9 months then every 3 months until 2 years and if the patient develop allograft dysfunction.
Usually monitored by serum and urine quantitative PCR for BKV DNA. Viral replication goes through stages, with viruria preceding viremia by about 4 weeks and nephropathy by 12 weeks.
Management of BKVN:
The usual approach in the management of BKV viremia or BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR.
Concomitant administration of antiviral agents (including cidofovir, leflunomide, fluoroquinolone and intravenous immunoglobulin) with immunosuppression reduction was only documented in uncontrolled retrospective observational studies; therefore, it is difficult to make firm conclusions about their therapeutic efficacy.
The common approach for BKV infection management is active screening every 3 months after renal transplant; with any levels of BKV viremia, immunosuppression should be reduced and there should be continuous follow-up of BKV viremia levels using quantitative PCR and renal function tests.
Adoptive T-cell therapy to restore antiviral immunity in immunocompromised patients may carry potential hope for treatment of BKV infection. Level of evidence: level v
BK virus is DNA polyoma virus that infects human especially immunocompromized individuals. It was first isolated in 1971 in a renal transplant recipient. BK virus may cause Tubulointerstitial, nephritis, ureteric stricture and associated with risk of graft rejection. There are four serotypes, among which serotype 1 is most prevalent. Mode of transmission;
Primary BKV occurs in first decade of life and tends to be dormant. It is transmitted via air droplets, fecal –oral and blood transfusion or solid organ transplant. BKV infection occurs during immunosuppression phase and viruria occurs in up to 60% patients. BKVN prevalence is reported in 5% patients of kidney transplants. Risk factors for BKV; · Mainly the degree of immunosuppressant and immunosuppressive drugs like ATG, MMF and Tacrolimus. · History of Diabetes mellitus · DGF · HLA mismatch · ABO incompatibility and · Allograft rejection. Presentation
· Asymptomatic
· Slowly raising creatinine
· Progressive renal damage on surveillance biopsy. Diagnosis:
Kidney Biopsy is definitive diagnostic tool but can miss diagnosis in 30% due to focal tropism in medulla. Usual biopsy finding are
1. Cytopathic changes with immunohistochemistry (SV 40)
2. Basophilic Viral inclusion on EM
Other diagnostic tests are:
· DNA PCR plasma
· DNA PCR urine
· Decoy cells in urine Differential diagnosis
· CMV infection
· Adenovirus and
· HSV infection Therapeutic intervention;
Ø There is no specific treatment available so for against BKV, although there are reports on the use of some medications. The key intervention is reduction of immunosuppression some time stopping it altogether with greater risk of rejection.
Ø Cidofovir ———-risk of nephrotoxicity
Ø Brancidofovir———-In phase III trial
Ø Lefulonmide——–Risk of TMA and marrow suppression
Ø IVIG —————No controlled study only case reports
Ø Flouroquinolone —-no evidence
Ø Immunotherapy ——adoptive immunotherapy with positive results. Conclusion:
BKV is a human polyomavirus with incidence of 10% in renal transplant patients depending on in immunosuppression dosage and other risk factors like diabetes, old age recipient, HLA mismatches, ABO incompatibility, Male gender, acute rejection and delayed graft function. The choice of investigation in kidney biopsy and mainstay of treatment is reduction of immunosuppression. Level of evidence
Level -V
BKV is a small DNA virus, member of polyoma virus family, first isolated in 1971.
serologically/genetically …..4 types
causes infection in human, especially in immunocompromised patients.
the average incidence about 10% of KTX
the management mainly focus on reduction of immunosuppresant medications, contiouns follow up via PCR and balance between preventing BKVN and risk of rejection
route of transmission …..air droplets (airborne), feco-oral/ uro-oral, solid organ transplantation, blood transfusion and vertical (placenta).
classification of infections: 1.primary infection:
usually in first decade ,around 4-5 year
often clinically insignificant/asymptomatic
the virus stays within the kidneys
2.latent infection 3.serologic evidence of infection 4.viral activation 5.viral disease
Risk factors:
Absolute: degree of immunosuppression rather than type of immunosuppression
Relative : DGF,DM, treated episodes of acute rejection, ureteral trauma, use of ATG , co-infection with CMV, maintenance steroid therapy, older age, white race and presence of HLA C loci
clinical picture:\
90% seropositive during their life
reactivation of infection after transplantation/immunocompromised such as kidney and BM
in renal transplant cases causes both graft dysfunction and failure
in KTX …tubulointerstitial nephritis & ureteral stenosis
also lead to haemorrhagic cystitis especially in BM transplantation
asymptomatic
slow & progressive increase of serum creatinine
progressive renal damage (BKVN) on renal allograft biopsy
DIAGNOSIS:
URINE ANALYSIS: + renal function
may show haematuria, pyuria and cellular casts (interstitial nephritis)
decoy cells (BKV infected cells)
2 . PCR urine and blood (preferable) 3.biopsy (definitive)…IHC SV40 large T antigen/ require 2 core biopsy including medulla, 100% specific
stages of infection:
viruria
viremia
nephropathy
DDX.:
Other viral infections (CMV, herpes virus, adenovirus)
rejections vs BKVN
BKVN biopsy can be classified :
specific histologic patterns into A,B &C
Banff Grading into 1,2 &3
Treatments:
no definitive antiviral therapy
main treatment reduction of immunosuppresant
newer options such as cellular immunotherapy probably hope in future
BK virus is of polyomavirus family. A small DNA virus infecting human and other animals. It was first isolated in 1971 in a Sudanese renal transplant recipient and the virus name is actually his initials name of the patient. The viral genome (5000 base pairs) encodes 6 major proteins and classified into 3 regions:
early encoding region,
late encoding region,
and non-coding control region
In immune compromise patients BKV is associated with graft loss, ureteric stenosis & hemorrhagic cystitis.
Transmission
Usually, infection occurs in first few years of life. Many routes are responsible for its spread including air-bone, feco-oral, urinary-oral, organ transplantation, blood transfusions, & vertical. Primary infection is usually not clinically relevant.
Risk factors:
The major risk factors is immune-compromised host due to immunosuppression. Other risk factors includes; old Age (elderly), male gender, past history of acute rejection, the number of HLA mismatches, prolonged cold ischemia, BKV negative status before transplant, and co-infection with CMV.
Clinical picture:
The patient may be asymptomatic or having slowly progressive renal dysfunction or,allograft damage on routine surveillance biopsy.
Diagnosis:
BKVN IN 30% of cases is focal disease in nature and it may involve the medulla
only rather than the cortex diagnosed on histopathology.
Three main biopsy pattern are seen
early or pattern A (cytopathic changes with no inflammation)
pattern B (cytopathic changes + patchy or diffuse tubulointerstitial inflammation)
Late or pattern C (Graft fibrosis). The definitive diagnosis is cytopathic changes in the biopsy + immune histochemistry (SV40).
Presumptive diagnosis is sustained viral shedding in the urine + BKV viremia > 10,000 copies/ml
looking in Urine for decoy cells
blood BKV PCR load
Serology: may not be helpful and Viral culture are used mainly in research setting
Differential diagnosis:
all other viral infections can be in DD e.g. CMV, HSV, & adenovirus
Treatment:
Reduction of immune suppression by reducing initially MMF and CNI if needed meanwhile looking for the risk of rejection.
Cidofovir; no major RCTs are available and are nephrotoxic as well.
Brin-cidofovir; prodrug of cidofovir therefor less nephrotoxic but more studies are needed
Leflunomide have been shown to decrease BKV viral load but it was not clear if this was due to reduction of immunesuppression or antiviral properties of leflunomide itself. the major side effects are association with TMA, hepatitis, & myelosuppression.
IVIG; again, no strong evidence is available as no RCTs have been carried out.
Fluoroquinolones; although in vitro it has shown inhibitory effect on BKV, but a single RCT conducted showed negative result.
Cellular immunotherapy; the is to restore anti-viral immunity in immune compromised hosts and still in research stage.
Conclusion
BKV is a member of polyomaviridae family acquired during the first few years of life .
Have been associated with allograft loss in renal transplantion The important risk factor is over-immune suppression.
The diagnosis is based on biopsy and immune histochemmistry (SV 40) but the biopsy may be negative in one-third cases because of patchy involment.
Urine decoy cells and BKV viremia are helpful for the diagnosis.
The treatment is mainly reduction of immune suppression with close monitoring for response or rejection. More studies are needed to consider the role of other adjunct therapies such antibiotics.
-What is the level of evidence provided by this article?
Polyomavirus, a DNA virus, infect human and animals.
Causes and more prevalent in immunocompromised patients.
Challenging management, based on balancing IS reduction as a gold standard treatment of BKV infection and risk of rejection.
Virus properties:
Double-strand DNA.
Categorized into 4 groups (I-IV), with different virulence.
1st discovered in 1971 in a Sudanese transplanted patient who came with ureteral stricture post-transplant.
Transmission:
Oro-fecal.
Uro-oral.
Airborn.
Sero-conversion after SOT.
Blood transfusion.
Vertical transmission.
Primary infection happens during childhood during at 4-5 years of life and is deposited in the organs and tissues (epithelial cell in the tubules and Bowmanes capsule), manifested as asymptomatic viruria and shedding is about 20%, rising up to 60% in immunocompromised patients. Risk factors:
Degree of IS.
Type of IS protocol, mostly TAC/MMF.
Depleting agent.
Acute rejection.
DGF.
D+/R-.
DM.
SLE, and other autoimmune diseases.
HLA, ABO incompatible, (exposed to heavy IS).
Clinical manifestation:
Asymptomatic.
Slaw rising creatinine.
BKVN.
Usually, BK infection occurs in 1st 10-13 months post-transplantation, but it can occur as earlier as 1st week and as late as 5 years postTx. Diagnosis:
Definitive diagnosis is biopsy-based, with areas of missing because of patchy patterns in some stages.
Quantitative PCR for BK viremia.
Urine Decoy cells, pyuria, hematuria, and cellular cast suggestive of tubulointerstitial nephritis.
Immunohistochemistry; against BK virus, or SV40 large T antigen,, pathognomic.
In a lightmicroscope;
1. Basophilic intranuclear viral inclusions without a surrounding halo. 2. Anisonucleosis, hyperchromasia, and chromatin clumping of infected cells. 3. tubular damage. 4. Tubular injury. 5. Tubulitis with lymphocyte invasion to the BM of the tubular epithelium.
Electronmicroscopy:
1. Viral inclusions. 2. Tubular damage. Banff Grading of BK virus nephritis:
Pattern A; cytopathic/cytolytic changes with minimal inflammation.
Pattern B; cytopathic/cytolytic changes associated with tubulointerstitial inflammation and atrophy.
Pattern C; graft sclerosis.
Steps of infection of BKV:(European Society Of Organ Transplantation 2006):
Primary infection; host infection and viral spreads in tissues.
Serologic evidence of infection; variations in antibody titer.
Viral activation; evidence of replication.
Viral disease; histologic evidence of viral replication in organs
Differential Diagnosis:
CMV infection.
Herpes simplex.
Adenovirus.
Management:
IS reduction, 30-50% of the maintenance dose.
1. Switch from TAC to CsA. 2. Switch MMF to mTORi.
IS reduction plus cidofovir, adverse; nephrotoxicity.
IS reduction plus leflunomide.
IS reduction plus IVIG.
Fluoroquinolone antibiotics; inhibit replication.
Follow-up response:
Serum Cr q 1 week.
Plasma BKPyV load q2 weeks.
Conclusion: BK viral infection is causing TIN and ureteral strictures, with an average incidence of about 10% in transplanted patients. Incidence and viral reactivation and replication depend on an intensive immunosuppressant regimen. Risk factors associated with BKV infection should be considered. BKV infection may be manifested as asymptomatic to invasive disease. Allograft biopsy-based diagnosis, with pathognomic immunohistochemistry against SV40 large T antigen. BKV infection should be differentiated from acute rejection. No specific antiviral medication proven till now, and concomitant use with IS reduction has been studied only in uncontrolled retrospective observational studies. Level of evidence: Level ((V))
BKV infections cause tubulointerstitial nephritis and ureteral stenosis in the population of kidney transplant recipients. BK virus is a member of the HPV family of DNA viruses. The incidence of kidney transplants is typically 10% of the population.
The prevalence of BKV infection & the level of IS are directly correlated, but not the drug itself.
Risk factors include:
Diabetes mellitus
Older patients
Male patients
DGF
Acute rejection episodes
Prior CMV infections
Clinical manifestations of BKV infection:
Asymptomatic
Slow and progressive increase of serum creatinine
Unsuspected finding of progressive renal damage (BKVN) on protocol biopsy.
Diagnosis:
Urine analysis may show hematuria, pyuria, & cellular casts.
Urine microscopy shows decoy cells.
Renal biopsy employing IHC, which cross-reacts with the BKV, specifically the SV40 large-T antigen component of the virus, is used to provide a conclusive diagnosis of BKVN. For confirmation, two core samples are required, ideally with the medulla included.
Renal transplant recipients are usually monitored by serum & urine quantitative PCR for BKV DNA. Viral replication goes through stages, with viruria preceding viremia by about 4 weeks and nephropathy by 12 weeks.
The main differential diagnosis for BKVN is acute rejection. BKV inclusions & immunohistologic tests can distinguish BK virus nephropathy from other types.
Correlating histologic findings with PCR evidence of viremia is important.
Treatment
There aren’t any antiviral treatments for BKV infections, & no controlled trials on how to treat BKV infections in kidney transplant recipients.
Only uncontrolled retrospective observational studies have reported the concurrent administration of these medications with immunosuppression reduction. It is difficult to draw clear conclusions regarding their therapeutic value.
Commonly used options:
Active screening every 3 months following transplantation.
IS should be reduced at any levels of BKV viremia.
Continuous follow-up of BKV viremia levels using quantitative PCR & renal function tests.
IS drug reduction, the mainstay of treatment, carries a higher risk of rejection making it a challenging decision.
Modification of IS also carries a higher incidence of long term chronic rejection.
Newer options: Cellular immunotherapy:
May carry potential hope for treatment of BKV infection.
It depends on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
============================ 2. What is the level of evidence provided by this article? Level V (Review article)
1-Please summarise this article? Introduction;.
-BK virus is a member of human polyomaviruses, which are DNA viruses
-BKV infections lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplant population. Incidence;.
-The average incidence is about 10% of the renal transplant population.
-There is a direct correlation between the incidence of BKV infection and the degree of immunosuppression, but not the drug itself. Risk Factors;.
-The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used.
-Transplant physicians consider BKV infection as a marker of heavy immunosuppression.
-Other risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection episodes, and previous CMV infections. Clinical Picture of BK virus infection;.
-About 90% of the population will become BKV seropositive during their life,
-Clinical manifestations of BKV infection range from being asymptomatic to frank nephropathy with disturbed renal function and progressive increase of serum creatinine levels.
-Urine analysis may show hematuria, pyuria, and cellular casts.
-Urine microscopy shows decoy cells that are BKV-infected cells. Diagnosis Overview;.
-A definitive diagnosis of BKVN is made by renal allograft biopsy using immunohistochemistry, which cross-react with the BKV, specifically SV40 large-T antigen part of the virus.
-BK virus nephropathy could be missed in about one-third of patients; therefore, 2 core biopsies are needed for confirmation, preferably including the medulla.
-Renal transplant recipients are usually monitored by serum and urine quantitative PCR for BKV DNA.
-Viral replication goes through stages, with viruria preceding viremia by about 4 weeks and nephropathy by 12 weeks.
-Acute rejection is the main differential diagnosis of BKVN. BK virus nephropathy could be differentiated with BKV inclusions and immunohistologic analyses.
-In addition, it is important to correlate histologic findings with PCR evidence of viremia.
Treatment;.
-There are no available antiviral medications for BKV infections, and there are few controlled studies available on management of BKV infection in renal transplant recipients.
-The concomitant administration of these agents (Cidofovir , Brincidofovir , Leflunomide , Intravenous immunoglobulin (IVIG) , Fluoroquinolone) with immunosuppression reduction has been reported in only uncontrolled retrospective observational studies; therefore, it is difficult to make firm conclusions about their therapeutic efficacy.
-The common approach for BKV infection management is active screening every 3 months after renal transplant; with any levels of BKV viremia, immunosuppression should be reduced and there should be continuous follow-up of BKV viremia levels using quantitative PCR and renal function tests.
-Newer options, including cellular immunotherapy, may carry potential hope for treatment of BKV infection. 2. What is the level of evidence provided by this article? (level V evidence)
Update on the Management of BK Virus Infection: This article address the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections. BK virus is common infection post transplant due to use of heavy immunosuppressive therapy and carrying risk for graft rejection and loss. Risk factors of BK virus:
Male
Old age
Previous episodes of rejection
Sero status of BK virus before transplant
Type and Heavy immunosuppressive therapy
Previous episodes of CMV infection
ABO incompatible
DM
There’s no specific treatment for BK virus but serial monitoring of BKV polymerase chain reaction (PCR) and screening for BK virus important to prevent infection.
Cellular immunotherapy is new modality promised to treat infection and also reducing dose of immunosuppressive drug help to treat infection. Introduction:
Polyomaviruses are small DNA viruses that can infect humans and animals.
It’s can lead to interstitial nephritis and ureteral stenosis and haemorrhagic cystitis in bone marrow transplant. Mode of Transmission:
Air droplets
Feco -oral
Urinary -oral
Blood transfusion
Vertical transmission
Transmitted by placenta to neonatal and it’s found in brain and renal tissue of aborted foetus. Clinical picture of BK virus:
Around 90% of population developing BK virus from childhood and reactivated if patient gets compromised or post kidney transplant.
It’s manifested by slow progress of disease and raised creatinine level and unexplained graft kidney failure.
Laboratory studies shows elevated serum creatinine and urine analysis shows pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. Diagnosis:
Presence of decoy cells indicates of BK virus.
Definitive diagnosis by renal biopsy //
Light microscopy examinations shows basophilic intranuclear viral inclusions without a surrounding halo/ anisonucleosis, hyperchromasia, and chromatin clumping of infected cells and areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates // tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining and tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
Extensive BK virus shows evidence of graft rejection.
Electron microscopy examinations shows viral inclusions with diameter size ranging from 30 to 50 nm and tubular damage and cell necrosis.
Absence of decoy cell does not exclude the disease.
Confirm diagnosis by PCR of BK virus.
The onset of viremia occur after 6 months post transplant, and it’s can detected in urine and plasma.
Serology:
Anti-BKV antibodies are not helpful in diagnosis of BKV infection.
During BKV infection, there are high levels of BKV IgG titers during the first 6 weeks of infection or 2 years after primary infection.
Virus culture is rarely done in diagnosis of BKV.
Treatment:
immunosuppression reduction:
But It’s carry risk of rejection. One study suggested that patients with persistent sustained BKV viremia are prone to the development of de novo donor-specific anti-HLA antibodies.
Cidofovir:
It’s unlikely to use because it’s nephrotoxic and no randomized control studies to support this approach. Brincidofovir (CMX001):
It’s prodrug of cidofovir and it’s bring successful outcome in treatment of BKV with brincidofovir. Leflunomide:
There’s good link between leflunomide and decrease in BKV viral load. Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression. intravenous immunoglobulin:
It’s good choice in treatment of BKV. Fluoroquinolone:
It’s inhibit replication of BKV.
Role of cellular immunotherapy in the management of BKv infection:
There’s no specific management to treat BKV. However cellular immunotherapy, may carry potential hope for treatment of BKV infection.
What is the level of evidence provided by this article?
Introduction
BKV are small DNA viruses (Polyomaviruses family)
It can cause tubulointerstitial nephritis, ureteral stenosis, and hemorrhagic cystitis
The main step in the management is to decrease immunosuppressione Aim of the study:address the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections
Virology
Polyomaviruses are small (40-50 nm in diameter), uncovered, icosahedrals, with a double circular chain
Primary infection occurs early (4-5 years of age)
Transmission:
1. Airborne through air droplets
2. Feco-oral
3. Urinary-oral route or seroconversion after solid-organ transplant
4. Blood transfusion and vertical transmission
Prevalence of BKVN in renal transplant recipients is 5%
Risk factors:
1. Degree of immunosuppression (the most important cause)
2. Others include diabetes mellitus, DGF, treated episodes of acute rejection, ureteral trauma, use of ATG, coinfection with CMV, maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci
Clinical Picture
Usually, BKV infection occurs 10 to 13 months posttransplant (may occur earlier at week 1 or as late as 5 years)
Clinical manifestations:
1. Asymptomatic
2. Slow and progressive increase of serum creatinine
3. Unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy
Laboratory:
1. Elevated serum creatinine
2. Urine analysis (pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells)
Diagnosis
A tissue biopsy is the definitive diagnosis (may be missed as the lesions are patchy)
Cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens)
Diagnosis in a renal biopsy may be missed in 30% (It could be patchy or isolated to the medulla)
Presumptive BKVN: sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction
Specific Histologic Findings of BK Virus Nephropathy:
1. Pattern A (Cytopathic/cytolytic changes with absent or minimal inflammation)
2. Pattern B (Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy)
3. Pattern C (Graft sclerosis)
Banff Grading of BK Virus Nephritis:
1. Grade 1( minimal viral replication in < 1% of biopsy with < 25% fibrosis)
2. Grade 2 (any between grades 1 and 3)
3. Grade 3 (marked virus replication in > 10% of cores with > 25% fibrosis)
Electron microscopy:
1. Viral inclusions with diameter size ranging from 30 to 50 nm
2. Tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts
Differential diagnosis
CMV, herpes simplex virus, and adenovirus
Urine cytology
Decoy cells (infected cells with an enlarged nucleus with a single, large basophilic intranuclear inclusion). Strongly suggestive of PKV infections, but not specific, sensitive, and their absence does not exclude the disease
Quantitative PCR
· Urine or plasma
· Sensitivity and specificity is 100% and 88% (plasma)
· Viruria precede viremia by 4 weeks
· During the first 6 months, 10-30% of patients show levels of BKV viremia (decrease later to 5% to 10%)
· Patients with a higher viruria level are highly prone to developing BKV viremia, and patients with high sustained viremia are susceptible to BKVN
Serology
Not helpful:
1. Common in the general population
2. During infection, there are high levels of BKV titers during the first 6 weeks of infection or 2 years after primary infection
Viral culture
Not clinically applicable
Urine electron microscopy
Show cast-like 3-dimensional polyomavirus aggregates (Haufen). It is 100% sensitivity and 99% specificity. Correlated with viremia, AKI and BKVN
Therapy
immunosuppression reduction
Carries a higher risk of rejection and a higher incidence of longterm chronic rejection
Cidofovir
Limited with nephrotoxicity
Brincidofovir (CMX001)
A prodrug of cidofovir that is administered orally
Less nephrotoxic
Leflunomide
Immunosuppressant and antiviral effects
Side effects include thrombotic microangiopathy, hepatitis, and bone marrow suppression
The active metabolite (known as teriflunomide or A771726) can be measured
Intravenous immunoglobulin
Contains neutralizing antibodies against BKV (good choice in the management of BKVN)
Fluoroquinolone
Inhibit replication of BKV or SV40 polyomavirus replication in vitro
Cellular immunotherapy
Transfer of primed BKV-reactive T cells
Interferon-capture technology or major histocompatibility complex multimers
What is the level of evidence provided by this article?
Level V (narrative review)
Review article published in Experimental and Clinical Transplantation (2020)
base of evidence V
Polyoma viruses are DNA viruses infects humans and animals and BK is one of the most common viruses which affect immunocompromised patients like solid organ transplant patients.
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BK is latent virus which activate in 10-20% of cases post-transplant causing viruria in 40% which associated with decoy cells in 30% of cases and progress to viremia after 4w in 20% of cases and finally BKVN in 10% of cases only after 12w. Diagnosis can be made by (as showen in figure 1)
1. PCR in urine if viral load more than 9 log which mean high viral load which probably will progress to viremia with sensitivity 90% and specificity 60%
2. Decoy cells in urine but its not specific as it can occur with other viral infections like herpes and CMV.
3. Urine electron microscopy: 3-dimensional polyomavirus aggregates, which are called Haufen with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients but limited still because need expert pathologist and it can’t diagnosis rejection.
4. PCR in serum which occurs in 20% of cases only who developed viruria with sensitivity 90% and specificity around 95% and if not treated it may progress to BKVN.
5. Kidney biopsy: BK patchy infiltrate tubule-interstitial cell so 30% maybe missed. BKV can lead to tubule-interstitial nephritis and ureteral stenosis. Interstitial inflammation giving picture similar to rejection and difficult to be differentiate and needs immune-histological examination using specific staining to differentiate with adequate sampling including medullary tissue. Specific Histologic Findings of BK Virus Nephropathy Pattern Characteristics (The presence of characteristic cytopathologic changes in infected cells (which have been called decoy cells due to their similarity to renal carcinoma cells) is strongly suggestive of polyomavirus infections.)
Pattern A Cytopathic/cytolytic changes with absent or minimal inflammation (Figure 3)
Pattern B Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy
Pattern C Graft sclerosis Banff criteria
BKVN can be graded into 3 grades according to the percentage of fibrosis and the amount of viral replication.
Grade 1 Minimal viral replication in < 1% of biopsy with < 25% fibrosis
Grade 2 Any between grades 1 and 3
Grade 3 Marked virus replication in > 10% of cores with > 25% fibrosis Treatment approach (as shown in figure 2)
There is no specific treatment and evidence based on retrospective studies and case series and include
· -decrease of immunosuppression 30%-50% with follow up of viral log in serum after 4w with further decrease if needed according to response
· -cidovir
· -baricidovir
· -leflenomide
· -IVIG
· -qunolonesfile:///C:/Users/ramya/AppData/Local/Temp/msohtmlclip1/01/clip_image004.gif
SUMMARY. Introduction.
BK is one of the prevalent forms of polymaviruses. In transplant recipients it causes tubulointerstitial nephritis and ureteral stenosis in kidney transplant recipients and hemorrhagic cystitis in bone marrow recipients.
Current consensus on management is to reduce immunosuppression, monitor renal functions to avoid allograft nephropathy and followup BK virus PCR. Transmission
Primary infection occurs in the first decade of life, average at 4-5 years of life.
Modes of transmission:
fecal oral
aerosol/airborne
Blood and vertical transmission
others: urinary-oral, after SOT.
Primary infection occurs through oral and respiratory route, it’s mainly clinically asymptomatic. It then remains dormant in the kidneys-tubular, parietal, transitional structures and Bowman’s capsule.
Immunocompetent individuals BKV replication is manifested by asymptomatic viruria with 20% incidence of shedding. While the immunocompromised have 60% incidence.
Risk factors
Degree of immunosuppression.- Most important. BKV infection is associated as a marker of heavy immunosuppression.
Others: DM, DGF, treated episodes of rejection, older age, white race, CMV co-infection, HLA C loci.
Presence of donor BKV antibodies- indicates recent reactivation and replication.
HLA and ABO incompatibility in donor and recipients- could be due to heavy immunosuppression use.
Clinical manifestations
Includes:
Asymptomatic
Slow rise in serum creatinine
Unexpected finding of progressive renal damage on surveillance biopsy.
Diagnosis
A renal biopsy required for definitive diagnosis, however may be missed because the lesions are patchy.
Diagnosis requires characteristic cytopathic changes plus positive immunohistochemistry against BKV or SV40 large T antigens.
May miss 30% of cases due to focal tropism in the medulla thus initial biopsy is not enough to rule out highly suspicious cases.
Presumptive diagnosis is made when there is persistent viruria (more than 2 weeks) and significant viral replication(plasma DNA PCR>10,000copies/ml). Serology for antibodies: Not found to be helpful since they are not protective. Viral culture: takes weeks to months to isolate a specimen thus not routinely done outside research. Urine electron microscopy: Haufen bodies have 100% sensitivity and 99% specificity for detection of biopsy proven BKVAN. Thus it’s a non-invasive method of differentiating BKVAN and BKV infection. However it doesn’t differentiate between BKVAN and rejection and requires sophisticated analysis and tedious interpretation by pathologists.
Treatment
No antivirals approved.
Cornerstone of management is reduced immunosuppression that carries a risk of rejection. Cidofovir: No RCT to support its use and its nephrotoxic. Brincidofovir: Prodrug of cidofovir that is oral. Less nephrotoxic. Larger clinical trials needed to establish its use. Leflunomide: Immunosuppressive drug with antiviral properties. RCT required to confirm its safety and efficacy. IVIG: Its immunomodulatory effect may guard against rejection in context of reduced immunosuppression. No RCT Fluoroquinolone: Retrospective studies had shown a role in prophylaxis against BKV infection. However prospective studies have shown no benefit. Further studies required. Cellular immunotherapy: Based on transfer of primed BKV T cells to control the replication.Studies are still in the early stages.
Level of evidence: This is a narrative review hence level V.
Update on the Management of BK Virus Infection. Introduction.
It is considered small DNA virus that infect humans who are immunocompromised such as post kidney transplant which may affect graft survival and lead to many co-morbidities such as tubulointerstitial nephritis and ureteral stenosis; it can also lead to hemorrhagic cystitis, and it is management mainly depends on Immunosuppression medications reduction with balance to avoid the risk of rejection. Genome structure and transcription.
Polyomaviruses are small (40-50 nm in diameter), uncovered, icosahedral, with a double circular chain, serologically and genotypically into 4 groups (I to IV). Route of transmission:
Multiple Faeco-oral, Respiratory, Organ transplantation and Transplacental. Risk factors and pathogenesis.
Primary infection occurred in childhood and then latent infection in renal tubules and urothelial cells, reactivation, mostly asymptomatic viruria, with decoy cells in urine and when lyses of the infected tubular cells releases the virus into the tubules, the BKV can leak back into the interstitium, hence the capillaries causing viremia.
The most important risk factor is degree of immunosuppressive status and others such as diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci. Clinical Picture of BK virus infection.
Clinical manifestations are as follows: (1)asymptomatic, (2) slow and progressive increase of serum creatinine, and (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy. There are no signs and symptoms are identified with BKV infection. Usually, BKV infection occurs 10 to 13 months post transplant. BK virus nephropathy may occur earlier at week 1
post transplant or as late as 5 years posttransplant.3 Diagnosis Overview.
Renal biopsy is considered the gold standard for diagnosis of BKN, plus positive immunohistochemistry (against BKV or against SV40 large T antigens) and BK PCR and detection od Decoy cell in urine increase suspicion for diagnosis, but diagnosis of BKV in a renal biopsy could be missed in about 30% of cases because BKV has a focal tropism in the medulla rather than in the cortex. Differential diagnosis
BK virus infection can be similar to other types of
viral infections (CMV, herpes simplex virus, adenovirus). Therefore, to confirm a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed and decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients. Quantitative polymerase chain reaction.
PCR analyses in detecting BKV DNA were about 100% and 88%, respectively, viruria precede viremia by 4 weeks, serology not helpful to examine serum for anti-BKVantibodies for a definitive diagnosis of BKV infection. Urine electron microscopy.
Show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen (Figure 8).57 In a retrospective single-center study, Haufen presence was shown to be associated with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients. Therapeutic interventions. 1-immunosuppression reduction.
It is considered the cornerstone in the management of BKV
infection, it also carries a higher risk of rejection, making this decision challenging.
2-Cidofovir.
There is no randomized controlled trials are available to support
this approach, and one of the limitations of this approach is nephrotoxicity. Brincidofovir (CMX001).
is a prodrug of Cidofovir but lower incidence of nephrotoxicity. Leflunomide.
is an immunosuppressant agent that also has antiviral properties against BKV in vitro and association between leflunomide and decrease in BKV viral load, side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression. Intravenous immunoglobulin.
In patients with hypogammaglobinemia, IVIG therapy was beneficial with regard to anti-BKV immunity; the immunomodulatory effects of IVIG may guard against allograft rejection in the context of reduced immunosuppression. Fluoroquinolone.
Inhibit replication of BKV or SV40 polyomavirus replication in vitro. Role of cellular immunotherapy in the management of BKv infection.
The idea of this approach depends on the transfer of primed BKV reactiveT cells, which may help in controlling the BKV-associated disease. Conclusions.
BK virus infection one of the most common infection post kidney transplant recipient that mainly due to heavy immunosuppreive status which lead to reactivation of the dominant infection and lead to BKVN, hemorrhagic cystitis and or ureteric obstruction, the corner stone of treatment is reduction of immunosuppression drugs and there are no available antiviral medications for BKV infections, and there are few controlled studies available on management of BKV infection in renal transplant recipients. Level of evidence: V (narrative review).
· BK virus is a member of the family Polyomaviruses. This family is a double-stranded DNA virus
· BK virus has been categorized into 4 groups (I to IV),
· About 90% of the population will become BKV seropositive during their life
it reactivates after solid-organ transplant, especially in bone marrow or kidney transplant recipients
· Usually, BKV infection occurs 10 to 13 months posttransplant.
BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
· BKV can lead to tubulointerstitial nephritis and ureteral stenosis; it can also lead to hemorrhagic cystitis in bone marrow transplant patients.
Risk factors and pathogenesis
· the degree of immunosuppression rather than the type of immunosuppression used.
· Other risk factor include
diabetes mellitus,
delayed graft function,
treated episodes of acute rejection,
ureteral trauma,
use of antilymphocyte antibodies,
coinfection with Cytomegalovirus (CMV),
maintenance steroid immunosuppression,
older age, white race/ethnicity,
Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy,
Clinical manifestations
(1) may be asymptomatic
(2) slow and progressive increase of serum creatinine
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Laboratory findings
(1) elevated serum creatinine and
(2) urine analysis with pyuria, hematuria , findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. However, these results could be normal
Diagnosis
· Quantitative PCR is used to diagnose BKV viremia
· BK virus nephritis is suspected when the clinical diagnosis of tubulointerstitial nephritis is suspected
· The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis (an enlarged nucleus with a single large basophilic intranuclear inclusion )
· (decoy cells) are suggestive but not specific, sensitive, or definitive for BKV infection because
(1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus
(2) decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients.
(3) their absence does not exclude the disease.
· the definitive diagnosis of BKVN the presence of
1-cytopathic changes on the renal biopsy plus
2-positive immunohistochemistry which cross-react with the BKV, specifically SV40 large-T antigen part of the virus.
has a specificity of 100%, however in 30 % of cases diagnosis could be missed (pathchy lesion in medulla )
· a presumptive diagnosis
sustained (more than 2-week duration) urinary viral shedding and significant BKV replication ((plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction
· BKVN, light microscopy examinations
(1) basophilic intranuclear viral inclusions without a surrounding halo
(2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells
(3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates
(4) tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining
(5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
When extensive, it is difficult to differentiate between BKVN and allograft rejection
· In BKVN, electron microscopy examinations
(1) viral inclusions with diameter size ranging from 30 to 50 nm and
(2) tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
· Pattern of BKVN Pattern A
Cytopathic/cytolytic changes with absent or minimal inflammation Pattern B
Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy Pattern C
Graft sclerosis
· Banff grading of BKVN
Grade 1-Minimal viral replication in < 1% of biopsy with < 25% fibrosis
Grade 2- Any between grades 1 and 3
Grade 3 -Marked virus replication in > 10% of cores with > 25% fibrosis
Therapeutic interventions
immunosuppression reduction
· the reduction of immunosuppression is the cornerstone in the management of BKV infection BUT it carry high risk of rejection
· Histologically, there is a similar feature between rejection and BKVN,.modification of immunosuppression to treat BKV infection carries a higher incidence of long- term chronic rejection.
. Cidofovir
no ran- domized controlled trials are available to support . nephrotoxic Brincidofovir
Successful outcomes in renal and hematopoietic transplant have been described in multiple case reports after treatment of BKVN with brincidofovir
Leflunomide
· Has immunosuppressant and antiviral properties against BKV.
· Side effects thrombotic microangiopathy, hepatitis, and bone marrow suppression. The active metabolite of leflunomide (known as teriflunomide or A771726) can be measured, level of 50 to 100 g/mL of teriflunomide was associated with a reduction of BKV viral load, intravenous immunoglobulin
· (IVIG) contains neu- tralizing antibodies against BKV,
· The evidence of using IVIG as adjunctive therapy for BKVN has been described in multiple case reports and case
· the immunomodulatory effects of IVIG may guard against allograft rejection in the context of reduced immunosuppression.
Fluoroquinolone
· In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication
· No data suggest that fluoroquinolones have a clinically significant role in the management of BKV-related diseases.
BK polyomavirus is a DNA virus that has affects humans,s especially those with an immunocompromised state like solid organ transplantation. it usually affects the kidney allograft with a clinical presentation like tubulointerstitial nephritis, ureteral stenosis, and hemorrhagic cystitis. The risk of graft loss could be high when trying to treat the infection because of the need to reduce the immunosuppressive medications in the recipients.
Transmission mechanism
Primary BKV infection occurs in the first decade of life and remains dormant
It is transmitted by fecal-oral, air droplets, solid organ transplantation, and blood transfusion.
BKV infection replication occurs during immunosuppression with the shedding of the virus from the urine in 60% of cases
The mean prevalence of BKV in renal transplant patients is 5%
Risk factors for BKV
the degree on immunosuppression
immunosuppressive drugs like Tacrolimus, MMF. and T- cell depleting
Diabetes mellitus
Delay graft function
Acute rejection treatment
uretral traumal
HLA mismatch and ABO incompatibility
Clinical Picture of BK virus infection
It could be asymptomatic
Slow and progressive increase in serum creatinine
progressive structural renal damage
pyuria, hematurai, urine cellular cast
Diagnosis
PCR test for plasma DNA > 10000 copies/m
PCR DNA BKV in urine
presence of decoy cells in urine cytology
Definitive diagnosis is kidney biopsy with :
-characteristic cytopathic change with immunohistochemistry against BKV OR SV40 large T antigen (note, this could be missed in 30% of case)
Presence of basophilic viral inclusion in electron Microscope study
Presence of Haufen cell in urine EM study – 100% sensitive and 99%specific for biopsy verified BKV infection
Differential Diagnosis
CMV infection
Herpex virus infection
Adenovirus
Therapeutic intervention
There is no available potent antiviral agent against BKV, although few report has been published on use of few medications.
The key in the management is reduction of immunosuppressive medication and sometimes stopping some completely
Immunosuppresives reduction – challenge of graft loss is highy
Cidofovir – risk of nephrotoxicity
Brancidofovir – pro-drog of cidofovir, I’m phase III trial
Leflunomide – risk of TMA, hepatitis, and bone marrow suppression
IVIG- no controlled study, though good for acute allograft rejection
Flouroquinolone- current data do not support the use in BKV
Immunotherapy
This involves the use of BKV-reactive T cells to control viral replication
The identification of the viral immunogenic antigens is necessary for successful generation of virus-specific T cells
Conclusion
The BKV is a member of human polyomal viral that is primary acquired by about 9)5 of general population and usually remain dormant in kidney tissue (medulla) until reactivated by immunosuppressive state like after kidney transplantation. Diagnosis requires persistent rising PCR DNA of BKV and a kidney tissue containing medula.
The main stay of treatment with some consistent result remain reduction of immunosuppression, but this could be accompanied by unintended allograft loss.
Introduction
It was first discovered as a cause of ureteric stricture following transplantation in early 1971.
BK A tiny, double-stranded, non-enveloped DNA virus is known as a polyomavirus. There are four serotypes; serotype 1 is the most prevalent. Six viral proteins, two early, one non-coding, and three late, are encoded by its genome.
The majority of people (around 90% of people globally by the age of 4) are infected by the time they are 4 years old, and infection is typically acquired in childhood through either a feco-oral, respiratory, or transplantation with the graft route. Infection remains lifetime.
In people with a functioning immune system, the infection is typically benign and asymptomatic. Only 20 percent of the virus sheds.
In immune-compromised renal transplant recipients, infection can be acquired through the reactivation of latent infection or newly transmitted from the donor kidney. Infections can be subclinical or symptomatic, leading to BK nephropathy, graft dysfunction, and likely graft loss. Shedding of the virus increases to 60% in the transplant setting.
Viremia risk is related to following contributors:
The degree of immunosuppression
The stronger the immunosuppression being used, in ABO and HLA incompatible transplants, the higher the risk of BKPyVN.
Patients with DGF and those who experience recurrent rejection episodes are more likely to experience it.
No individual medication has been connected to infection, but a tacrolimus plus MMF protocol may be associated with higher risk comparing to cyclosporine-based regimen.
When it comes to donor’s factors BK serostatus is of great value, such as kidney transplantation from a donor who is BK+ to a recipient who is BK-.
Viruria in the donor before transplantation increases the risk of viruria and viremia in the recipient post-transplantation.
C: Recipient variables
Older males
The prevention of ureteric leaks through the application of ureteric stents
Kidney transplantation-related ischemia or rejection damage
Routes of transmission
Airborne transmission via an air droplet is one of the transmission routes.
Transmission through the feces.
Oral and urinary routes
Vertical transmission and blood transfusion.
Clinical picture
Ninety percent of the population develops seropositivity during the course of their lifetime.
The manifestations seen in solid organ transplantation include tubulointerstial nephritis, uretric stricture, and graft malfunction.
Hemorrhagic cystitis in recipients of bone marrow transplants.
BKV, which is typically asymptomatic and manifests in the first year following a kidney transplant, can cause progressive elevations in serum creatinine or progressive kidney damage that can be verified by a kidney biopsy (BKVN).
Increased creatinine, sham cells, pyuria, hematuria, and cellular casts in urine are some of the laboratory results.
Diagnosis
Kidney biopsy is required for a conclusive diagnosis of BKVN; however, because viropathic lesions are patchy, a diagnosis may be missed in the tissue collected. In addition, the tropism of BKV is the medulla, not the cortex, which may enhance the possibility of missing viropathic lesions. In around 30% of instances, a BKV diagnosis could be missed in a kidney biopsy.
BKV viremia is diagnosed by quantitative PCR, which demonstrates BKV replication regardless of renal dysfunction.
BK viral nephritis is suspected when tubulointerstitial nephritis is suspected; however, there are no tubulointerstitial nephritis clinical characteristics that are unique to BKVN.
The presence of decoy cells in a urine examination raises the suspicion of BKV nephritis, which should be confirmed by quantitative PCR on blood rather than urine.
Since BKV-positive serology is frequent, it cannot be used for diagnosis.
BKV Ig G titers are elevated from six weeks to two years after primary infection.
It is debatable if BKV serology investigations before and after transplants are beneficial. Approach of treatment
Decrease in immunosuppression
Immunosuppression reduction is the initial step in managing BKPyVN. Treatment begins with reduction in the dose of MMF by 50%, and followup on viremia titers every week. Alternative approach is to lower CNI dose to acheive lower trough levels 4-6 ng/ml. MMF can be dropped from the management of no improvement in the followup, and the risk of rejection is low.
Histologically, BKVN and rejection can be identical, making it difficult to diminish immunosuppression, which is the primary treatment for BKVN.
In addition, altering immunosuppression to treat BKV infection increases the incidence of chronic long-term rejection.
Cidofovir
It was tested in conjunction with RI, but nephrotoxicity prevents its usage.
Brincidofovir
Is an oral prodrug of cidofovir with a reduced risk of nephrotoxicity.
Leflunamide
Is an immunosuppressant with antiviral properties; studies have demonstrated its association with viral load decrease; nonetheless, it is associated with thrombotic microangiopathy, hepatitis, and suppression of bone marrow.
IVIG
It had anti-BKV immunity in hypogammaglobulinemia, and the immunomodulatory effects of IVIG can protect against allograft rejection.
Fluoroquinolone
Can inhibit BKV or SV40 polyomavirus replication in vitro; it has also been hypothesized to play a function in preventing BKV infection.
There is currently no evidence to suggest its significance in BKV treatment.
Immunocellular treatment
Utilize BKV-reactive T lymphocytes primed for therapy.
A study utilized pools of overlapping peptides derived from all five BKV antigens to expand BKV-specific T lymphocytes in humans.
Positive results were observed in research evaluating the efficacy of the
Transfer of BKV-reactive T cells adoptively. In conclusion, Polyomaviridae BKV is acquired in childhood. Renal transplant recipients are at risk of allograft loss because of BK virus . Over-immune suppression is the great concern. Biopsy and immunohistochemistry (SV 40) determine the diagnosis, but one-third of patients have negative biopsies. BKV viremia and urine decoy cells aid diagnosis. The treatment approach consists primarily of Immune suppression reduction and monitoring for response or rejection. Antibiotics and other adjunct medicines need more research.
Please summarise this article. BK Virus : Is a polyomavirus, small non enveloped DNA virus, affects immunocompromised patients, supposed to be due to heavy immunosuppression( ATG,Tacrolimus and MMF), 4 gdenotypes has been identified.
RISK FACTORS: Diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci, ABO I transplants, and D+/R- (Serostatus of donor and recipient).
Routes of transmission: Airborne transmission through air droplet. Feco-oral transmission. Urinary-oral route. Blood transfusion and vertical transmission.
Clinical Picture of BK virus infection: 90% of population become seropositive during their life. Tubulointerstial nephritis, uretric stricture and graft dysfunction are the presentations in solid organ transplantation. Hemorrhagic cystitis in bone marrow transplant patients. In kidney transplant BKV present in the first year post tratnsplantation, mostly asymptomatic, can present with progressive elevation of serum creatinine, or progressive kidney damage proved by kidney biopsy (BKVN). Laboratory findings: elevated creatinine, decoy cells, pyuria, hematuria, and cellular casts in urinalysis.
Diagnosis of BKV : – Kidney biopsy is the gold standard definitive diagnostic tool. Light microscopy:- : (1) basophilic intranuclear viral inclusions. (2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells. (3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates. (4) tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining. (5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium. Electron microscopy:- (1) viral inclusions with diameter size ranging from 30 to 50 nm. (2) tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts. Patterns of BKVN : Pattern A= Cytopathic/cytolytic changes with absent or minimal inflammation. Pattern B= Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy. Pattern C= Graft sclerosis. – Quantitative blood BKV PCR. >60-100 copies/ml + pathological findings.( sensitivity 100%, specificity 88%). – Urinary BKV PCR > 10000 copies/ml.(sensitivity 70%, specificity 70%). – Anti BKV can increase in both primary infections and reactivation of infections. – Viral culture takes long time so clinically inapplicable. – Haufen/urine electron microscopy, a cast-like 3-dimensional polyomavirus aggregates.(sensitivity 100%, specificity 99%). The study cannot discriminate between rejection and BKVN. Differential diagnosis: Other viral infections: CMV, HSV, and adenovirus. Acute rejection. Patients with a higher viruria level are highly prone to developing BKV viremia, and patients with high sustained viremia are susceptible to BKVN. Therapeutic interventions: The gold standard approved therapeutic intervention is immunosuppression reduction by 50% or more of both antimetabolites and CNI, and reduction of steroids as well. Cidofovir, Leflunomide, are of limited evidence needs further studies. Intravenous immunoglobulins, are of limited evidence may be used. Fluoroquinolone, in vitro there is some inhibitory effects, in vivo no evidence, but may be protective of BK virema. Adoptive immunotherapy, is a possible premature treatment option. Conclusion: BKV is a DNA virus from, a human polyomavirus, with incidence of 10% in renal transplant patients, depends on the immunosuppression dosage, other risk factors includes, DM , old age recipients, male, old CMV infection, HLA missmatch and ABOi transplants, acute rejection, and delayed graft function. The gold standard diagnostic tool is kidney biopsy, and reduction of immunosuppression is the treatment of choice up till now. What is the level of evidence provided by this article? Level of evidence V – review article.
It is first identified early in 1971 as a cause of ureteric stricture post transplantation
BK polyomavirus is a small, double stranded, non-enveloped DNA virus. 4 serotypes exsists, the most common is serotype 1. Its genome encodes for 6 viral proteins, 2 early, 1 none coding and 3 late proteins.
Infection is usually acquired in childhood, through either feco-oral, respiratory route or during transplantation with the graft, it infects renal tubules and uroepithelium of most of people ( around 90% of people are infected worldwide by the age of 4 ) and infection remain lifelong
In immune-competent individuals the infection is usually benign and asymptomatic. Shedding of the virus is limited (20%)
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, shedding of the virus in transplant setting increase to 60%.
BK infection has a stereotypical pattern, starting by viruria (occurring in 30% of transplant recipients), then viremia (occurring in 12% of transplant recipients) and lastly nephropathy (occurring in 5 % of transplant recipients)
Risk factors for viremia
A- The intensity of immunosuppression
It is more common in cases of ABO and HLA mismatches due to aggressive immunosuppression used
It is more common also in patients with frequent rejection episodes and patients with DGF
No specific drug is linked to infection but protocol using tacrolimus and MMF may be associated with more infection than cyclosporine based regimen
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
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 (cheaper) 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
Present in 10-30% of renal transplant recipient in the first 6 months and in 5-10% later on
Level > 10000 copies/ml has 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
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, best seen by EM,
Interstitial mononuclearand PNL infiltration
Tubulitis (lymphocyte penetration of tubular BM)
Tubular injury
Infected cells show anisonucleosis, hyperchromasia and chromatin clumping
And
B- Positive IHC test for SV40 antigen
BK nephropathy is classified into 3 classes
Class 1 – pvl 1, ci ≤1
Class 2 – pvl 1, ci ≥2 or pvl 2, any ci score or pvl 3, ci ≤1
Reduction of immunosupression which represents the main line of therapy wit monitoring of viral load by plasma PCR, clearance of viremia precedes viruria by around 4 weeks so monitoring of viruria has no clinical implication in follow up
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
What is the level of evidence provided by this article?
Summary BKV infection occurs 10 to 13 months post transplant. BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
The mean prevalence of BKVN in renal transplant recipients is 5%
The viruria in a potential donor can be considered as a predictor for posttransplant BKV infection.
Graft dysfunction – failure risk factors heavy immunosuppression the main risk factor most commonly tacrolimus and mycophenolate mofetil based- immunosuppressive agents can affect T cells, use of antilymphocyte antibodies,maintenance steroid immunosuppression,
Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy, possibly due to heavy immunosuppression (whether due to induction or maintenance immunosuppression or episodes of rejection).
elderly recipients male sex -white race/ethnicity, prior rejection episodes- prolonged cold ischemia time
human leukocyte antigen mismatching-delayed graft function, treated episodes of acute rejection, and presence of specific human leukocyte antigen (HLA) C loci. ureteral stenting.ureteral trauma pretransplant BK virus serostatus- coinfection with Cytomegalovirus (CMV) diabetes mellitus
Laboratory findings
(1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.However, these results could be normal
Diagnosis
A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN; however, a diagnosis may be missed in the tissue obtained because viropathic lesions are patchy. In addition, for BKV, tropism is medulla, not the cortex, which may increase the risk of missing the viropathic lesions.
Quantitative PCR is used to diagnose BKV viremia, which demonstrates BKV replication whether there is renal involvement or not.
Definitive diagnosis of BK virus nephropathy A definitive diagnosis of BKVN requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection
Anti-BKV antibody does not seem to be protective; therefore, it can increase in both primary infections and reactivation of infections.
The utility of conducting BKV serology examinations before and after transplant is controversial because it is not entirely clear which antibodies are neutralizing.
The risk of developing a clinically significant BKV infection is high when transplant is performed between a positive BKV donor and a negative recipient viral culture
Viral culture is rarely used as a method for BKV infection detection outside the research setting.
Viral isolation from the clinical specimen can take weeks to months; therefore, this method is not clinically applicable.
Urine electron microscopy Urine examinations using negative-staining electron microscopy for patients with BKV infection will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen
In a retrospective single-center study
Haufen presence was shown to be associated with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients.
In addition, a relationship was reported among Haufen, high-level BKV viremia (median copy 1 206 325 copies/mL), and the occurrence of acute kidney injury and BKVN.
However, urine analyses in patients with a low viremia (median of 26 959 copies/mL) did not show Haufen bodies. Thus, urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis in renal transplant recipients.
This diagnostic technique is of a great utility, especially in differentiating between BKVN and asymptomatic BKV infection. However, it remains to be determined whether this method can be used for diagnosis as it depends on a sophisticated analysis and it also requires a meticulous interpretation by pathologists. In addition, the study did not determine whether urine electron microscopy can discriminate between rejection and BKVN.
Management of BKV viremia decrease immunosuppression regular follow-up of BKV polymerase chain reaction (PCR) continuous monitoring of renal functions in an attempt to prevent allograft
Currently, there are no available antiviral medications against BKV.
cellular immunotherapy
the idea of this approach depends on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
Identifying viral immunogenic antigens is necessary for successful generation of virus-specific T cells.
Brincidofovir a prodrug of cidofovir that is administered orally.
Leflunomide has antiviral properties against BKV in vitro.
Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression. The active metabolite of leflunomide (known as teriflunomide can be measured, which can be helpful in continuous monitoring of the level of leflunomide and avoid toxicity.
Further prospective controlled studies of leflunomide are needed to confirm the efficacy and safety of this drug against BKV infection
intravenous immunoglobulin contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKVN.
The evidence of using IVIG as adjunctive therapy for BKVN has been described in multiple case reports and case series however, no controlled studies have been reported.
fluoroquinolone antibiotics have been considered as potential agents for controlling BKV infection in renal transplant recipients
In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication in vitro
What is the level of evidence provided by this article?
Level III Evidence – other studies with essentially minimal design, ‘descriptive’ and lowest level of evidence
Virology Properties; ————————————————————————————
BK virus is a member of the family Polyomaviruses. This family is a double-stranded DNA virus with icosahedral symmetry. BK virus has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence .
Transmission mechanism; ————————————————————————–
Primary BKV infection occurs in the first decade of life, on average at 4 to 5 years of age. Possible routes include the following:
(1) Airborne transmission through .
(2) Feco-oral transmission .
(3) Urinary-oral route or seroconversion after solid-organ transplant .
(4) Blood transfusion and vertical transmission .
Risk factors —————————————————————————— 1-The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used.
2-Diabetes mellitus.
3- Delayed graft function .
4-Treated episodes of acute rejection .
5-Ureteral trauma .
6-Use of antilymphocyte antibodies .
7- Coinfection with Cytomegalovirus (CMV) .
8- maintenance steroid immunosuppression .
9-older age .
10-white race/ethnicity .
11-Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy.
Clinical Picture of BK virus infection; ———————————————————————–
Clinical manifestations are as follows:
(1) Asymptomatic .
(2) slow and progressive increase of serum creatinine .
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Usually, BKV infection occurs 10 to 13 months post transplant.
BK virus nephropathy may occur earlier at week 1 post transplant or as late as 5 years post transplant.
Diagnosis Overview; —————————————————————————— 1-A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN; however, a diagnosis may be missed in the tissue obtained because viropathic lesions are patchy. In addition, for BKV, tropism is medulla, not the cortex, which may increase the risk of missing the viropathic lesions.A diagnosis of BKV in a renal biopsy could be missed in about 30% of cases .
2-Quantitative PCR is used to diagnose BKV viremia, which demonstrates BKV replication whether there is renal involvement or not.
3-BK virus nephritis is suspected when the clinical diagnosis of tubulointerstitial nephritis is suspected; however, there are no clinical features of tubulointerstitial nephritis that are unique to BKVN.
4-The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis, which should be followed by quantitative PCR of blood preferable to urine.
A definitive diagnosis of BKVN requires; ————————————————————————–
A-Characteristic cytopathic changes on the renal biopsy .
B- Positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection .
In the absence of definitive criteria for BKVN diagnosis ; —————————————————————————————–
a presumptive diagnosis can be done if there is ;
1-Sustained (more than 2-week duration) urinary viral shedding .
2-Significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction .
BKVN can be graded into 3 grades using Banff criteria according to the percentage of fibrosis and the amount of viral replication . —————————————————————————————————–
Grade 1 Minimal viral replication in < 1% of biopsy with < 25% fibrosis
Grade 2 Any between grades 1 and 3
Grade 3 Marked virus replication in > 10% of cores with > 25% fibrosis
Specific Histologic Findings of BK Virus Nephropathy; ————————————————————————————————–
1-Pattern A Cytopathic/cytolytic changes with absent or minimal inflammation .
2-Pattern B Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy
3-Pattern C Graft sclerosis .
Differential diagnosis ; ———————————————————————————
BK virus infection can be similar to other types of viral infections (CMV, herpes simplex virus, adenovirus).
Therefore, to confirm a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed.
Urine cytology findings for BK virus infections; ———————————————————————————
Urine examinations may reveal BKV-infected cells. The most characteristic abnormality of infected cells is an enlarged nucleus with a single, large basophilic intranuclear inclusion .
The presence of characteristic cytopathologic changes in infected cells (which have been called decoy cells due to their similarity to renal carcinoma cells) is strongly suggestive of polyomavirus infections.
Quantitative polymerase chain reaction; —————————————————————————————
1-Sustained high viral DNA levels in the plasma of renal transplant recipients who have an appropriate clinical picture can suggest BKVN.
2- Patients with a higher viruria level are highly prone to developing BKV viremia, and patients with high sustained viremia are susceptible to BKVN.
3- BK virus DNA levels can alter weekly by 1 to 2 log-folds depending on the commercially available PCR assay. It is recommended that medical decisions, especially those with regard to alterations of immunosuppression, be made on the basis of trends in quantitative DNA levels rather than on a single measurement.
Serology; ————————————————————
1-It is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection because positivity for these antibodies is quite common in the general population.
2- Anti-BKV antibody does not seem to be protective; therefore, it can increase in both primary infections and reactivation of infections.
Viral culture; ———————————————–
Viral isolation from the clinical specimen can take weeks to months; therefore, this method is not clinically applicable.
Urine electron microscopy; —————————————————–
1-Urine examinations using negative-staining electron microscopy for patients with BKV infection will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen .
2- It depends on a sophisticated analysis and it also requires a meticulous interpretation by pathologists.
3- The presence of a high load of Haufen with equivocal biopsy would highly support the possibility of BKVN rather than rejection as a cause of allograft dysfunction, which could support medical decisions of reduction of immunosuppression rather than augmentation as in cases of rejection.
Therapeutic interventions; ————————————————-
1-immunosuppression reduction. ——————————————————————————-
Despite the fact that reduction of immunosuppression has been the cornerstone in the management of BKV infection, it also carries a higher risk of rejection, making this decision challenging.
2- Cidofovir; ———————————————————-
One of the limitations of this approach is nephrotoxicity, thus making the decision to use cidofovir unlikely.
3- Brincidofovir (CMX001); ———————————————————-
Because of the nephrotoxicity with cidofovir, scientists had developed brincidofovir, which is a prodrug of cidofovir that is administered orally. Phase 3 clinical trials have shown a lower incidence of nephrotoxicity with brincidofovir.
4- Leflunomide; ———————————————————-
Leflunomide is an immunosuppressant agent that also has antiviral properties against BKV in vitro. Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression.
Intravenous immunoglobulin (IVIG) contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKVN. The immunomodulatory effects of IVIG may guard against allograft rejection in the context of reduced immunosuppression.
6- Fluoroquinolone; ———————————————————————
In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication in vitro; therefore, fluoroquinolone antibiotics have been considered as potential agents for controlling BKV infection in renal transplant recipients.
Role of cellular immunotherapy in the management of BKv infection; —————————————————————————————————
Therefore, the idea of this approach depends on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
Research on treating BKV-associated diseases using immunotherapeutic approaches is still in the early stages, and data on immunodominant BKV epitopes for T-cell priming are limited.
What is the level of evidence provided by this article?
Level V .
I- Summary: Virology:
– One of the polyomaviruses (double-strand DNA)
– KK virus has 4 genotypes (I-IV). Transmission mechanisms:
1- Airborne transmission through air droplets
2- A feco-oral transmission.
1- Urinary-oral.
2- Blood transfusion and vertical transmission; as BKV DNA has been found in the placenta, brain, and renal tissue of aborted fetuses
· Primary polyomavirus infections usually occur during childhood through respiratory or oral routes.
· It is usually asymptomatic and the virus remain in renal epithelium (tubules)
· It becomes reactivated in immunocompromised patients.
Risk factors:
1- The degree of immunosuppression.
· Most common with tacrolimus and mycophenolate mofetil based IS.
· Immunosuppressive agents can affect T cells, which can lead to increased BKV replication.
2-Other risk factors: DM, delayed graft function, treated episodes of acute rejection, ureteral
trauma, coinfection with CMV, maintenance steroid use, older age and white
race/ethnicity.
3- Transmitted infection from the donor (the risk is high with D+ and R-)
4- ABO and HLA incompatible transplantation.
Clinical picture:
– About 90% of the population will become BKV seropositive during their life.
– It reactivates after bone marrow and renal transplantation
– In kidney transplant recipients, reactivation may lead to BKVN, which may end with graft dysfunction and failure by causing tubule-interstitial nephritis and/or ureteral obstruction.
– In bone marrow transplant recipients, BKV can lead to hemorrhagic cystitis.
– Usually, BKV infection occurs 10 to 13 months post-transplant. BK virus nephropathy may occur earlier at week 1 post-transplant or as late as 5 years post-transplant Clinical manifestations are
1- Asymptomatic
2- slow and progressive increase of serum creatinine
3- An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy. Laboratory findings: (may be normal)
a- Elevated serum creatinine
b- Urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. Diagnosis of BK virus infection: 1- Renal biopsy:
BKVN diagnosis requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens)
However it may be missed (in 30%) because infection is patchy and affect the medulla not the cortex.
Light microscopy examinations would show the following:
· Basophilic intra-nuclear viral inclusions.
· Anisonucleosis, hyperchromasia, and chromatin clumping of infected cells.
· Areas of tubular damage showing interstitial mononuclear or polymorphonuclear
cell infiltrates.
· Tubular injury: tubular cell apoptosis, desquamation, and flattened epithelial lining.
· Tubulitis with lymphocyte invasion to the basement membrane.
2- Presence of urine decoy cells (infected cells with an enlarged nucleus with a single, large basophilic intranuclear inclusion) and viral shedding. N.B: decoy cells is not specific to BKV infection ( can be present with CMV or other polyoma viruses) and poorly correlated with BKVN.
3- Confirmed by quantitative PCR ( in blood is preferred) > 10000 copies/ml (sensitivity 100% and specificity 80%)
Both can diagnose infection in case with normal biopsy.
4- Serology:
Not recommended to test for BK virus antibodies.
DD: CMV infection, adenovirus and HSV.
Therapeutic intervention:
There are no available antiviral medications against BKV.
The usual approach in the management of BKV viraemia or BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR.
Cidofovir: Multiple single-center studies and case series have described the benefits of adding cidofovir with immunosuppression reduction. It is associated with nephrotoxicity.
Brincidofovir: a pro-drug of cidofovir administered orally to avoid the nephrotoxic effect. Some reported successful outcome in small scale studies.
Leflunomide: IS agent with antiviral properties. No available RCT to prove its effect.
IV Immunoglobulin: the available Ig contains neutralizing antibodies against BK virus. Till now, not recommended as a treatment.
Flouroquinolone: In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV. However, RCT did not prove it.
Polyoma viruses are small DNA virus infect the mammalian including human.
BKV is a common polyoma virus infect human especially immunocompromised.
BKV in renal transplant recipients can cause tubular interstitial nephritis, ureteric stenosis & hemorrhagic cystitis in bone marrow transplant recipients..
Virology:
BKV has classifies serological & genetypically into 4 groups.
External layer of the virus consist of 3 structural protein: VP1( determine receptor specificity), VP2 & VP3 ( involved in viral particle stabilization outside host cell).
BKV transmitted through:
air-born
feco-oral
urinary-oral route or seroconversion after transplantation.
blood transfusion & vertical transmission.
Primary infection usually asymptomatic, but the virus stay dormant in renal epithelium.
impaired cell mediated immunity responsible for activation of virus.
Risk factors of BKV infection:
intensity of immunosuppression
DM
DGF
treatment of acute rejection
urethral injury.
use of anti-lymphocytes antibodies.
co-infection with CMV
Presence of specific HLA loci
old age, white race.
presence of BKV antibodies in donor.
Clinical features:
asymptomatic infection
slow & progressive increase in serum creatinine.
finding of unsuspected progressive renal damage on renal biopsy.
BKV infection usually occur between 10-13 month post transplantation.
Early BKV infection can occur 1 week post transplant, & late infection can be occur after 5 years.
Diagnosis:
renal biopsy needed for definitive diagnosis, but it may be missed due to patchy lesion & BKV involvement restricted to medulla.
presence of decoy cells in urine increase suspicion of BKV nephritis.
PCR in blood indicate viremia.
cytopathic changes in renal biopsy with positive SV40 staining has 100% specificity for BKV infection.
presumptive BKVN: sustained (2weeks) urinary viral shedding & PCR>10000 copies/ml with or without renal dysfunction.
Histologically BKVN graded into 3 grade.
BKVN microscopical finding include:
basophilic intranuclear viral inclusion without complete halo.
anisonucleosis, hyperchromatosis & chromatin clumping of infected cell.
tubular damage with mononuclear or polymorphonuclear cell infiltrate.
tubular injury
tubulitis with lymphocyte invade tubular basement membrane.
Detection of decoys cells in urine suggestive of BKV infection with low sensitivity & specificity.
BKV PCR has sensitivity 100% & specificity 88%.
monitoring of BKV infection by blood or urine PCR.
viruria can precede viremia by 4 weeks.
anti-BKV antibodies are not useful BKV infection diagnosis & it is not protective.
viral culture rarely used for diagnosis of infection out side research setting.
presence of Haufen bodies in urine has 100% sensitivity & 99% specificity for biopsy-verified BKVN, so it can be non invasive method for BKVN diagnosis in renal transplant recipients.
Differential diagnosis of BKV infection include CMV, adenovirus & herpes simplex virus.
Treatment:
Immunosuppression reduction.
Cidofovir ( nephrotoxicity).
Brincidofovir : lower nephrotoxicity , need large clinical trial to establish its safety & efficacy.
Leflunomide: use as alternative to MMF, side effects include thrombotic microangipathy, hepatitis, & bone marrow suppression.
IVIG
Fluoroquinolone ( data suggest its insignificant role in BKV infection).
cellular immunotherapy can be effective in treatment of BKV infection.
Introduction
BK polyomavirus (BKV) is highly prevalent in immunocompromised patients. The average incidence is
about 10% KTRs.
Virology
It is a ds-DNA virus, a member of the family Polyomaviruses, and has genotype (I to IV) with different virulence. Transmission mechanism: *Route of transmission:
– Airborne transmission
– Feco-oral or urinary-oral transmission.
– Blood transfusion
– Vertical transmission.
*Primary BKV infection occurs early in life during childhood and often clinically insignificant.
*Latent infection: followed the 1ry infection) the virus stays in the renal epithelium and becomes dormant until it is reactivated
* BKV replication in immunocompetent population; asymptomatic viruria, ( viral shedding 20%)
*immunocompromised individuals, shedding reaches 60% and the viruria is more common.
Risk factors and pathogenesis
– Impaired cell-mediated immunity increase the risk of BKV.
-The degree of immunosuppression rather than the type used ( The most important risk factor ).
– Others; diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of rATG, coinfection CMV, maintenance steroid IS, older age, white race/ethnicity, and presence of specific (HLA) C loci.
– High donor BKV antibody titers, donor viruria is a predictor for posttransplant BKV infection.
– HLA and ABO-incompatible transplants.
Clinical Picture of BK virus infection:
– BKV infection occurs as early as 1 week or as late as 5 years posttransplant
– Asymptomatic, no signs and symptoms.
– Slow and progressive increase of serum creatinine.
– BKVN on surveillance biopsy may end with graft dysfunction and failure by causing tubulointerstitial nephritis and/or ureteral obstruction.
– In HSCT, BKV can lead to hemorrhagic cystitis.
Laboratory findings
– elevated serum creatinine and
– urine analysis with pyuria, hematuria, and findings of interstitial nephritis as cellular casts Diagnosis Overview
-A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN; might be missed in 30 % as virus tropism is patchy and affect medulla. therefore, 2 core biopsies are needed for confirmation.
– PCR is used to diagnose BKV viremia. sensitivity and specificity about 100% and 88%,
– Characteristic; decoy cells in the urine analysis increases the suspicion of BKV nephritis.
– Serology anti-BKV antibodies: It is not helpful.
– viral culture not clinically applicable , only in research settin.
– Urine electron microscopy; urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis.
Definitive diagnosis of BKVN;
-Requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens)
Presumptive diagnosis
if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication
(plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction.
– Different pathological patterns and associations with BKV infection
– Specific Histologic Findings of BK Virus Nephropathy
– BKVN can be graded into 3 grades using Banff criteria according to the percentage of fibrosis and the amount of viral replication.
Differential diagnosis
– BK virus nephropathy can be similar to cellular rejection, IHC and in situ hybridization used to differentiate
-It can be similar to other types of viral infections (CMV, herpes simplex virus, adenovirus). Therapeutic interventions.
*Currently, there are no available antiviral medications against BKV.
*Approach in the management of BKV viremia or BKVN in renal transplant recipients is reduction of IS and continuous monitoring of BKV viremia level via PCR.
– Immunosuppression reduction; cornerstone, carries a higher risk of rejection.
Other agents used with reducing IS:
– Cidofovir; No RCT, associated with nephrotoxicity
– Brincidofovir; prodrug, less nephrotoxic, successful outcomes in renal and HSCT.
– Leflunomide; IS and antiviral properties.
– Intravenous immunoglobulin; neutralizing antibodies, used as adjunctive therapy, immunomodulatory
effects may guard against allograft rejection in the context of reducing IS.
– Fluoroquinolone; inhibit replication of BKV or SV40.
– Adoptive cellular immunotherapy; may carry potential hope
Introduction
BK polyomavirus is DNA virus, highly prevalent causing infection in immunocompromised patients. BKV can cause tubulointerstitial nephritis and ureteral stenosis in renal transplant cases ; and in bone marrow transplant cases it can lead to haemorrhagic cystitis. BKV viremia main treatment is reduction of immunosuppression that can preserve allograft function, and follow up BKV PCR and renal function.
Balancing between rejection avoidance due to Immunosuppression reduction and immunosuppression continuation at the same level that can lead to BK viremia and BKV nephropathy. Virology Properties BK polyomavirus is divided into 4 groups of variable virulence. Histological aspect It was detected in the ureteric lining of a Sudanese renal transplant recipient presented with urinary obstruction ,whom the virus was named from his initials The Genome has nearly 5000 base pairs, which is stable at high temperature rendering it a virulent virus , it encodes 6 main proteins divided into 3 regions: early encoding region, late encoding region, and noncoding control region. Transmission mechanisms
It usually occurs in the first decade of life transmitted through airborne ,feco-oral ,urinary -oral route or seroconversion after SOT ,through blood transfusion and vertical transmission.
Virus stays in the renal tubular, parietal, and transitional structures and in Bowman’s capsule. In
immunocompromised individuals, the risk of shedding reaches 60% and the viruria is more
common than in immunocompetent .
The risk of the infection increases in patients with impaired cell mediated immunity. Risk factors and pathogenesis
Immunosuppression degree is the most important risk factor which is considered a marker of heavy immunosuppression possibly particularly associated with Tac( through a mechanism involving FK-binding protein) and MMF.
Other less common risk factors are diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with CMV, maintenance steroid , older age, white race ,specific HLA C loci , BKV Ab titers in donors , and HLA and ABO-incompatible transplants have a higher risk of BKV nephropathy specially ABO incompatible due to higher rejection risk. Clinical presentation
90% of the population are BKV seropositive ,which is reactivated when a candidate is immunosuppressed as in kidney and bone marrow transplant recipients while it’s reactivation is rare in other immunocompromised cases.
In kidney transplant recipients, reactivation may lead to BKVN, graft dysfunction ,tubulointerstitial nephritis ,ureteric obstruction and failure .
In bone marrow transplant recipients, BKV can lead to haemorrhagic cystitis.
CP varies from being asymptomatic to gradual worsening of kidney function
BK virus nephropathy can occur early during first week of transplant or 5 years posttransplant.
Laboratory findings are variable ,urine analysis can show decoy cells which raises the suspicion of BKV nephritis.
A renal biopsy is mandatory for diagnosis presented by non specific tubulointerstitial lesions meanwhile the patchy nature of the virus and it’s involvement of the medulla increases the possibility of missing the diagnosis.
Quantitative PCR to detect BKV viremia and replication whether kidney is involved or not.
Definitive diagnosis of BK virus nephropathy represent pathognomonic cytopathic changes on the renal biopsy along with positive immunohistochemistry (against BKV or against SV40 large T antigens).
Presumptive diagnosis is done if there is sustained urinary viral shedding and significant BKV replication in the absence of definitive criteria for BKVN diagnosis .
BKVN can be divided into 3 grades using Banff criteria according to fibrosis percent
and the degree of viral replication.
BKV LM examination:
-basophilic intranuclear viral inclusions without a surrounding halo,
-anisonucleosis, hyperchromasia, and chromatin clumping of infected cells,
– areas of tubular damage with interstitial mononuclear or polymorphonuclear cell infiltrates -tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining,
-tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
– Differentiate between BKVN and allograft rejection.
BKVN, EM examinations :
-viral inclusions with diameter ( 30 to 50 nm )
-tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein
and cellular casts.
BK virus nephropathy can mimic cellular rejection, in situ hybridization or immunohistologic methods are used to differentiate between both. Differential diagnosis
BK virus infection can be similar to other types of viral infections Urine cytology findings for BK virus infections
Urine analysis reveal BKV-infected cells, it is an enlarged nucleus with a single, large basophilic
intranuclear inclusion the decoy cells which is neither specific nor sensitive to BKV, quantitative urine PCR can be done as well. Quantitative PCR
It is 100% sensitive and 88% specific in detecting BKV DNA .
Decreasing immunosuppression ,lead to disappearance of the virus DNA.
Viral replication in the urine as detected by urine cytology or demonstration of the virus by quantitative PCR .
During the first 6 months viremia can be detected and latter can decrease.
Cases having high viruria levels are more liable to have viremia and subsequently BKVN.
Since BKV level varies ,the decision of immunosuppression reduction need to be built on the basis of trends in quantitative DNA levels rather than a single measurement. Serology
Positivity of BKV Ab is common therefore it cannot be used for diagnosis .
BKV Ig G titers are high during the first 6 weeks till 2 years after primary infection
The benefit of BKV serology examinations before and after transplant is controversial. Viral culture is non applicable Urine EM
It shows cast-like 3-dimensional polyomavirus aggregates (Haufen) it is highly sensitive and specific for BKVN.
It is relate to high BK viremia level, BKVN ,AKI.
It can differentiate between asymptomatic BKVN and asymptomatic BKV infection.
high level of Haufen along with equivocal biopsy can increase BKVN possibility rather than
rejection. Treatment Reduction of immunosuppression(RI)
The BKVN and rejection are can be similar histologically therefore treatment is challenging to reduce the immunosuppression which is the main treatment for BKVN.
In addition , immunosuppression alteration as a treat BKV infection increases the incidence of long term chronic rejection. Cidofovir
It was studied with RI in the therapy but nephrotoxicity is a limitation for it’s use. Brincidofovir
Is a prodrug of cidofovir orally taken with lower risk of nephrotoxicity. Leflunamide
Is an immunosuppressive with antiviral role, Studies revealed it’s relation to viral load reduction but it’s drawbacks are thrombotic microangiopathy, hepatitis, and bone marrow suppression. IVIG
In hypogammaglobulinemia, it had anti-BKV immunity; also it’s immunomodulatory effects of IVIG can guard against allograft rejection Fluoroquinolone
Can inhibit replication of BKV or SV40 polyomavirus replication in vitro,also it was proposed to have a role in prevention of BKV infection.
At the time being there is no data to support it’s important role in BKV treatment Cellular immunotherapy
Involve using primed BKV-reactive T cells for treatment.
A study used overlapping peptide pools from all 5 BKV antigens to expand BKVspecific human T cells.
There was positive outcomes for studies regarding the treatment of BKV infection using the
adoptive transfer of BKV-reactive T cells. Conclusion
It’s diagnosis is challenging .BK virus nephropathy can be detected with BKV inclusions and immunohistologic analyses along with correlation of histologic findings with BKV PCR .
BKV infection treatment is active screening every 3 months after renal transplant, immunosuppression should be reduced along with continuous monitoring of BKV viremia levels using quantitative PCR and renal function test.
Cellular immunotherapy is under studies
This article discusses BK virus, starting from virology, and historical aspects to management. Virology: BK virus is a member of the family Polyomaviruses. This family is a double-stranded DNA virus. Transmission through: (1) airborne transmission through air droplets
(2) feco-oral transmission.
(3) other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation)
(4) both through blood transfusion and vertical transmission. Risk factors:
· Importantly, the Degree of immunosuppression, commonly tacrolimus and mycophenolate mofetil based.
· Other risk factors that could be involved, although not common, include diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci. Clinical Picture of BK virus infection:
Clinical manifestations are as follows: (1) asymptomatic, (2) slow and progressive increase of serum creatinine, and (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Usually, BKV infection occurs 10 to 13 months posttransplant. Laboratory findings in patients with BKV infection are as follows: (1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. However, these results could be normal. Diagnosis:
· A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN; however, a diagnosis may be missed in the biopsied tissue.
· Urine examinations may reveal BKV-infected cells (decoy cells). The most characteristic abnormality of infected cells is an enlarged nucleus with a single, large basophilic intranuclear inclusion.
· High viral DNA PCR levels in the plasma of renal transplant recipients.
· Viral culture is rarely used as a method for BKV infection detection outside the research setting.
· Urine electron microscopy. Therapeutic interventions include:
· Immunosuppression reduction
· Leflunomide
· Cidofovir and Brincidofovir (CMX001)
· intravenous immunoglobulin
· Fluoroquinolone
BK virus is a virus that belong to the family of polyomavirus.
It is a small DNA virus that infect human and other animals
It was first isolated in 1971 in a Sudanese renal transplant recipient and the virus name is actually his initials name.
The viral genome (5000 base pairs) encodes 6 major proteins and classified into 3 regions: early encoding region, late encoding region, and non-coding control region
In immune compromise patients BKV is associated with graft loss, ureteric stenosis & hemorrhagic cystitis.
Mean prevalence is kidney transplant recipient ~ 5%
Transmission
This occur during the first few years of life 4 to 5 years
Many routes including ; air-bone, feco-oral, urinary-oral, organ transplantation, blood transfusions, & vertical
Primary infection may not be clinically relevant
Risk factors:
The major risk factors is over immune-suppression
Other risk factors are; Age (elderly), male gender, history of acute rejection, HLA mismatch, prolonged cold ischemia, BKV negative status before transplant, co-infection with CMV & ureteric stenting
Clinical picture:
The patient may be asymptomatic or having slowly progressive renal dysfunction or,allograft damage on routine surveillance biopsy
Diagnosis:
Biopsy; may miss the BKVN IN 30% due to focal disease or involvement of the medulla rather than the cortex.
Three main biopsy pattern; 1.early or pattern A (cytopathic changes with no inflammation) 2.pattern B (cytopathic changes + patcy or diffuse tubulointerstitial inflammation) 3. Late or pattern C (Graft fibrosis). The definitive diagnosis is cytopathic changes in the biopsy + immune histochemistry (SV40). Presumptive diagnosis is; sustained viral shedding in the urine + BKV viremia > 1000 copies/ml
Urine for decoy cells
BKV PCR (blood better than urine)
Urine electron microscopy: Haufen bodies (cast-lke 3 dimensional polyoma virus aggregates) but this a sophisticated technique & requires skills
Serology: may not be helpful
Viral culture: mainly in research setting
Differential diagnosis:
Consider other viral infections e.g. CMV, HSV, & adenovirus
Treatment:
Reduction of immune suppression; this is challenging because the risk of rejection may go up
Cidofovir; no RCTs, nephrotoxic
Brin-cidofovir; prodrug of cidofovir, less nephrotoxic, more studies are needed
Leflunomide; it may decrease BKV viral load but this was not clear if it is due to reduction of immunesuppression or antiviral properties of leflunomide. it is associated with TMA, hepatitis, & myelosuppression
IVIG; so far no RCTs
Fluoroqulinolone; in vitro it has inhibitory effect on BKV, but a single RCT was negative
Cellular immunotherapy; the is to restore anti-viral immunity in immune compromised hosts. However, it is still under research and data are limited.
Conclusion
BKV is a member of polyomaviridae family acquired during the first few years of life . It is associated with allograft loss in renal transplant recipient. The most important risk factor is over-immune suppression. The diagnosis is based on biopsy and immune histochemmistry (SV 40) but the biopsy may negative in one-third of the patients. Urine decoy cells and BKV viremia are helpful for the diagnosis. The treatment is mainly reduction of immune suppression with close monitoring for response or rejection. More studies are needed to consider the role of other adjunct therapies such antibiotics.
-What is the level of evidence provided by this article?
BK polyomavirus (BKV) is a common human polyomavirus, particularly in immunocompromised people. BKV may cause tubulointerstitial nephritis, ureteral stenosis, and hemorrhagic cystitis in renal and bone marrow transplant recipients.
Transmission mechanism:
Primary BKV infection develops around 4–5 years old. Possible routes:
(1) airborne transmission through air droplets;
(2) feco-oral transmission, as hospitalized children have fecally eliminated polyomaviruses;
(3) other mechanisms, such as urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation); and
(4) both blood transfusion and vertical transmission, as BKV DNA has been found in the placenta, brain, and renal tissue.
Risk factors and pathogenesis:
The severity of immunosuppression is the biggest risk factor for BKV illness.
Immunosuppression procedures, especially tacrolimus and mycophenolate mofetil, have been linked to active BKV illness.
Diabetes mellitus, delayed graft function, treated acute rejection, ureteral trauma, usage of anti-lymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race or ethnicity, and a particular human leukocyte antigen may all be risk factors.
Clinical Picture of BK virus infection:
Range from Asymptomatic, slow-growing serum creatinine and BKVN on surveillance renal allograft biopsies are clinically symptomatic and may end with graft dysfunction and failure by causing tubulointerstitial nephritis and/or ureteral obstruction. BKV infection has no symptoms. BKV infection develops 10–13 months post-transplant.
BK virus nephropathy may emerge at week 1 or 5 years posttransplant.
Diagnosis of BK virus nephropathy:
The renal biopsy must show distinctive cytopathic alterations and positive immunohistochemistry (against BKV or SV40 big T antigens), which is 100% specific and pathognomonic for BKV infection. Because BKV has a localized tropism in the medulla rather than the cortex, a renal biopsy may miss BKVN in 30% of patients.
If there is prolonged (more than 2 weeks) urine viral shedding and considerable BKV replication (plasma DNA PCR load > 10,000 copies/mL), as measured by a particular test with or without kidney impairment, presumptive BKVN may be diagnosed.
Specific Histologic Findings of BK Virus Nephropathy: Pattern A Cytopathic/cytolytic changes with absent or minimal inflammation Pattern B Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy Pattern C Graft sclerosis
Laboratory Tests:
Cytological urine abnormalities (decoy cells) are suggestive but not specific, sensitive, or definitive for BKV infection because.
the sensitivity and specificity of quantitative PCR analyses in detecting BKV DNA were about 100% and 88%, respectively.
the urine as detected by either analysis of urine cytology or demonstration of the virus by quantitative PCR has been shown to be present in 20% to 60% of renal transplant recipients.
Therapeutic interventions:
1-immunosuppression reduction: Despite being the cornerstone of BKV infection management, immunosuppression decrease increases the chance of rejection, making this option difficult.
2-Cidofovir: Multiple single-center studies and case series have described the benefits of adding cidofovir with immunosuppression reduction. Nephrotoxicity makes using cidofovir improbable.
3-Brincidofovir: Brincidofovir reduces nephrotoxicity in clinical studies. Multiple case reports of brincidofovir-treated BKVN resulted in successful renal and hematopoietic transplants.
4-Leflunomide: Immunosuppressant leflunomide also inhibits BKV in vitro. It replaced mycophenolate in many case series. These studies have shown a substantial relationship between leflunomide and BKV viral load reduction, but they do not indicate the reason (i.e., immunosuppression reduction or leflunomide’s antiviral activities).
5-IVIG: treats BKVN because it includes BKV-neutralizing antibodies.
Multiple case reports and case series have described IVIG as a supplementary treatment for BKVN, but no controlled trials have been published.
6-fluoroquinolone: data suggest that fluoroquinolones do not currently have a clinically significant role in the management of BKV-related diseases.
7-cellular immunotherapy: This method involves transferring primed BKV-reactive T cells to manage BKV-associated illness.may carry potential hope for the treatment of BKV infection.
What is the level of evidence provided by this article?
Level 5, Narrative review
Polyoma viruses are DNA virus. It is characterised genetically into 4 groups. BK virus is a polyoma virus affecting humans.
o Transmission Primary BKV infection occurs in the first decade of life. Routes – Airborne feco – oral Urinary -oral route Seroconversion often SOT Blood transfusion Vertical transmission
o Risk factor and pathogenesis Degree of immunosuppression DM DGF Ureteral trauma treated episode of acute rejection use of anti-lymphocyte antibody coinfection with CMV older age maintenance steroid immunosuppression older age white race/ ethnicity specific HLA – C loci presence of BKV Titre in donor H LAI and ABO i transplant
o Clinical Picture asymptomatic slow and progressive increase in Serum creatinine progressive renal damage BKVN on surveillance renal allograft biopsy. BKV infection occurs from 10th to 13th month post transplant BKVN can our from 1 week post transplant to as late as 5years post transplant.
o Laboratory Increased Serum creatinine Urine shows pyuria, hematuria
BKV causes interstitial nephritis and/ or Urethral obstruction
o Diagnosis Tissue biopsy, however involvement may be patchy. BKV tropism in for medulla.
Quantitative PCR of body fluid BKV infection mimics tubulointerstitial nephritis.
If decoy cells present in urine then QPCR to be done of blood rather than urine.
o Definitive diagnosis of BKVN
Requires characteristic cytopathic changes on renal biopsy Plus Positive immunohistochemistry against BKV or against SV40 large T antigens – specificity of 100%. BY Can be missed on renal biopsy in 30%. 2 core biopsies are needed which include the media.
o Specific histologic findings Pattern A – Cytopathic changes with no /or minimal in flammation. Pattern B – Cytopathic changes with tubulointerstitial inflammation and atrophy. Pattern C- graft sclerosis.
o Presumptive diagnosis >2 week duration urinary viral shedding and plasma DNA PCR load > 10000 copies /mI. With or without Kidney dysfunction.
o Banff grading for BKVN Grade 1 – Minimal viral replication in<1% of biopsy with< 25% fibrosis Grade 2- Any between grade 1 and 3 grade 3- Marked virus replication in >10% of cores with > 25% fibrosis.
o BKVN light microscopy Basophilic intranuclear viral inclusion with surrounding halo. anisonucleosis, hyperchromasia, and chromatin cIumping in cells. interstitial infiltration with tubular damage tubular cell apoptosis,desquannation and flattened epithelial lining. tubulitis with lymphocyte invasion.
o BKVN EM 30 to 50nm sized viral inclusions tubular cell necrosis, prominent lysosomal inclusions, luminal protein and cellular casts.
o D/D CMV H SV adenovirus
So a blood QPCR showing > 60 to 100 BKV copies plus characteristic pathologic morphology is needed.
o Urine Cytology Decoy cells- cell with enlarged nucleus with a single large basophilic intranuclear inclusion. Urine Q PCR decoy cells are Sensitive not specific
Decoy cells also seen in – CMV adenovirus
o QPCR Sensitivity is 100% and specificity is 88%. Viriuria precede viraemia by 4 weeks and nephropathy by 12 weeks. Decision to be made on trends than single value.
Active screening every 3 months post renal transplant.
o Serology Not useful
o Viral culture Not clinically applicable
o Urine EM Haufen bodies Can act as an non-invasive method Dr BkvAN diagnosis.
o Therapeutic intervention. Immunosuppression reduction
Cidofovir nephrotoxicity
Brincidofovir lower nephrotoxicity
Leflunomide SIE TMA hepatitis bone marrow suppression
Iv Ig In patients with hypogammaglobulinemia may be beneficial. also guards against rejection.
Fluoroquinolone Currently no significant role
Cellular immunotherapy Transfer of primed BKV reactive Tcells is being studied.
BK virus :is a small DNAthat usually affect immune compromised individuals
Diseases caused by BKV:
BKV nephropathy
leucoencephalopathy by JC part
ureteric stenosis (ureteric obstruction)
transmission:
feco oral
airborn transmission
vertical and blood transfusion
Diagnosis:
BK quantitative PCR
DEcoy cells in urine
histopathology and graft biopsy with SV 40 stain
treatment:
No sufficient evidence on spescific and effective antiviral therapy
Lefluonamide,cidofivir ,IVIG may be beneficial
Decrease immunosuppression can give better outcome
Polyomaviruses are small DNA viruses that can infect humans and animals like rabbits, rodents, and birds. BK polyomavirus (BKV) is a highly prevalent forms of polyomaviruses causing infection in immuno – compromised patients.
The BK polyomavirus was isolated in 1971. Since that time no specific treatment option has been available for effective
treatment or prophylaxis.
The current consensus on management of BKV viremia
is to decrease immunosuppression, because infection is related to the degree of immunosuppression rather than the drugs used in immunosuppression.
Transmission mechanism
Primary BKV infection occurs in the first decade of life, at 4 to 5 years of age.
The following are possible routes of transmission :
1- airborne transmission
2- feco-oral transmission
3- other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation)
4- blood transfusion and vertical transmission
Clinical Picture of BK virus infection :
90% of the population will become BKV seropositive during their life, it can occur after solid-organ transplant, especially in bone marrow or kidney transplant recipients. In kidney transplant
recipients, reactivation may lead to BKVN causing graft dysfunction and failure through tubulointerstitial nephritis and/or ureteral obstruction. In bone marrow transplant recipients,
BKV can lead to hemorrhagic cystitis.
It is very rare to have BKV reactivation in other immuno –
compromised patients.
Definitive diagnosis of BK virus nephropathy :
-This needs a characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which is 100% specific, and pathognomonic. The diagnosis of BKV in a renal biopsy
can be missed in about 30% of cases because BKV has a focal tropism in the medulla rather than in the cortex.
-The confirmation of BKVN diagnosis, need blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed.
Urine examinations may reveal BKV-infected cells.
The most characteristic abnormality of infected cells is an enlarged nucleus with a single, large basophilic intra-nuclear inclusion which called decoy cells.
– Serology test is not helpful for anti-BKV antibodies for a definitive diagnosis of BKV infection because these antibodies can commonly be positive in the general population.
-Viral culture is rarely used as for BKV infection detection outside the research setting because this can take weeks to months; therefore, this method is not clinically applicable.
Therapeutic interventions
1- immunosuppression reduction
2- Cidofovir
3- Brincidofovir (CMX001)
4- Leflunomide
5- intravenous immunoglobulin
6- Fluoroquinolone
level 5
BK virus is one of the viruses that present since childhood and will be in the dormant phase in the tubule interstitial tissue. Will reactivate once the patient is immunocompromised.
This type of virus causes interstitial nephrites and picture mimic acute rejections
Risk factors and pathogenesis: The risk factors include
· Factors related to recipient includes: high immunological risk like (HLA incompatibility, ABO incompatibility, and use of antilymphocyte antibodies) which reflect on degree of immunosuppression, diabetes mellitus, rejection episodes, older age, steroid use cytomegalovirus co-infection.
· Factors related donor: seropositive renal donor, viruria in the donor.
Update on the Management of BK Virus Infection
Its Narrative review (level of evidence v) published in Experimental and Clinical Transplantation (2020) about management of BK virus infection.
Introduction:
BK virus is one of polyomavirus which usually primary infection occurs early during childhood and remain latent in the tubuloepithelial cell of kidney but after solid organ transplant and immunosuppression reactivation occurs causing tubulointerstitial nephritis, ureteral stenosis and hemorrhagic cystitis. Management of BK viremia involves reduction of immunosuppression, monitoring of BK virus polymerase chain reaction (PCR), and renal function.
Risk factors and pathogenesis: The risk factors include
· Factors related to recipient includes: high immunological risk like (HLA incompatibility, ABO incompatibility, and use of antilymphocyte antibodies) which reflect on degree of immunosuppression, diabetes mellitus, rejection episodes, older age, steroid use cytomegalovirus co-infection.
· Factors related donor: seropositive renal donor, viruria in the donor.
Clinical picture:
1. Asymptomatic
2. slow progressive rise in serum creatinine
3. an unexpected finding of BK virus associated nephropathy on graft biopsy.
4. Laboratory tests include pyuria, recurrent UTI, hematuria, cellular casts, etc.
Diagnosis overview:
A graft biopsy is definitive for diagnosis, but can be negative due to patchy involvement and showed contain medullary specimen.
Quantitative PCR diagnoses BK viremia (sensitivity 100%, specificity 88%) but there is not cutoff can be predict associated with BK nephropathy.
Urinary decoy cells: it can be used only for screening but it neither sensitive nor specific (cell with enlarged nucleus and single, large basophilic intranuclear inclusion)
Definitive diagnosis requires cytopathic changes on biopsy with positive immunohistochemistry (SV40 large T antigens), and positive BK viremia.
BK virus nephropathy has 3 different patterns on histology, and has 3 different grades according to Banff classification.
Therapeutic interventions:
Immunosuppression reduction is the cornerstone of therapy, but associated with increases risk of rejection.
there is no strong evidence in the form of randomized controlled trials support the use of the following agents
· Cidofovir and Brincidofovir: not widely used because of nephrotoxicity.
· Leflunomide: promising treatment because of its immunosuppression and antiviral effect which can replace MMF.
· IVIG (intravenous immunoglobulins), and Fluoroquinolones have been used.
Conclusions: BK viremia only 10% post kidney transplant recipients but BK nephropathy around 2-4%. Management involves reduction of immunosuppression.
Human polyomaviruses, which are DNA viruses, include the BK virus; BKV infections result in
Among recipients of renal transplants, tubulointerstitial nephritis and ureteral stenosis are common. On average, there are
10% of people had kidney transplants.
The prevalence of BKV infection and the level of immunosuppression are directly correlated, but not the medication itself. Diabetes mellitus, older patients, male patients, delayed graft function, acute rejection episodes, and prior CMV infections are additional risk factors.
Asymptomatic to frank nephropathy with distorted renal function and gradually rising blood creatinine levels are among the clinical symptoms of BKV infection. A urine assay may reveal cellular casts, pyuria, and hematuria. BKV-infected decoy cells are visible in urine microscopy.
Renal allograft biopsy with immunohistochemistry that cross-reacts with the BKV, specifically SV40, provides a conclusive diagnosis of BKVN.
Renal allograft biopsy with immunohistochemistry that cross-reacts with the BKV, specifically SV40, provides a conclusive diagnosis of BKVN.
the virus’ large-T antigen component. About one-third of individuals may not develop BK virus nephropathy, hence two core biopsies are required for confirmation, ideally involving the medulla.
BKV DNA quantitative PCR is typically used to monitor renal transplant recipients. Viral replication occurs in stages, with viruria occurring around 4 weeks before viremia and nephropathy appearing 12 weeks later.
The primary differential diagnosis for BKVN is acute rejection. BKV inclusions and immunohistologic tests could be used to distinguish BK virus nephropathy from other types.
Correlating histologic findings with PCR evidence of viremia is also crucial.
summary of the article:
level of evidence 5
-Evidence level 5 (narrative review)
-Risk factors include
Diabetes mellitus, delayed graft function, ureteric insult, immunosuppression, CMV infection, elderly individuals and white race.
-BKV infection may be asymptomatic or may cause BKVN, hemorrhagic cystitis or ureteric strictures, rarely neurological manifestations and ophthalmic complications.
-The mainstay management is IS reduction, antivirals still have no good evidence.
-IVIG may have a role especially in BKVN, in the setting of rejection.
-Cellular immunotherapy may have future role.
Summary
BKV is an infection that affects immunocompromised patients to a large extent. BKV can lead to tubulointerstitial nephritis and ureteral stenosis in kidney transplant patients and also hemorrhagic cystitis in bone marrow transplant patients.
BKV is a double stranded DNA virus and is a member of the polyomavirus family. Transmission routes include the following :
Primary infection can occur during childhood, but is insignificant in most cases. The virus remains in the renal epithelium. In immunocompromised population, BKV replication results in asymptomatic bacteriuria.
Risk factors include the following :
Clinical features include possible asymptomatic patient, slow increase in creatinine, progressive renal damage which is nephropathy.
Tissue biopsy is needed for diagnosis, with features such as basophilic intranuclear viral inclusions without a surrounding halo, anisonucleosis, hyper hero Asia, and chromatin clumping of infected cells.
Differential diagnosis include other viral infections such as CMV, HSV, and adenovirus,
Level of evidence
The given article is a narrative review, and thus level of evidence 5.
Introduction:
Polyomaviruses are small DNA viruses that can infect humans and animals like rabbits, rodents, and birds.
Virology Properties:
BK virus is a member of the family Polyomaviruses. This family is a double-stranded DNA virus with icosahedral symmetry. BK virus has been categorized serologically and genotypically into 4 groups.
Genome structure and transcription:
Polyomaviruses are small (40-50 nm in diameter), uncovered, icosahedral, with a double circular chain.
The external layer consists of structural proteins VP1, VP2, and VP3. VP1 is organized into 72 each one associated with a unique copy of smaller structure proteins (VP2 or VP3)
VP1 determines receptor specificity, whereas VP2 and VP3 are involved in viral particle stabilization.
The genomic structure encodes 6 chief proteins divided into 3 regions: early encoding region, late encoding region, and noncoding control region.
Transmission mechanism:
First decade of life, on average at 4 to 5 years of age. Possible routes include the following:
(1) Airborne transmission.
(2) Feco-oral transmission.
(3) Urinary-oral route or seroconversion after solid-organ transplant.
(4) Blood transfusion and vertical transmission.
Primary infection is asymptomatic, the virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule.
Patients with impaired cell-mediated immunity have a particularly greater risk of BKV.
Prevalence of BKVN in renal transplant recipients is 5%..
Risk factors and pathogenesis:
Degree of immunosuppression.
Tacrolimus specifically can increase BKV replication by a specific mechanism involving FK-binding protein (BP-12).
Diabetes mellitus.
Delayed graft function,
Treated episodes of acute rejection,
Ureteral trauma
Use of antilymphocyte antibodies.
Coinfection with CMV.
Maintenance steroid immunosuppression,
Older age, white race/ethnicity,
Presence of specific human leukocyte antigen (HLA) C loci.
Presence of BKV antibody titers and viruria in a potential donors.
Both HLA and ABO-incompatible transplants.
Clinical Picture of BK virus infection:
About 90% of the population will become BKV seropositive during their life; this reactivates after solid-organ transplant.
Usually 10 to 13 months post-transplant.
But may be as early as on week or late up to 5years.
(1) Asymptomatic.
(2) Slow and progressive increase of serum creatinine.
(3) An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
(4) Especially in bone marrow presents as hemorrhagic cystitis.
Laboratory findings:
(1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria.
Diagnosis Overview:
A tissue (renal) biopsy.
PCR.
decoy cells in the urine analysis increases the suspicion of BKV nephritis.
Definitive diagnosis OF BK virus nephropathy :
characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection.
presumptive diagnosis :
if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction.
In BKVN, light microscopy :
(1) viral inclusions (2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells (3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates (4) tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining; and (5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
Electron microscopy:
(1) Viral inclusions (2) tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
Banff grading of BKV:
Grade Percent Fibrosis and Viral Replication
Grade 1 Minimal viral replication in < 1% of biopsy with < 25% fibrosis
Grade 2 Any between grades 1 and 3 Grade
Grade 3 Marked virus replication in > 10% of cores with > 25% fibrosis.
Differential diagnosis:
CMV.
Herpes simplex virus.
Adenovirus.
Therefore, to confirm a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed.
Urine cytology findings for BK virus infections:
Viral replication in the urine is demonstrated by either decoy cells or BKV urine quantitative PCR.
Decoy cells are suggestive but not specific, sensitive, or definitive for BKV infection because
(1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus)
(2) Decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients.
Note, their absence does not exclude the disease.
Quantitative polymerase chain reaction:
Sustained high viral DNA levels in the plasma of renal transplant recipients who have an appropriate clinical picture can suggest BKVN.
Renal transplant recipients can be monitored with quantitative or real-time PCR for BKV infections in either the plasma or urine.
Patients with a higher viruria level are highly prone to developing BKV viremia, and patients with high sustained viremia are susceptible to BKVN.
Medical decisions, should be made on the basis of trends in quantitative DNA levels rather than on a single measurement.
Urine electron microscopy:
Polyomavirus aggregates, which are called Haufen, Haufen presence was shown to be associated with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients.
Therapeutic interventions:
Currently, there are no available antiviral medications against BKV.
Usual approach in the management of BKV viremia or BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR.
Immunosuppression reduction:
Pros: Help In viral clearance.
Cons: Risk of rejection.
Cidofovir:
Pros: Help in viral clearance.
Cons: Nephrotoxicity.
Brincidofovir
Pros: shown a lower incidence of nephrotoxicity.
Leflunomide
Pros: decrease in BKV viral load.
Cons: thrombotic microangiopathy, hepatitis, and bone marrow suppression.
Intravenous immunoglobulin:
Pros: anti-BKV immunity; the immunomodulatory.
Fluoroquinolone:
No significant role.
Role of cellular immunotherapy in the management of BKV infection.
Possible role in the future by using adoptive T-cell therapy approach.
Conclusions:
Member of human polyomaviruses, which are DNA viruses;
BKV infections lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplant population. The average incidence is about 10% of the renal transplant population.
There is a direct correlation between the incidence of BKV infection and the degree of
immunosuppression, but not the drug itself.
Level of evidence V.
INTRODUCTION:
BK polyomavirus is a small DNA virus that establishes lifelong infection in the renal tubular and uroepithelial cells of most of the world’s population. In the majority, infection is quiescent and benign. but, in immunocompromised patients, it can reactivate, and in some, lead to BK polyomavirus-associated nephropathy Among kidney transplant recipients, its reactivation is common. which is frequently subclinical, although it may manifest with acute kidney injury (AKI), and is a risk factor for premature allograft loss.
Route of transmission:
Primary infection is acquired during childhood, possibly via fecal-oral or respiratory transmission after primary infection, the virus establishes lifelong infection in renal tubular and uroepithelial cells. For most individuals, both primary infection and persistent infection are clinically silent and not associated with any known adverse effects.
Risk factors for replication:
· strong immunosuppression,
· elderly
· male recipients,
· prior rejection episodes,
· HLA mismatching,
· prolonged ischemia time,
· pretransplant BK virus serostatus
· Ureter stenting.
Diagnosis:
Clinically and laboratory
Clinical features:
BKV infection occurs 10 to 13 months posttransplant.
BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
The clinical picture can be:
1) Asymptomatic,
2) Slow and progressive increase of serum creatinine,
3) An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy. Importantly, no signs and symptoms are identified with BKV infection.
Laboratory:
1) Renal biopsy: definite diagnosis
2) PCR has 100% sensitivity and 88 % specificity.
3) Urinalysis – cytology= Decoy cells – Good screen test.
EM shows presence of cast-like, three-dimensional polyomavirus aggregates, termed Haufen
Treatment:
1) Reduction of Immunosuppression.
2) Cidofovir; but it is nephrotoxic.
3) IVIG
4) Fluoroquinolone: In vitro has ability to inhibit replication of BKV or SV40 polyomavirus replication.
5) cellular immunotherapy with limited data.
LEVEL OF EVIDENCE IS 5
Introduction
BK polyomavirus (BKPyV) is a small DNA virus that establishes lifelong infection in the renal tubular and uroepithelial cells of most of the world’s population. For the majority, infection is quiescent and benign. However, in immunocompromised patients, BKPyV can reactivate, and in some, lead to BKPyV-associated nephropathy (BKPyVAN).Among kidney transplant recipients, BKPyV reactivation is common. Reactivation is frequently subclinical, although it may manifest with acute kidney injury (AKI), and is a risk factor for premature allograft loss.
Transmission mechanism-
BK polyomavirus (BKPyV) is a ubiquitous virus with a worldwide seroprevalence of approximately 80 to 90 percent Primary infection is typically acquired during childhood, possibly via fecal-oral or respiratory transmission . Following primary infection, the virus establishes lifelong infection in renal tubular and uroepithelial cells. For most individuals, both primary infection and persistent infection are clinically silent and not associated with any known adverse effects.
Risk factors for viral replication –
The intensity of immunosuppression (particularly suppression of cellular immunity) appears to be a dominant risk factor for BKPyV replication and disease. Consistent with this, replication rates are higher in the early posttransplant period and following treatment for allograft rejection when immunosuppression intensity is highest.
No specific immunosuppressive drug or regimen has been definitively associated with clinically significant BKPyV infection. Several studies have suggested that certain drugs (particularly tacrolimus) may be associated with an increased relative risk Other important risk factors include high risk serostatus (ie, kidney transplant from a BKPyV-.seropositive donor to a seronegative recipient) impaired immune response to BKPyV and donor BKPyV viruria prior to transplant. The last two factors suggest that the donor is an important source of transmission .
Other risk factors associated with an increased risk of BKPyVAN or disease severity include older age, ureteral stent placement, ABO incompatibility ], rejection or ischemia of the transplanted kidney , delayed graft function HLA mismatch specific HLA-C alleles , BKPyV polymorphisms , and transplantation from an HCV-positive donor .
In kidney transplant recipients,
Clinical Picture of BK virus infection-
BK polyomavirus (BKPyV) replication typically develops in stages: viruria followed by viremia and then, if viral replication persists, nephropathy can ensue. Asymptomatic viruria, viremia, and/or a slow progressive rise in serum creatinine are typically the only indicators of BKPyVAN. The incidence of BKPyVAN is highest in the first two to six months posttransplant. While the majority of cases occur in the first posttransplant year, BKPyVAN can occur years after transplantation. . Without resolution of infection, progressive kidney allograft dysfunction and graft loss can ensue over a period of months . Within the allograft, early infection triggers interstitial inflammation, which then progresses to fibrosis and tubular injury. Accordingly, urinalysis may reveal pyuria, hematuria, and/or cellular casts consisting of renal tubular cells and inflammatory cells, or may be normal.
Other manifestation-ureteral stenosis and In bone marrow transplant recipients, BKV can lead to hemorrhagic cystitis
SCREENING AND DIAGNOSIS-
Posttransplant screening — Screening and preemptive reduction in immunosuppression for patients with clinically significant BKPyV viremia prevent progression to BKPyVAN in the majority of patients. Screening should be done with Plasma PCR Monthly for the first six months following transplant, then every three months until two years posttransplant, and then annually until five years posttransplan and Whenever kidney allograft dysfunction occurs or when an allograft biopsy is performed for allograft dysfunction.
Diagnosis–
Kidney allograft biopsy is the gold standard for diagnosing BKPyVAN, assessing its severity, and evaluating for concomitant processes. However, because biopsy is invasive and sampling error can occur, a presumptive diagnosis is often made based upon the presence of significant viremia (plasma BKPyV viral load ≥10,000 copies/mL).
A definitive diagnosis of BKPyVAN requires the following findings on kidney biopsy
Characteristic cytopathic changes.
plus
Positive immunohistochemistry tests using antibodies directed specifically against BKPyV or against the cross-reacting SV40 large T antigen.
In BKVN, light microscopy examinations would show the following:
(1) basophilic intranuclear viral inclusions without a surrounding halo ; (2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells; (3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates (4)tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial liningand (5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium
Urine cytology in BK virus nephropathy-
Cytologic examination of the urine, which may reveal BKPyV-infected cells, Decoy cells,is infrequently used to screen for BKPyVAN. Although the presence of characteristic cytopathologic changes in infected cells (which have been called decoy cells due to their resemblance to renal carcinoma cells) is strongly suggestive of BKPyV infection .Cytological urine abnormalities (decoy cells) are suggestive but not specific, sensitive, or definitive for BKV infection because (1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus and (2) decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients..Of note, their absence does not exclude the disease
Urine electron microscopy–
Negative-staining electron microscopy of the urine of patients with BKPyVAN often reveals the presence of cast-like, three-dimensional polyomavirus aggregates, termed Haufen .Haufen form in injured tubules with BKPyV replication and a high intratubular uromodulin concentration and are excreted into the urine similar to other urinary casts. In one cohort study of >300 kidney transplant recipients, the detection of Haufen in voided urine had a sensitivity, specificity, negative predictive value, and positive predictive value for biopsy-proven BKPyVAN of greater than 95 percent , suggesting that this may be a noninvasive way to diagnose BKPyVAN. However, the urinary Haufen test requires electron microscopy.
TREATMENT-
Since there are no specific antiviral therapies for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN), the cornerstone of management is to decrease immunosuppressive medications .Several agents have been shown to have in vitro anti-BKPyV activity. However, we do not routinely use any of these agents for the treatment of BKPyV infection, given that the efficacy of these agents has not been established and use of these therapies has not been clearly shown to be superior to reduction in immunosuppression alone
Level of evidence 5
Abstract
– The BK polyomavirus was isolated in 1971;
– It is risk factor for both graft lose in renal transplant recipients.
– no specific treatment or prophylaxis available .
– Ais precipitated by varisble risk factors
o heavy immunosuppression
o elderly recipients,
o prior rejection episodes,
o male sex,
o human leukocyte antigen mismatching,
o prolonged cold ischemia time,
o pretransplant BK virus serostatus,
o ureteral stenting.
Regular follow-up for BK virus infections is effective in early detection and preventing allograft loss.
The mainstay of management is reduction of immunosuppression. But cellular immunotherapy may be anew option
Introduction
BK Virus has been a significant risk factor for graft lose .
Risk factors –
· strong immunosuppression,
· elderly
· male recipients,
· prior rejection episodes,
· HLA mismatching,
· prolonged ischemia time,
· pretransplant BK virus serostatus
· Ureter stenting.
No effective and specific treatment and prophylaxis available . cellular immunotherapy may be anew treatment option.
virology
Properties
BK virus is a Polyomaviruses.ds-DNA virus. Has four types (I toIV), with each one having a different virulence.
Historical aspects
Discovered In 1971, a Sudanese renal transplant patient presented with ureteralobstruction after renal transplant.
Transmission mechanism:
Possible routes include the following:
(1) airborne transmission through air droplets
(2) a feco-oral transmission, as fecally eliminated polyomaviruses are detected in hospitalized children; (3) other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation)
(4) both through blood transfusion and vertical transmission.
Risk factors and pathogenesis:
1- degree of immunosuppression is important risk factor.
2- It is a marker of heavy immunosuppression.
3- immunosup – pressive agents can affect T cells, which can lead to increased BKV replication.
4- Tacrolimus specifically can increase BKV replication by a specific mechanism involving FK-binding protein .
5- Other risk factors include
a. diabetes mellitus,
b. delayed graft function,
c. treated episodes of acute rejection,
d. ureteral trauma,
e. use of antilymphocyte antibodies,
f. Coinfection with Cytomegalovirus (CMV),
g. maintenance steroid immunosuppression,
h. older age,
i. white race/ethnicity,
j. and presence of specific human leukocyte antigen (HLA) C loci.
k. presence of BKV antibody titers in donors, which reflects recent BKV reactivation and replication .
The viruria in a potential donor can be considered as a predictor for posttransplant BKV infection.
Recent studies have demonstrated that BKV replication in a transplant recipient is usually due to transmitted infection from the donor.
Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy, possibly due to heavy immunosuppression (whether due to induction or maintenance immunosuppression or episodes of rejection).
, ABOincompatible recipients are at a higher risk of BKVN than HLA-mismatched recipients as they may have a higher rate of rejection and need more immuno – suppression than HLA-incompatible patients.
Clinical Picture of BK virus infection:
About 90% of the population will become BKV seropositive during their life; this reactivates with immune suppression.
reactivation may lead to BKVN, by causing tubulointerstitial nephritis and/or ureteral
obstruction.
In bone marrow transplant recipients, BKV can lead to hemorrhagic cystitis.
rare to reactivate in other immuno –
compromised patients, such as AIDS , SLE other autoimmune diseases .
Clinical manifestations are as follows:
(1) asymptomatic,
(2) slow and progressive increase of serum creatinine,
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Importantly, no signs and symptoms are identified with BKV infection.
BKV infection occurs 10 to 13 months posttransplant.
BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
Laboratory findings in patients with BKV infection are as follows:
(1) elevated serum creatinine
(2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
DIAGNOSIS:
-Definitive dx need renal biopsy, but it is present in the medulla which is easily missed on biopsy.
-BK PCR has 100% sensitivity and 88 % specificity .
-Urinalysis – Decoy cells – Good screen test . BKV PCR can used .
– viremia follows viruia by 4 weeks.
-Definitive dx ; Cytopathic changes + +VE SV40 antigen- 100%Specificity .
-Presumptive diagnosis – Continuous viruria (>2 weeks) + BK PCR > 10000 Copies/ml
-Anti BKV antibodies are not sensitive for diagnosis .
-Highest risk of infection in D+/R- transplantation.
-Viral cultures usually not indicated.
–Haufen presence ( by EM) has 100% sensitivity and 99% specificity in detecting biopsy proven BKVN post KTR.
ifferential diagnosis
Other types of viral infections:
CMV, herpes simplex virus and adenovirus.
Treatment:
1. manipulation of Immunosuppression .
2. Cidofovir; but it is nephrotoxic.
3. Brincidofovir (CMX001) is a prodrug of cidofovir that is administered orally and non ephrotoxicity.
4. IVIG.
5. Fluoroquinolone: In vitro has ability to inhibit replication of BKV or SV40 polyomavirus replication.
6. cellular immunotherapy . data is limited.
Level of evidence is 5
Reduction in immunosuppression 25 to50% in CNI and 50% in alkylating agents, if not responding can reduce more with up-to 75% with reduction in steroid dose.
other option adjuvant treatment with CIDOFOVIR, IVIG, LEFLONAMIDE, and QUINOLONES.
However, no conclusive evidence available.
How would you treat BKV infection in 2 words only?
Reduce Immunosuppressives
Introduction
BK Virus has been a significant risk factor for graft dysfunction and failure in renal transplant recipients.
This review addresses diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.
Virology
It is a ds-DNA virus, a member of the family Polyomaviruses, and has genotype (I to IV) with different virulence.
Transmission mechanism
Route :
– Airborne transmission
– Feco-oral or urinary-oral transmission.
– Blood transfusion
– Vertical transmission.
-Primary BKV infection occurs early in life during childhood and often clinically insignificant.
-Latent infection: followed the 1ry infection) the virus stays in the renal epithelium and becomes dormant until it is reactivated
– BKV replication in immunocompetent population; asymptomatic viruria, ( viral shedding 20%)
– immunocompromised individuals, shedding reaches 60% and the viruria is more common.
Risk factors & pathogenesis
– Degree of immunosuppression (most important)
– Others
* DM
* Delayed graft function
* Treated episodes of acute rejection
* Ureteral trauma
* Use of antilymphocyte antibody
* Coinfection with CMV
* Older age
Clinical picture
– Asymptomatic
– Slow & progressive increase in creatinine
– On allograft biopsy progressive renal damage
Investigation
– Raised s. creatinine
– Urine analysis
– Urine cytology (>3 decoy cell/ hpf)
– Renal biopsy ( basophilic intranuclear inclusions) plus positive immunohistochemistry
– Blood PCR & Urine PCR
Treatment
Currently, there are no available antiviral medications against BKV.
– Approach in the management of BKV viremia or BKVN in renal transplant recipients is reduction of IS and continuous monitoring of BKV viremia level via PCR.
– Immunosuppression reduction; cornerstone, carries a higher risk of rejection.
Other agents used with reducing IS:
– Cidofovir; No RCT, associated with nephrotoxicity
– Brincidofovir; prodrug, less nephrotoxic, successful outcomes in renal and HSCT.
– Leflunomide; IS and antiviral properties.
– Intravenous immunoglobulin; neutralizing antibodies, used as adjunctive therapy, immunomodulatory
effects may guard against allograft rejection in the context of reducing IS.
– Fluoroquinolone; inhibit replication of BKV or SV40.
– Adoptive cellular immunotherapy; may carry potential hope
Level V
BKV NEPHROPATHY IN KIDNEY TRANSPLANTS;A STATE OF THE ART REVIEW:
INTRODUCTION:
-Good post transplant outcomes from adequate immunosuppression has led to increased BKVAN with viremia being seen in up to 30% post transplant.
-We are yet to get adequate tx for BK infection.
HX OF BK VIRUS:
-Discovered in 1971 in pt with ureteral stricture post transplant.1st BKVAN proven biopsy seen in 1993.
-Initially had graft loss of 50-100%,this has decreased to < 15% in last two decades.
VIROLOGY:
-BK is a non enveloped ,icosahedral shaped double stranded DNA virus.
-Gene has an early, non coding and late region. Early has T and t antigens with the former binding to p53 and protein RB while the later codes for VP1.VP2 and VP3 viral caspid proteins.
EPIDEMIOLOGY:
-Prevalence of 90% in general population by 4 yrs.
-Stages of infection ; Viruria,viremia and nephropathy.
-After viruria,50% KTR will have viremia in 2-/ time.
-Transmission routes ; Oral, GIT and resp tract.
-Plasma VL>4 log 10 are associated with more risk of BKVAN.
RISK FACTORS:
-These include ;
CELLULAR IMMUNE RESPONSE AND PATHOGENESIS:
-T cell mediated immunity ;CD4 and CD8 cells key in clearing BK infection. Increased interferon gamma is a good pointer yo BK specific cellular response.
-Post childhood infection, BK maintains latency in renal epithelium, prostate, testes, seminiferous tubules, cervix, vulva and lymphoid tissues ,with reduced immunity, the infection flares up and pt becomes symptomatic.
CLINICAL MANIFESTATION:
-Stepwise ; Viruria, viremia then nephropathy. Viruria occurs in up to 50% in 1st 1 yr post transplant.
-Viremia is a better marker of those at risk of BKVAN. Viremia may present as increase in creatinine +/- urinary anomalies.
-Others; Ureteral stenosis, hemorrhagic cystitis.
-Rare ; GU malignancies.
SCREENING AND DIAGNOSIS:
-BK viremia screening is the preferred modality.
Presumptive dx ;VL > 10000 Copies/ml.
TREATMENT:
2.Other therapies;
3.Future therapeutic trials.
KIDNEY RE-TRANSPLANTATION:
-Successful post graft dysfunction from BKVAN.
-Graft/Native nephrectomy not recommended.
-Careful dosing of immunosuppression to avert rejection to be adhered to.
-Graft survival post transplant 98% and 94% at 1 yr and 3 yrs respectively.
Summary:
· BKV infection is associated with graft dysfunction and loss.
· It is named after the initials of Sudanese patient with ureteric stenosis with discovered viral particle in the epithelial lining.
· Mode of transmission:
feco-oral, respiratory, transplacental and organ transplantation
· Primary infection in childhood
usually asymptomatic viuria , while the virus remains dormant in uroepithelial cells then become activated in immunocompromised patients (as renal transplant recipients) with increasing viruria up to 60%..
· Risk factors for infection:
high immunological risk, increased HLA mismatch, ABO and HLA incompatible transplantation, strong induction as ATG, TAC and MMF containing IS therapy, repeated treatment of rejection episodes, so the most important is the net immunosuppression state, D+/R- serological status prior to transplantation, old age and diabetes in the recipient, DGF and prolonged cold ischemia time.
· No specific antiviral to be used in prophylaxis or ttt of BKV cases.
· BKN clinical manifestations in kidney transplantation:
o Interstitial nephritis and ureteral stenosis commonly occur at 10-13 months post-transplant.
o Rising creatinine, hematuria and pyuria and cellular casts.
o Definitive BKN is diagnosed by allograft biopsy which has interstitial nephritis that turn chronic and cause allograft dysfunction and loss.
o Biopsy may be false -ve (patchy affection and mainly in medulla), so 2 core biopsies are needed including renal medulla.
o Biopsy shows 3 patterns (A, B, C) with early cytopathic changes then acute interstitial nephritis then chronic tubulointerstitial nephritis.
o Special staining fir IHC (SV 40) simian virus 40, stains large T antigen present in polyoma virus, is diagnostic for polyoma virus (SV, BK and JC). Specificity is 100 % and sensitivity is 77.7 %
o Blood BKV PCR indicates viremia whether has BKN or not,
o BKV PCR can be done in urine sample.
o Decoy cells (cells with large inclusion bodies replacing the normal chromatid) in urine increases suspicion of BKN. But definitive diagnosis is biopsy.
o Decoy cells=infected tubular and urothelial cells (only epithelial) with large basophilic nucleus (looks like high grade urothelial atypia),
o DD from owl eye appearance of CMV inclusion bodies (that is surrounded by complete halo around it )
o Decoy cells in urine (infected urothelial cells), with :
§ Sensitivity 100 % of BKN.
§ Specificity 84%.
§ NPV is 100%.
§ PPV is 6%.
o Presumptive BKN means sustained (>2 weeks) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction
o Hemorrhagic cystitis occurs in bone marrow transplantation.
· BKN Differential diagnosis:
o Other viral infections as CMV and adenovirus.
o Acute rejection (DD by presence of viral inclusion bodies, and positive PCR (viremia))
· The main line of ttt is reduction of immunosuppressive therapy, but the problem is increasing risk of rejection and graft loss (so achieving the balance between both conditions is difficult.
· Reduction of MMF dose by 50 %, reduction of CNI by 25-50 % is started, then FU PCR if not decreasing stop MMF.
· Still not proved, to shift from tacrolimus to cyclosporin or to shift from MMF to mTORi.
· Adoptive specific T cell immunotherapy may be future therapy for refractory cases.
· Follow up PCR every 2 weeks and FU graft function every week.
· NO RCT to demonstrate specific therapy, but additional use of cidofovir, leflunamide, quinolones and IVIG in refractory cases (not decrease in viral load with reduction of IS).
Level of evidence: V (narrative review).
1. Summary of the article:
Introduction
BK Virus has been a significant risk factor for graft dysfunction and failure in renal transplant recipients.
Risk factors – strong immunosuppression, elderly male recipients, prior rejection episodes, HLA mismatching, prolonged ischemia time, pretransplant BK virus serostatus and Ureter stenting.
No effective and specific treatment as such – main stay of treatment is immunosuppression reduction; cellular immunotherapy provides new insight.
This review addresses diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.
Virology
Polyomavirus family – small double-stranded DNA virus
4 genotypes with different virulence – Type 1 most prevalent 80%, type IV 15%
Transmission
(1) airborne transmission (droplet)
(2) feco-oral transmission – community
(3) urinary-oral route (children to care giver) or seroconversion post-transplant
(4) blood transfusion and vertical transmission (mother à foetus)
pathogenesis
· Viral inoculation in childhood (respiratory / oral routes) – asymptomatic
· Primary viremia à dissemination through blood to different tissues
· Virus stays latent in kidney, urothelial lining
· BKV replication and urinary shedding – asymptomatic viruria – 20% in immunocompetent hosts,
· Reactivation and increased Viral replication in immunocompromised and transplant patients – secondary viremia, urinary shedding (viruria 60%)
· Patients with impaired cell-mediated immunity have a particularly greater risk of BKV Nephropathy (mean prevalence 5%) and ureter stenosis (rare).
Risk factors
Clinical Picture of BK virus infection
Preliminary Lab findings:
· Azotaemia
· urinalysis – pyuria, haematuria, cast (Interstitial Nephritis)
· Decoy cells in urine
Diagnosis:
· A presumptive diagnosis can be made with sustained viruria (>2weeks) and significant viremia (plasma DNA PCR load > 10,000 copies/mL) with or without kidney dysfunction
– Characteristic cytopathic changes* (large intranuclear inclusion) + positive IHC against BKV or SV40 large T antigens is pathognomonic of BKV infection with 100% specificity.
– Medullary tropism – viropathic lesions may be missed
*Light microscopy (Cytopathic changes):
Urine electron microscopy (with negative staining) shows –
– Cast-like 3-D polyomavirus aggregates, called “Haufen” non-invasive method for BKVN diagnosis in renal transplant recipients
– differentiates between BKVN and asymptomatic BKV infection
Management:
· Few controlled studies available on management of BKV infection in renal transplant recipients.
Various Medications used successfully in case series / case reports
Cidofovir and Brincidofovir along with IS reduction
Leflunomide – immunosuppressant + antiviral properties
o replacing MMF, have shown control of BKV in in few case-series
Intravenous immunoglobulin (IVIg)
o contains neutralizing antibodies against BKV – good choice in the management of BKVN
o used as adjunctive therapy for BKVN in multiple case reports and case series, but no RCT
o may also guard against allograft rejection
Adoptive T cell transfer –
· BKV reactivation occurs due to failure of BKV-reactive T cells to control viral replication. Transfer of primed BKV-reactive T cells can help in controlling the BKV-associated disease.
· CMV- or EBV- or BKV-specific T cells are produced by various techniques using immunodominant epitopes / peptides /overlapping peptide, using MHC-multimers or interferon-capture technology or in-vitro expansion of T cells.
· Adoptive T- cells were used successfully in HSCT patients for prophylaxis as well as treatment of resistant viral infections.
o Few participants had active BKV infection, which improved after adoptive T-cell transfer.
CONCLUSIONS:
· BKV infection in SOT recipients flares up due to heavy immunosuppression (Tac + MMF + high steroid), manifests from asymptomatic to frank nephropathy, with progressive renal dysfunction and graft failure.
· Abnormal Urinalysis with Decoy cells indicates shedding of BKV, and suggests for Quantitative PCR in blood.
v Definitive diagnosis of BKVN is made by renal allograft biopsy with IHC with SV40 large-T antigen.
– BKVN could be missed in 30% patients – 2 core biopsies preferably including the medulla are needed for confirmation.
– Acute rejection is the main differential diagnosis of BKVN, which also gets precipitated after IS reduction.
Ø There are no effective antiviral medications for BKV infections. Concomitant administration of various agents with IS reduction has been reported in only uncontrolled case series or retrospective observational studies – lack firm conclusions on their therapeutic efficacy.
Ø The common approach for BKV infection management is active screening (quarterly for 2 years post-transplant) – by serum and urine quantitative PCR for BKV DNA.
o Viral replication goes in stages – viruria preceding viremia by about 4 weeks and nephropathy by 12 weeks.
o With any level of rising BKV viremia – IS reduction and then continuous monitoring viral load (quantitative PCR in blood) and RFT should be performed.
Ø Newer treatment, including cellular immunotherapy, may carry potential hope.
2. Level of evidence: Level V (Narrative review)
1. Please summarise this article;
BK virus belongs to a family of polyomavirus family, small double-stranded DNA virus, categorized into four groups with different virulence.
It has been a significant risk factor for both graft dysfunction and failure in allograft.
It was observe that the strong immunosuppression has been the risk factor for BKV infection and reactivation.
Other risk factor are BKV serostatus, AMR, elderly recipient, male gender, and prolong cold ischemia time.
It is no such effective and specific treatment, although, the main stay of treatment is immunosuppression modification, other newer options are cellular immunotherapy.
Transmission;
. Primery infection–à first decade.
. Possible routes-à droplets (airborne), feco-oral, urinary-oral rout, blood born, during renal transmission, trans-placental.
. Remain dormant state in EPITHELIAL cells of tubular, parietal, transitional structure, and bowman’s capsules.
The incidence of shedding in immunocompetent patient is around 20%.
The incidence of shedding of viruria in immunocompromissed recipient is around 60%.
In pregnant women the shedding disappear two weeks after delivery.
The prevalence of BKVN in renal transplant recipient is 5%.
Risk factors and pathogenesis;
There is increased risk of
1. Degree of immunosuppression, ( Tacrolimus has associated with increased replication by involving FK-binding protein( BP-12).
2. Diabetes mellitus, DGF, AMR episodes, older age.
3. Co-infection with CMV.
4. White race and specific HLA C locus.
5. Donor seropositivity, antibodies.
6. ABO miss-match.
Clinical Picture of BK virus infection;
The prevalence of infection is around 90% in first decade of life, however, there is risk of reactivation in immonocompromissed patients.
They can present with hemorrhagic cystitis in bone marrow recipients,
BKVN in renal transplant.
Usually BKV infection occurs in first year post-transplantation, but could be as soon as first week and as late after 5 years.
Diagnosis;
For definitive diagnosis needs biopsy histopathological evaluation.
Steps are,
1. Primery infection present with no or mild symptoms.
2. Latent infection asymptomatic inactive infection and virus infection is detected with molecular technique.
3. Serologic evidence of infection à almost all healthy children and 60-90% of adults.
4. Viral activation à viruria, decoy cells detection,
5. Viral disease à histological evidence of viral replication and associated with clinical symptoms.
However, can miss the diagnosis because the BKV tropism focally in medulla not in cortex.
But can do diagnosis if persistent viruria and PCR copies >10000/ml.
Its difficult to differentiate between rejection and BKVN, except IF, and to differentiat between other viral infection need PCR showing >60-100 copies+ histological result.
Viral culture; Not applicable,
Urinalysis; using negative staining electron microscopy show cast like 3-dimentional polyomavirus aggregates Haufen with sensitivity of 100% and specificity of 99%.
Treatment;
There is such randomized control trails and guidelines in management of BKVN, however, the Immunosuppression reduction up-to 30 to 50% is the main stay of treatment.
No specific antiviral medication, however, Cidofovir, prodrug of cidofovir the Brincidofovir, leflonemaide, quinolones in addition to IS modification can have additive effects
2. What is the level of evidence provided by this article;
Level V
Transmission:
(1) airborne transmission
(2) a feco-oral transmission
(3) urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation
(4) both through blood transfusion and vertical transmission;
Risk factors and pathogenesis
Clinical Picture of BK virus infection
(1) elevated serum creatinine and
(2) urine analysis with pyuria, hematuria, and findings consistent with interstitial
nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
Diagnosis:
A definitive diagnosis of BKVN requires characteristic cytopathic changes on the
renal biopsy plus positive immunohistochemistry (against BKV or against
SV40 large T antigens), which has a specificity of 100%, and pathognomonic results
for BKV infection.
Urine electron microscopy
Management:
Level of evidence: Level V (Narrative review)
Introduction
● The BK polyomavirus is a risk factor for both graft dysfunction and failure in renal transplant recipients.
● BKV infections lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplants and hemorrhagic cystitis in bone marrow transplant patients
● The average incidence is about 10% of the renal transplant population.
● Viruria preceding viremia by 4 weeks and nephropathy by 12 weeks.
● Acute rejection is the main differential diagnosis of BKVN.
● The challenging management of BKV infection is the balance between the fear of rejection due to reduction of IS drugs and the maintenance of IS at the same level, which could cause more BKV viremia and consequently BKVN
virology
● Primary BKV infection occurs in the first decade of life
● Transmission
(1) airborne transmission
(2) a feco-oral transmission
(3) other as urinary-oral route or seroconversion after solid-organ transplant
(4) both blood transfusion and vertical transmission
● The virus stays in the renal epithelium, tubular, parietal, and transitional structures and in Bowman’s capsule
The risk factors for BK virus infection :
☆ Heavy immunosuppression
☆ Elderly recipients
☆ Prior rejection episodes
☆ Male sex
☆ HLA mismatching, ABO-incompatible
☆ Prolonged cold ischemia time and DGF
☆ Pretransplant BK virus serostatus
☆ Ureteral stenting and trauma
☆ Diabetes mellitus
☆ Previous CMV infections
☆ Immunosuppressive agents affect T-cells and antilymphocyte antibodie
☆ Maintenance steroid
☆ white race/ethnicity
☆ Presence of BKV antibody titers in donor
Clinical Picture of BK virus infection
(1) asymptomatic
(2) slow and progressive increase of Sc
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
● BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant
● Urine show hematuria, pyuria, cellular casts and decoy cells
● Monitoring in kidney recipients is by serum and urine quantitative PCR for BKV
Definitive diagnosis of BK virus nephropathy
● A positive SV40 in renal allograft biopsy is a definitive diagnosis of BKVN with 2 core biopsies are needed for confirmation preferably including the medulla because viropathic lesions are patchy in the medulla rather than in the cortex
● Renal biopsy plus positive immunohistochemistry has a specificity of 100%
● A presumptive diagnosis if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL) with or without kidney dysfunction
● Electron microscopy show the following
(1) viral inclusions
(2) tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
Differential diagnosis
● Other viral infections (CMV, HSV, adenovirus).
● To confirm a diagnosis of BKVN, a blood PCR showing > 60 to 100 copies plus characteristically pathologic morphology
Urine cytology findings for BK virus infections
● Enlarged nucleus with a single, large basophilic intranuclear inclusion in urin
● The presence of decoy cells which can be present in CMV or adenovirus infection
● BKV urine quantitative PCR with sensitivity and specificity of 100% and 88%
● Higher viruria levels are prone to BKV viremia, and high viremia are susceptible to BKVN.
● A strong correlation was shown between the negativity of urine BKV PCR and blood BKV PCR
Serology
● Anti-BKV antibody does not seem to be protective
● Previous BKV seropositivity in the recipient can affect progression of BKV infection, from viruria to viremia then BKVN
● The risk of developing a clinically BKV
infection is high when D+/R-
● Viral culture take weeks to months so it is not applicable
● Urine electron microscopy show cast-like 3-dimensional polyomavirus aggregates which are called Haufen which has 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients
● Haufen associated with high-level BKV viremia and acute kidney injury and BKVN. So it is of a great utility, in differentiating between BKVN and asymptomatic BKV infection.
● It’s limitations are :
☆ Depends on a sophisticated analysis
☆ Requires a meticulous interpretation
☆ It cannot discriminate between rejection and BKVN.
● So high load of Haufen support BKVN rather than rejection as a cause of allograft dysfunction
Therapeutic interventions
● Reduction of immunosuppression
● Monitoring of BKV viremia using PCR
● Cidofovir but nephrotoxicity limit it
● Brincidofovir (CMX001) is a prodrug of cidofovir administered orally with a lower incidence of nephrotoxicity
● Leflunomide is an immunosuppressant and has antiviral properties against BKV
● Side effects of leflunomide include TMA , hepatitis, and bone marrow suppression.
● Intravenous immunoglobulin (IVIG)
however it may guard against allograft rejection in the context of reduced IS
● Fluoroquinolone considered as
potential agents for controlling BKV infection in renal transplant recipients.
● fluoroquinolones reduce large T antigen
expression and inhibit of large T antigen helicase activity.
Role of cellular immunotherapy in the management of BKv infection
● Performed by use of overlapping peptide pools that included antigens from Epstein-Barr virus, CMV, adenovirus, BKV, and human herpesvirus
● Cell products using either prophylactically or in response to single or
multiple viral infections.
Level evidence :5
I. Update on the Management of BK Virus Infection
Summarise this article
I. Introduction
– polyomaviruses are small DNA viruses which infect humans, rodents, birds, rabbits
– BK virus (BKV) causes infection in immunocompromised patients
– BKV causes tubulointerstitial nephritis and ureteral stenosis in kidney transplant recipients
– BKV causes hemorrhagic cystitis in bone marrow transplant recipients
– mainstay of management is reduction in immunosuppression and close monitoring of BKV PCR and kidney function to prevent BKVAN which can increase the risk of graft failure and loss
– the main challenge is balancing between rejection (with reduction of immunosuppression) and progression to BKVAN (with maintenance of immunosuppression)
II. Virology
o Transmission mechanism
– primary infections occur during childhood through respiratory or fecal route, the virus remains dormant in the renal epithelium (tubular, parietal, transitional structures and in the bowman’s capsule)
– the risk of viral shedding is 60% in immunocompromised patients making viruria more common than in the immunocompetent population (20%)
o Risk factors and pathogenesis
III. Clinical picture and BK virus infection
– asymptomatic
– slow progressive increase in serum creatinine
– unsuspected finding of BKVAN on surveillance graft biopsy
– there are no specific signs and symptoms identified with BKV infection
– BKV infection occurs 10-13 months post-transplant
– BKVAN can occur as early as week 1 post-transplant or as late as 5years following transplant
– Laboratory findings in BKV infection: –
IV. Diagnosis overview
– kidney biopsy is required for a definitive diagnosis of BKVAN
– the viropathic lesions are patchy and the tropism in BKV is the medulla (not cortex) hence a diagnosis can be missed
– quantitative BKV PCR demonstrates BKV replication whether there is renal involvement or not hence can be used to diagnose BKV viremia
– presence of decoy cells in urine increases the suspicion for BKV nephritis but should be followed by a blood quantitative PCR rather than urine
o Definitive diagnosis of BKVAN
– characteristic cytopathic changes on kidney biopsy plus
– positive IHC (against BKV or SV40 large T antigens)
– specificity 100% and is pathognomonic for BKV infection
– BKV has a focal tropism in the medulla rather than in the cortex hence BKV diagnosis can be missed on kidney biopsy in 30% of the cases
– presumptive diagnosis of BKVAN can be made when there is
– it can be difficult to differentiate between BKVAN and rejection
o Differential diagnosis
– other viral infections e.g., CMV, HSV, adenovirus
– confirmed BKVAN diagnosis requires characteristic pathologic findings plus a blood BKV quantitative PCR of >60 to 100 BKV copies
o Urine cytology findings for BKV infections
– BKV infected cells on urine examination are characterized by an enlarged nucleus with a single, large basophilic intranuclear inclusion
– decoy cells (characteristic cytopathologic changes in infected cells) are strongly suggestive of polyomavirus infections
– decoy cells are cytological urine abnormalities which resemble renal carcinoma cells
– decoy cells and BKV urine quantitative PCR are indicators of viral replication in urine
– decoy cells are not specific, sensitive or definitive for the diagnosis of BKV infection
– decoy cells can be present in other renal viral infections e.g., CMV, adenovirus
– decoy cells correlate poorly with biopsy-proven BKVAN
– absence of decoy cells does not exclude BKV disease
o Quantitative PCR
– sensitivity and specificity of quantitative BKV PCR for BKVAN is about 100% and 88% respectively
– useful in monitoring for BKV infections
– viruria precedes viremia by 4 weeks
– patients with a higher viruria level are likely to develop BKV viremia
– patients with a high sustained BKV viremia are susceptible to BKVAN
– alterations in immunosuppressive drugs should be based on BKV quantitative PCR trends rather than a single reading
o Serology
– examining serum for anti-BKV antibodies is not useful since these antibodies can be present even in the general population
– the utility of assessing anti-BKV Ab levels before and after surgery remains unclear
o Viral culture
– not clinically applicable since it takes weeks to months to isolate the virus from a clinical specimen hence it is rarely used to detect BKV infection unless in research settings
o Urine electron microscopy
– can detect haufen i.e., polyoma aggregates using negative-staining electron microscopy
– detection of urine haufen bodies is a noninvasive method for the diagnosis of BKVAN
– there is a relationship between haufen, high-level BKV viremia and occurrence of AKI and BKVAN
– this technique requires expertise and it is not known whether it can differentiate between BKVAN and rejection
V. Therapeutic interventions
– there are no antiviral medications against BKV
– mainstay of management of BKVAN or BKV viremia remains immunosuppression reduction and continuous monitoring of BKV viremia using quantitative PCR
o Immunosuppression reduction
– carries a high risk for rejection
– at times differentiating rejection from BKVAN is a histologic challenge
o Cidofovir
– there are no RCTs to support its use in BKVAN
– cidofovir is also nephrotoxic making it unfavourable
o Brincidofovir
– this is a prodrug of cidofovir, administered orally, less nephrotoxic
– larger clinical trials are needed to establish its safety and efficacy in management of BKVAN
o Leflunomide
– an immunosuppressant with antiviral properties against BKV in vitro
– side effects include bone marrow suppression, hepatitis, TMA
– prospective controlled studies are needed to confirm its efficacy and safety in BKV infection
o Intravenous immunoglobulin (IVIG)
– contains neutralizing antibodies against BKV making it a good alternative in BKVAN management
– no RCTs have been reported
– IVIG helps guard against rejection in the context of reduced immunosuppression
o Fluoroquinolone
– inhibit BKV and SV40 replication in vitro
– the data available indicates that fluoroquinolones do not play a significant role in management of BKV diseases
o Role of cellular immunotherapy
– involves adoptive transfer of primed BKV-reactive T cells to help control BKV disease in patients
VI. Conclusion
– BKV is a polyomavirus, DNA virus which causes tubulointerstitial nephritis and ureteral stenosis in kidney transplant recipients
– there are established risk factors and clinical manifestations
– definitive diagnosis is dependent on kidney biopsy and IHC findings, 2 cores are needed including the medulla t reduce the chances of a missed diagnosis
– patients require regular monitoring with BKV serum or urine BKV DNA PCR (preferably serum)
– viruria precedes viremia by 4 weeks and BKVAN by 12 weeks
– acute rejection is a key differential diagnosis of BKVAN, the latter is characterized by specific cytopathic changes and IHC analysis correlated with PCR evidence of viremia
– currently, there are no antiviral medications targeting BKV infections
– so far, there are no RCTs to support use of the other therapeutic interventions
– the mainstay of management remains reduction of immunosuppression, continuous follow up with quantitative PCR and kidney function tests
– cellular immunotherapy is the newer option which is still being explored
Level of evidence provided by this article
– Level V
*Introduction
Polyomaviruses are small DNA viruses that can infect humans and animals .
BK polyomavirus (BKV) is
the most prevalent forms of polyomaviruses infecting humans, especially in
immunocompromised patients as renal
transplant recipients, BKV can lead to tubulointerstitial nephritis and
ureteral stenosis; it can also lead to hemorrhagic cystitis in bone marrow
transplant patients.
The cornerstone in management of BKV viremia is to decrease immunosuppression, which will be challenging due to fear of rejection.
BK virus is one of the most common infections in renal transplant recipients.
Reports showed reduction of immunosuppression has been effective in preserving allograft function and management of BKVN.
*Virolo
Properties
Polyomaviruses is a double-stranded DNA virus with icosahedral symmetry. BK categorized serologically and genotypically into 4
groups
Polyomaviruses are small (40-50 nm in diameter),heat stable , their
genome is about 5000 base pairs, contained in the histones derived from host cells.
*Transmission mechanism
Primary BKV infection occurs early in life at 4 to 5 years of age.
routes of transmission include:
(1) airborne.
(2) a feco-oral
(3) urinary-oral.
(4)seroconversion after solid-organ transplant(such as renal transplantation).
(5)blood transfusion and vertical transmission.
Primary infections are often clinically insignificant;
however, the virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule.
*Risk factors and pathogenesis:
Heavy immunosuppression is the most important risk factor , Transplant
physicians consider BKV infection as a marker of heavy immunosuppression.
BKV disease can occur with any immunosuppression medication,
.But more common with tacrolimus and
mycophenolate mofetil.
Tacrolimus specifically can increase BKV replication by a specific mechanism involving FK-binding protein (BP-12).
*Other risk factors Include:diabetes mellitus, DGF, treated
episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies,
coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression,
older age, white race/ethnicity, and presence of specific human leukocyte
antigen (HLA) C loci, and presence of BKV antibody titers in donors.
*Clinical Picture of BK Virus Infection
Reactivation of bk virus occurs in bone marrow or kidney transplant recipients.
Clinical manifestations range from asymptomatic infection to slow and
progressive increase of serum creatinine, and an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
*Diagnosis Overview
-Quantitative PCR is used to diagnose BKV viremia.
-The presence of decoy cells in the urine analysis which is infected cells with enlarged
nucleus with a single, large basophilic intranuclear inclusion these cells are suggestive
but not specific, sensitive, or definitive and their absence does not exclude
the disease.
Viruria precede viremia by 4 weeks, Patients with a higher viruria level are more prone to develope BKV viremia, and patients with high
sustained viremia are susceptible to BKVN.
-renal biopsy needed for a definitive diagnosis of BKVN and it should be at least 2 cores containing medulla to Minimis the chance of missing the pathology .
-Definitive diagnosis of BKVN requires
characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry
(against BKV or against SV40 large T antigens), which has a specificity of 100%.
By light microscopy Biopsy shows tubulointerstitial nephritis
which is sometimes difficult to differentiate between BKVN and allograft rejection.
-Presumptive diagnosis can be done if there
is sustained (more than 2-week duration) urinary viral shedding and significant
BKV replication (plasma DNA PCR load > 10 000 copies/mL),
-Urine electron microscopy using negative-staining electronmicroscopy for patients with BKV infection will show cast-like 3-dimensional
polyomavirus aggregates, which are called Haufen
Presence of a high load of Haufen with equivocal biopsy would highly support the possibility of BKVN rather than rejection as a cause of allograft dysfunction.
-Examine serum for anti-BKV antibodies is
not helpful for a definitive diagnosis of BKV infection.
-Viral culture is not clinically applicable.
*Therapeutic Interventions
-Reduction of immunosuppression is
the cornerstone in the management of BKV infection, but it carries a higher
risk of rejection.
-Modification of immunosuppression to treat BKV infection
carries a higher incidence of long-term chronic rejection.
One study suggested
that patients with persistent sustained BKV viremia are prone to the development of de novo donor-specific anti-HLA antibodies.
– Currently, there are no available
antiviral medications against BKV
Potential anti-BKV agents have been suggested by several reports to be beneficial together with immunosuppression reduction.
*These agents includes:
-Cidofovir but nephrotoxicity
is a main limitation.
– Brincidofovir (CMX001):prodrug of cidofovir that is administered orally. Phase 3 clinical trials have shown a lower incidence of
nephrotoxicity with brincidofovir.
Successful outcomes in renal and hematopoietic transplant have been described but larger-scale clinical trials are needed.
-Leflunomide
used to replace MMF and its not clear whether its effective against BKV or its
effect related to reduction of immunosuppression.
-Intravenous immunoglobulin contains neutralizing antibodies against BKV,
which makes it a good choice in the management of BKVN.
The immunomodulatory effects
of IVIG may guard against allograft rejection in the context of reduced
immunosuppression.
-Fluoroquinolone In
vitro studies have shown that fluoroquinolone antibiotics can inhibit
replication of BKV or SV40,but data suggest that fluoroquinolones do not
currently have a clinically significant role in the management of BKV-related
diseases.
-Role of cellular immunotherapy in the management of BKV infectio
Idea of this approach depends
on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
Researches are still in the early stages, and data on immunodominant BKV epitopes for T-cell priming are limited.
*Conclusion
-BKV infections lead to
tubulointerstitial nephritis and ureteral stenosis in the renal transplant population.
-The average incidence is about 10% of the renal transplant population.
‘Direct correlation exists between
the incidence of BKV infection and the degree of immunosuppression, but not the drug itself.
-Definitive diagnosis of BKVN
is made by renal allograft biopsy using immunohistochemistry, which cross-react
with the BKV, specifically SV40 large-T antigen part of the virus.
-Acute rejection is the main differential diagnosis of BKVN.
-Immunosuppression reduction is cornerstone in management.
What is the level of evidence?
Narrative review level of evidence v
SUMMARY – UPDATE ON MGT OF BKV INFECTION.
INTRODUCTION.
–Polyomavirus infect both humans and animals .Amongst the immunosuppressed, BK is one of the most common infections. Post KTR, it can cause tubulointerstitial nephritis, ureteral stenosis and hemorrhagic cystitis(In BMT).
-BKV current management is via monitoring with BKV PCR,RIS and careful attention to the graft function.
TRANSMISSION.
-Primary infection occurs in 1st decade of life via ; airborne spread, fecal oral route, urinary oral route, seroconversion post SOT and vertical route.
-Primary infections are latent but get reactivated in immunosuppressed in real epithelium with above mentioned manifestations.
-Viruria is at % in immunocompetent vs 60% in immunosuppressed.
RISK FACTORS AND PATHOGENESIS.
-This include;
CLINICAL PRESENTATION.
-Mostly reactivated post transplant -BMT & SOT.
-BKVN – Graft dysfunction could occur from interstitial nephritis +/- ureteral stenosis.
-Hemorrhagic cystitis in BMT.
-Could be asymptomatic or present with ;
DIAGNOSIS.
-Definitive dx established by renal biopsy, it resides in the medulla and thus can be easily missed on biopsy.
-BK PCR is 100% sensitive and 88 % specific to access infection.
-Urinalysis – Decoy cells – Good screen test followed by BKV PCR as a follow up test. BKV urine PCR can also be done.
-Viruria precedes viremia by 4 weeks.
-Definitive dx ; Cytopathic changes + +VE SV40 large T antigen- 100%Specific.
-Presumptive diagnosis – Continuous viruria (>2 weeks) + BK PCR > 10000 Copies/ml
-Anti BKV antibodies are not protective and lag in the circulation and thus are not sensitive in diagnosing infection. They peak 1st 6 weeks of infection or 2 years post primary infection.
-Highest risk of infection in D+/R- pair.
-Viral cultures take long to get results and is thus not indicated.
-On urine electron microscopy, Haufen presence has 100% sensitivity and 99% specificity in detecting biopsy proven BKVN post KTR. It cn be use for dx minus biopsy.
TREATMENT.
-RIS – This is done in a stepwise fashion involving CNIs, Steroids and anti metabolites while monitoring the graft function.
-Cidofovir – Main SE is nephrotoxicity but can be combined with RIS.
-Brincidofovir – PO prodrug of cidofovir with less nephrotoxicity but still needs more studies before adoption in clinical use.
-Leflunomide – Has antiviral properties against BK and has been used as a substitute to MMF with good results in limited studies. It is associated with TMA, hepatitis and BM Suppression. More studies needed to establish efficacy against BKV.
-IVIG -Has neutralizing antibodies against BKV and can be used as an adjunctive.
-Fluoroquinolones – Some studies have shown their inhibitory effects on BKV replication by decreasing expression of large T antigen and equally inhibition of Large T antigen Helicase activity. We have mixed results with their use and thus not adopted in use yet.
-Cellular immunotherapy- looks Promising but more studies needed on it.
LEVEL OF EVIDENCE-Narration – 5
Summary
· BKV infection is associated with graft dysfunction and loss.
· It is named after the initials of Sudanese patient with ureteric stenosis with discovered viral particle in the epithelial lining.
· Mode of transmission: feco-oral, respiratory, transplacental and organ transplantation
· Primary infection in childhood usually asymptomatic viuria , while the virus remains dormant in uroepithelial cells then become activated in immunocompromised patients (as renal transplant recipients) with increasing viruria up to 60%..
· Risk factors for infection: high immunological risk, increased HLA mismatch, ABO and HLA incompatible transplantation, strong induction as ATG, TAC and MMF containing IS therapy, repeated treatment of rejection episodes, so the most important is the net immunosuppression state, D+/R- serological status prior to transplantation, old age and diabetes in the recipient, DGF and prolonged cold ischemia time.
· No specific antiviral to be used in prophylaxis or ttt of BKV cases.
· BKN clinical manifestations in kidney transplantation:
o Interstitial nephritis and ureteral stenosis commonly occur at 10-13 months post-transplant.
o Rising creatinine, hematuria and pyuria and cellular casts.
o Definitive BKN is diagnosed by allograft biopsy which has interstitial nephritis that turn chronic and cause allograft dysfunction and loss.
o Biopsy may be false -ve (patchy affection and mainly in medulla), so 2 core biopsies are needed including renal medulla.
o Biopsy shows 3 patterns (A, B, C) with early cytopathic changes then acute interstitial nephritis then chronic tubulointerstitial nephritis.
o Special staining fir IHC (SV 40) simian virus 40, stains large T antigen present in polyoma virus, is diagnostic for polyoma virus (SV, BK and JC). Specificity is 100 % and sensitivity is 77.7 %
o Blood BKV PCR indicates viremia whether has BKN or not,
o BKV PCR can be done in urine sample.
o Decoy cells (cells with large inclusion bodies replacing the normal chromatid) in urine increases suspicion of BKN. But definitive diagnosis is biopsy.
o Decoy cells=infected tubular and urothelial cells (only epithelial) with large basophilic nucleus (looks like high grade urothelial atypia),
o DD from owl eye appearance of CMV inclusion bodies (that is surrounded by complete halo around it )
o Decoy cells in urine (infected urothelial cells), with :
§ Sensitivity 100 % of BKN.
§ Specificity 84%.
§ NPV is 100%.
§ PPV is 6%.
o Presumptive BKN means sustained (>2 weeks) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction
o Hemorrhagic cystitis occurs in bone marrow transplantation.
· BKN Differential diagnosis:
o Other viral infections as CMV and adenovirus.
o Acute rejection (DD by presence of viral inclusion bodies, and positive PCR (viremia))
· The main line of ttt is reduction of immunosuppressive therapy, but the problem is increasing risk of rejection and graft loss (so achieving the balance between both conditions is difficult.
· Reduction of MMF dose by 50 %, reduction of CNI by 25-50 % is started, then FU PCR if not decreasing stop MMF.
· Still not proved, to shift from tacrolimus to cyclosporin or to shift from MMF to mTORi.
· Adoptive specific T cell immunotherapy may be future therapy for refractory cases.
· Follow up PCR every 2 weeks and FU graft function every week.
· NO RCT to demonstrate specific therapy, but additional use of cidofovir, leflunamide, quinolones and IVIG in refractory cases (not decrease in viral load with reduction of IS).
Level of evidence: V (narrative review).
Summary of the article
Update on the Management of BK Virus Infection
BK polyomavirus (BKV) is considered one of the highly prevalent forms of polyomaviruses.
BKV is a double-stranded DNA virus with icosahedral symmetry, has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence.
In KTR can cause TIN and ureteral stenosis while causing hemorrhagic cystitis in bone marrow transplant patients.
Transmission mechanism
1. Airborne transmission through air droplets.
2. A feco-oral transmission, as fecally eliminated polyomaviruses are detected in hospitalized children.
3. Other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation).
4. Blood transfusion.
5. Vertical transmission
Risk factors for BKV infection
1. The degree of immunosuppression(BKV infection is a marker of heavy immunosuppression).
2. Diabetes mellitus.
3. Delayed graft function.
4. Treated episodes of acute rejection.
5. Ureteral trauma.
6. Use of antilymphocyte antibodies.
7. Coinfection with Cytomegalovirus (CMV).
8. Maintenance steroid immunosuppression.
9. Older age.
10.White race/ethnicity.
11.Presence of specific human leukocyte antigen (HLA) C loci.
12.The presence of BKV antibody titers in donors.
Steps of BK Virus Infection in Renal Transplant Recipients
1. Primary infection: Initial infection of the host including viremic spread to susceptible tissues with mild or no clinical symptoms
2. Latent infection: Asymptomatic inactive infection of susceptible cells after primary infection. Virus detection is perfomed only by molecular techniques.
3. Serologic evidence of infection: Variation in antibody titers occurs in almost all healthy children and 60% – 90% of asymptomatic adults. No correlation with intrarenal latent viral load. Presents a weak correlation with viral disease.
4. Viral activation: Evidence of replication can be detected by observing “decoy cells” or free urine virions. Viral detection by a polymerase chain reaction in urine, serum, or cerebrospinal fluid, can be considered to be a transient and asymptomatic event or as part of a viral disease.
5. Viral disease: Histologic evidence of viral replication in organs (cytopathic signs and/or positive immunohistochemistry or in situ hybridization) and virus-induced tissue damage is often associated with clinical symptoms.
BKVN; light microscopy examinations
1. Basophilic intranuclear viral inclusions without a surrounding halo.
2. Anisonucleosis, hyperchromasia, and chromatin clumping of infected cells.
3. Areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates.
4. Tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining.
5. Tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
6. When extensive, it is difficult to differentiate between BKVN and allograft rejection.
BKVN; electron microscopy examinations
a) Viral inclusions with diameter size ranging from 30 to 50 nm.
b) Tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
Clinical Picture of BK virus infection
1. Asymptomatic.
2. Slow and progressive increase of serum creatinine.
3. An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
4. Usually, BKV infection occurs 10 to 13 months posttransplant.
5. BKVN may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
Diagnosis of BKV
1. Laboratory findings;elevated serum creatinine and urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis.
2. The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis.
3. Quantitative PCR is used to diagnose BKV viremia(a blood quantitative PCR showing > 60 to 100 BKV copies).
4. A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN(may be missed in the tissue obtained because viropathic lesions are patchy.)
Definitive diagnosis of BK virus nephropathy
A definitive diagnosis of BKVN requires:
a) Characteristic cytopathic changes on the renal biopsy. plus
b) positive immunohistochemistry (against BKV or against SV40 large T antigens). It has a specificity of 100%, and pathognomonic results for BKV infection.
A presumptive diagnosis of BKV can be done if there is:
a) Sustained (more than 2-week duration) urinary viral shedding.
b) Significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction.
Differential diagnosis
Other types of viral infections:
CMV, herpes simplex virus and adenovirus.
BKV infection; therapeutic interventions
1. Immunosuppression reduction.
2. Cidofovir; nephrotoxicity is a limitation.
3. Brincidofovir (CMX001) is a prodrug of cidofovir that is administered orally and nonephrotoxicity.
4. IVIG.
5. Fluoroquinolone: In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication.
6. Role of cellular immunotherapy in the management of BKV infection: data on immunodominant BKV epitopes for T-cell priming are limited.
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
1. Please summarise this article.
The article deals with management of BK virus infection.
Introduction: BK virus, one of the most common infections in renal transplant recipients, is a form of polyomavirus which causes tubulointerstitial nephritis and ureteral stenosis if renal transplant recipients, and hemorrhagic cystitis in bone marrow transplant recipients. Management of BK viremia involves reduction of immunosuppression, monitoring of BK virus polymerase chain reaction (PCR), and renal function.
Virology: BK virus was first diagnosed in 1971 in a Sudanese renal transplant recipient with ureteral stenosis. It is a small virus with 5000 base pair genome, encoding 6 chief proteins divided into 3 regions (early encoding, noncoding, and late encoding regions).
Transmission: Primary BK virus infection occurs in first decade of life, through feco-oral route, airborne transmission, and through solid organ transplant (10-13 months post-transplant), blood transfusion, and vertical transmission. Post-primary infection, the virus remains latent in renal epithelium, and multiplies when the immunity of the person decreases.
Risk factors and pathogenesis: The risk factors include degree of immunosuppression, diabetes mellitus, ft function, ureteral trauma, acute rejection treatment, older age, steroid use, seropositive renal donor, viruria in the donor, cytomegalovirus co-infection, white race, HLA C loci, HLA incompatibility, ABO incompatibility, and use of antilymphocyte antibodies.
Clinical picture: Clinically BK virus infection can be asymptomatic, or can present as slow progressive rise in serum creatinine, or as an unexpected finding of BK virus associated nephropathy on graft biopsy. Laboratory tests show elevated serum creatinine, pyuria, hematuria, cellular casts, etc.
Diagnosis overview: A graft biopsy is definitive for diagnosis, but can be negative due to patchy involvement, more so in the medulla. Quantitative PCR diagnoses BK viremia (sensitivity 100%, specificity 88%). Urinary decoy cells (cell with enlarged nucleus and single, large basophilic intranuclear inclusion) point towards BKV nephritis, and should be followed by blood or urine quantitative PCR. Definitive diagnosis requires cytopathic changes on biopsy with positive immunohistochemistry (SV40 large T antigens), and positive BK viremia. Presumptive diagnosis requires sustained viruria with plasma DNA PCR >10000 copies/ml. BK virus nephropathy has 3 different patterns on histology, and has 3 different grades according to Banff classification. Serology (serum anti BK virus antibody) is not helpful in diagnosis. Viral culture is used oly in research setting. Urine electron microscopy can show Haufen (3-dimentional polyomavirus aggregates).
Differential diagnosis: It includes other viral infections like cytomegalovirus, herpes simplex virus, adenovirus etc.
Therapeutic interventions: Immunosuppression reduction is the cornerstone of therapy, but increases risk of rejection. Other medications including Cidofovir, Brincidofovir, Leflunomide, IVIG (intravenous immunoglobulins), and Fluoroquinolones have been used, but there are no randomized controlled trials with respect to use of these agents. Use of adoptive transfer of BK virus reactive T cells is a potential therapeutic way of managing BK virus associated nephropathy.
Conclusions: 10% of renal transplant recipients get affected by BK virus infections, with direct correlation with the degree of immunosuppression. Management involves reduction of immunosuppression, and antiviral use has been shown to be effective in uncontrolled retrospective studies, with no randomized controlled trial. Active screening for the BK virus levels, and continuous follow-up using BK virus PCR levels and renal function is imperative for optimal management.
2. What is the level of evidence provided by this article?
Level of evidence: Level 5 – Narrative review.
Introduction :
Polyomaviruses are small DNA viruses and one of the common infections in kidney transplant patients that can lead to tubulointerstitial nephritis and ureteral stenosis in kidney transplant patients also lead to hemorrhagic cystitis in bone marrow transplant patients. The mainstay of treatment is reduction of immunosuppression. The balance between the fear of rejection due to reduction of immunosuppression and the maintenance of immunosuppression at the same level,is challenging .
virology Properties:
BK virus is a member of the family Polyomaviruses which is a double-stranded DNA virus with icosahedral symmetry first discovered in 1971, in a Sudanese renal transplant patient who presents with ureteric stenosis . BK virus has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence.
Transmission mechanism :
Primary BKV infection occurs during childhood and is often clinically insignificant. Possible routes of transmission include the following:
(1) Airborne transmission through air droplets .
(2) Afeco-oral transmission, as fecally eliminated polyomaviruses are detected in hospitalized children.
(3) Urinary-oral route or seroconversion after solid-organ transplant
(4) Blood transfusion and vertical transmission.
After transmission the virus stays dormant in the renal epithelium and reactivated in a state of immunosuppression .
Risk factors and pathogenesis :
1. The degree of immunosuppression is the most important risk factor for developing BKV disease.
2. Immunosuppression protocols especially tacrolimus and mycophenolate mofetil based regimen.
3. Other risk factors include treated episodes of acute rejection ,use of antilymphocyte antibodies, the presence of BKV antibody titers in donors, DM , DGF, ureteral trauma,, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci.30-32 ,
Clinical Picture of BK virus infection :
Patients can either be asymptomatic or show slow and progressive increase of serum creatinine, or an unsuspected finding of renal allograft biopsy in patients with progressive renal damage (BKVN). Laboratory findings will be (1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
Diagnosis :
Renal allograft biopsy : will give definitive diagnosis of BKVN but viropathic lesions are patchy and the BKV tropism is medulla, not the cortex, so diagnosis may be missed in the tissue obtained . Findings will be characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection.
Quantitative plasma PCR : for diagnosing BKV viremia if plasma DNA PCR load > 10 000 copies/mL)
Urine cytology: The presence of decoy cells in the urine analysis are suggestive but not specific, sensitive, or definitive for BKV infection , it should be followed by quantitative PCR of blood preferable to urine.
Differential diagnosis BK virus infection
viral infections (CMV, herpes simplex virus, adenovirus).
Monitoring of renal transplant recipients : can be with quantitative or real-time PCR for BKV infections in either the plasma or urine. The sensitivity, specificity, positive predictive value, and negative predictive values of urine levels were 70%, 70%, 53%, and 83% for any viremia and 91%, 66%, 33%, and 98% for sustained viremia, respectively.
Serology : Anti-BKV antibody levels before transplant will predict the risk of developing a clinically significant BKV infection which is high when transplant is performed between a positive BKV donor and a negative recipient.
Haufen: is a polyomavirus aggregate associated with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients . Thus, urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis in renal transplant recipients , it is a sophisticated analysis and requires a meticulous interpretation by pathologists.
Therapeutic interventions:
-The mainstay of treatment is reduction of immunosuppression although it is challenging because it carries higher risk of rejection.
– Currently, there are no available antiviral medications against BKV. – Follow up with continuous monitoring of BKV viremia levels using quantitative PCR.
– Cidofovir: Is nephrotoxic and has no strong evidence beyond its use.
-Brincidofovir (CMX001) : Is a prodrug of cidofovir that is administered orally less nephrotoxic .
– Leflunomide: is an immunosuppressant agent with antiviral properties against BKV in vitro . also no strong evidence to support its use. Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression.
Intravenous immunoglobulin : (IVIG) contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKVN. Again no strong evidence to support its use.
– Fluoroquinolone : Is an antibiotic which can inhibit replication of BKV or SV40 polyomavirus replication in vitro; but the clinical data suggest that fluoroquinolones do not currently have a clinically significant role in the management of BKV-related diseases.
Cellular immunotherapy : adoptive transfer of BKV-reactive T cells which may help in controlling the BKV-associated disease it is promising anyhow , but needs also stronger evidence .
This article is systematic review level V of evidence
Please summarise this article.
Introduction
-Polyomaviruses are small DNA viruses . BK polyomavirus (BKV) is highly prevalent forms of polyomaviruses causing infection in immuno -compromised patients.
– In renal transplant recipients, BKV can lead to tubulointerstitial nephritis and ureteral stenosis; it can also lead to hemorrhagic
cystitis in bone marrow transplant patients.
virology
Properties
-BK virus has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence.
Genome structure and transcription
-Polyomaviruses genome is about 5000 base pairs, contained in the histones derived from host cells.
-The external layer consists of structural proteins VP1, VP2, and VP3.
-VP1 determines receptor specificity, whereas VP2 and VP3 are
involved in viral particle stabilization outside the host cell and transport within it.
Transmission mechanism
– Possible routes of transmission include the following: (1) airborne transmission through air droplets (2) a feco-oral transmission. (3) other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant , and (4) both through blood transfusion and vertical
Transmission.
-Primary polyomavirus infections usually occur during childhood through respiratory or oral routes and often clinically insignificant.
-The virus stays in the renal epithelium, including in tubular, parietal, and transitional structures and in Bowman’s capsule.
-In the immunocompetent population, BKV replication is manifested by asymptomatic viruria, and the incidence of shedding is 20%. However, in immunocompromised individuals, the risk of shedding reaches 60% and the viruria is more common.
-The mean prevalence of BKVN in renal transplant recipients is 5%, whereas the prevalence of ureteral stenosis is less.
Risk factors and pathogenesis
-The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used.
-Active BKV disease is thae most commonly associates with tacrolimus and MMF.
– Immunosup – pressive agents can affect T cells, which can lead to increased BKV replication.
-Other risk factors include diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with CMV, maintenance steroid immunosuppression, older age, white race/ethnicity, presence of HLA C loci and the presence of BKV antibody titers in donors.
-Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy .
Clinical Picture of BK virus infection
-About 90% of the population will become BKV seropositive which reactivates after solid-organ transplant, especially in bone marrow or
kidney transplant recipients.
– In kidney transplant recipients, reactivation may lead to BKVN, which
may end with graft dysfunction and failure .
Clinical manifestations are as follows: (1) asymptomatic, (2) slow and progressive increase of serum creatinine, and (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance
renal allograft biopsy.
-No signs and symptoms are identified with BKV infection.
-BKV infection occurs 10 to 13 months posttransplant. BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
-Laboratory findings in patients with BKV infection are as follows:
(1) elevated serum creatinine and
(2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. However, these results could be normal.
Diagnosis Overview
-A Renal biopsy is needed for a definitive diagnosis of BKVN; however, a diagnosis may be missed in the tissue obtained because viropathic
lesions are patchy and locates in medulla, not the cortex, which may increase the risk of missing the viropathic lesions.
-Quantitative PCR is used to diagnose BKV viremia.
-BK virus nephritis is suspected when the clinical diagnosis of tubulointerstitial nephritis is suspected; however, there are no clinical
features of tubulointerstitial nephritis that are unique to BKVN.
– Decoy cells in the urine increases the suspicion of BKV nephritis,
which should be followed by quantitative PCR of blood preferable to urine .
Definitive diagnosis of BK virus nephropathy
-A definitive diagnosis of BKVN requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity ofm100%, and pathognomonic results for BKV infection.
-In the absence of definitive criteria for BKVN diagnosis , a presumptive diagnosis can be done if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction; these characteristics have been proposed to define presumptive BKVN.
Differential diagnosis
-BK virus infection can be similar to other types of viral infections (CMV, herpes simplex virus, adenovirus).
– Confirmation of a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic
morphology results are needed.
Urine cytology findings for BK virus infections
-Urine examinations may reveal BKV-infected cells( Decoy Cells) that
strongly suggestive of polyomavirus infections.
-Viral replication in the urine is demonstrated by either decoy cells or BKV urine quantitative PCR.
-Decoy cells are suggestive but not specific, sensitive, or definitive for
BKV infection because (1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus42) and (2) decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients.
Quantitative polymerase chain reaction
-Sustained high viral DNA levels in the plasma of renal transplant recipients who have an appropriate clinical picture can suggest BKVN.
-Renal transplant recipients can be monitored with quantitative or real-time PCR for BKV infections in either the plasma or urine.
-Multiple retrospective and prospective studies have agreed that viruria
precede viremia by 4 weeks.
-Viral replication in the urine as detected by either analysis of urine
cytology or demonstration of the virus by quantitative PCR has been shown to be present in 20% to 60% of renal transplant recipients, depending on the method of detection.
-It is recommended that medical decisions, especially those with regard to alterations of immunosuppression, be made on the basis of trends in
quantitative DNA levels rather than on a single measurement.
Serology
-It is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection because positivity for these antibodies is quite common in the general population.
– During BKV infection, there are high levels of BKV IgG titers during the first 6 weeks of infection or 2 years after primary infection. Anti-BKV
antibody does not seem to be protective.
– Previous BKV seropositivity in the recipient can affect progression of BKV infection, especially progression from viruria to viremia.
viral culture
-It is rarely used as a method for BKV infection detection outside the research setting. It can take weeks to months .
Urine electron microscopy
-Urine examinations using negative-staining electron microscopy for patients with BKV infection will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen .
-Urine analyses in patients with a low viremia (median of
26 959 copies/mL) did not show Haufen bodies.
-Urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis in renal transplant recipients.
-The presence of a high load of Haufen with equivocal biopsy would
highly support the possibility of BKVN rather than rejection as a cause of allograft dysfunction.
Therapeutic interventions
-Currently, there are no available antiviral medications against BKV.
-The usual approach in the management of BKV viremia of BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR.
Immunosuppression reduction
– it carries a higher risk of rejection, making this decision challenging.
Cidofovir
-One of the limitations of this approach is nephrotoxicity, thus making the decision to use cidofovir unlikely.
Brincidofovir (CMX001)
-It is prodrug of cidofovir that is administered orally. Phase 3 clinical trials have shown a lower incidence of nephrotoxicity with brincidofovir.
Leflunomide
-Leflunomide is an immunosuppressant agent that also has antiviral properties against BKV in vitro.
-Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression.
intravenous immunoglobulin
-Intravenous immunoglobulin (IVIG) contains neu – tralizing antibodies against BKV, which makes it a good choice in the management of BKVN.
Fluoroquinolone
-In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication in vitro.
Role of cellular immunotherapy in the management
of BKV infection
-Identifying viral immunogenic antigens is necessary for successful generation of virus-specific T cells.
What is the level of evidence provided by this article?
Level 5
Update on the Management of BK Virus InfectionIntroduction
Ø The main treatment of BK viremia is to decrease immunosuppression.
Ø The challenging part in the management of BKV infection is the balance between the fear of rejection due to the reduction of immunosuppression.
Ø Primary BKV infection occurs in the first decade of life on average at 4 to 5 years of age.
Ø Possible routes of infection include: airborne,feco-oral transmission, and others such as post-solid organ transplantation
Risk factors and pathogenesis:
Ø The degree of immunosuppression medication.
Ø Diabetes mellitus
Ø Delay graft function .
Ø A treated episode of acute rejection.
Ø Ureteral trauma.
Ø Use of ATG as induction therapy.
Ø Co-infection with CMV,.
Ø Maintenance steroid immunosuppression.
Ø Older age.
Ø White race /ethnicity.
Ø Post graft C loci.
Ø HLA and ABO incompatible transplants.
The clinical picture of BKV infection:
Ø 90% of BKV seropositive reactivate after solid organ transplant, especially in bone marrow or kidney transplant recipients.
Ø BKVN leads to tubulointerstitial nephritis and or ureteral obstruction which results in graft dysfunction.
Ø A definite diagnosis by kidney biopsy, however, quantitive PCR is used to diagnose BKV viremia
Ø Urine cytology for BKV infection:
Ø Urine examination reveals BKV infection cells is enlarged nuclear with single large basophilic internuclear inclusion.
Threptic intervention:
Ø A few controlled studies are available to guide us in the management of BKV infection in renal transplantation.
Ø No available antiviral mechanism against BKV.
Immunosuppression reduction:
Ø Reduction of immunosuppression therapy carries a higher risk of rejection (acute or chronic).
Cidofovir
Ø No randomized controlled trials are available to support its use
Cidofovir nephrotoxicity is limit its use.
Brin cidofovir
Ø Pro. drug of cidofovir has a lower incidence of nephrotoxicity.
Ø Need large studies to prove the safety and efficacy of brin cidofovir.
Leflunomide
Ø The immunosuppressant agent that has antiviral properties against BKV.
Ø It decreases viral load, however, this does not reflect the cause of BKV viral load .
Ø Side effect:TMA.hepatitis,B.M suppression.
Ø But still, more controlled trials are needed for leflunomide to confirm the efficacy and safety of this drug against BKV infection
IVIG
Ø Contain neutralizing antibodies against BKV which makes it a good choice in the management of BKVN.
Ø In hypogammaglobinaemia, IVIG therapy was beneficial with regard to anti BKV immunity.
Ø The immunomodulate effects of IVIG may guard against allograft rejection in the context of reduced immunosuppression.
Fluoroquinolone :
Ø Inhibit replication of BKV or SV40 polyomavirus replication in vitro.
Ø Data suggest that fluoroquinolone does not currently have a clinically significant role in the management of BKV-related disease.
Cellular immunotherapy in the management of BKV infection:
Ø Cellular therapy using T-cells to restore antiviral immunity.
Ø There are few controlled studies available on the management of BKV infection in a renal transplant recipient.
Ø Newer options including cellular immunity may carry potential hope for the treatment of BKV infection
level 5
I agree with your analysis, summary and level of evidence this article provides.I note that you consider adoptive cellular immunotherapy as a future potential
Introduction
Transmission mechanism
Clinical Picture of BK virus infection
Diagnosis Overview
Definitive diagnosis of BK virus nephropathy (BKVN)
and
plus
Since BK virus infection can be similar to renal viral infections like CMV, HSV and adenovirus, characteristically cytopathologic morphology on biopsy as well as PCR are necessary.
Serology
Viral culture & Urine electron microscopy
Therapeutic interventions
Conclusions
Level of evidence
I agree with your analysis, summary and level of evidence this article provides.
This is a review with a Level of evidence of 5
BK virus infection can be as early as the first decade of life but usually asymptomatic. The virus was isolated from many tissues shedding light on its variable modes of transmission, blood, fecal oral, urine-oral etc. Air-borne infection can happen as well. It belongs to polyomavirus family and have 4 subtypes that are different in terms of virulence. Viruria is detected early, and BK named from the first case in whom the virus was isolated when presented by ureteral obstruction. We can see BKVN or ureteral stenosis in Renal tx patients while hemorragic cystitis is more common in BM transplant patients.
90% of the population mostly become positive for BK during their life. In transplant patient average of infection is through 10th-13th months but can occur as early as 1st week and late in 5th year. association is mostly related to degree of immunosuppression.
BK viral infection can be asymptomatic, seen on biopsy or manifetsed as interstisial infection with deterorating renal function. Definitive BKAN is done with renal biopsy . infection can be patchy or confined to medulla, so 2 core biopsy is needed. around 30% of cases can be missed. screening can be by checking for decoy cells in the urine. Our aim is to prevent nephropathy by checking for vuria and viremia earlier on followup; usually done by PCR. Prevention , early manipulation is essential to prevent renal impairment. The main challenge is the balance between risk of rejection and BK nephropathy.
screening before transplant is not recommended but one suggested screening is to check for BK virus monthly till 9th month then every 3 months till the end of second year.
treatment is mainly be reduction of immunosuppression by %30-50. Leflomide, cidofovir, brincidofovir, IVIG are utilized. Quinilones are thought to have some benifit.
I agree with your analysis, summary and level of evidence this article provides.
I wish you could type headings and sub-headings as underline or in bold.
Its is a systemic rivew ,level of evience 5
I wish you could type headings and sub-headings as underline or in bold.I agree with your analysis, summary and level of evidence this article provides.
BK polyoma virus BKPyv is a main pathogen encountered during post transplant period. associated with variable presentations as its infecting different organs and and features variable presentations .
Its usually showcasing reactivation of of dormant BKPyv who used to be attracted early in life via air born, droplet born and feco-oral rout.
It might present as tubulo-interstitial disease as its infecting tubular epithelial and interstitial cells , ureteric epithelial cells resulting in ureteric obstructive uropathy.Hemorrhagic cystitis was frequently reported with Bone marrow transplantation.
Risk factors:
Main risk factors in patients with kidney transplantation is over immunsuppression, particularly with Tacrolimus and Mycophnolic acid or Azathioprim .Suppression of cell mediated immunity ,which is keeping the virus in quarantine , might flourish the virus growth , proliferation and disease propagation. Tacrolimus might enhance BKPyv growth via FK binding protein.
Other less common factors include:
Older age of recipient.
Diabetes mellitus.
Corticosteroid based maintenance medicine.
Treatment for acute CMR.
Co-infection with CMV.
HLA C locus.
The presence of BKPyv antibody titer in donors which reflect recent infection confer higher risk of attracting infection.
HLAi and ABOi transplantation carry higher risk of BKPyv infection , attributed to intense immune suppression and anti-rejection administration.
Its rarely reported in other immune deficient conditions like HIV , SLE and
Diagnosis of BKPN:
biopsy is the slandered modality for diagnosing BKPN. Its usually showcases characteristic features including:
1] Tubular epithelial cells with intra-nuclear inclusions which is distinctively without peripheral halo, to differentiate it from CMV infection.
2] Interstitial fibrosis.
3] Tubular infiltration with lymphocytes mimicking ACMR.
4]Infitration of interstitium with mononuclear and polynuclear Cells.
I like your analysis and summary
Please summarise this article.
Introduction
Polyomaviruses are one of the highly prevalent forms of small DNA viruses that can cause infection in humans, especially in immunocompromised patients.
Management of BKV viremia is to decrease immunosuppression, follow PCR, and monitor renal functions to prevent graft failure.
Virology
Properties
BK virus is a double-stranded DNA virus with icosahedral symmetry, categorized into 4 groups with different virulence.
Historical aspects
Viral particles were found in the ureters of a Sudanese renal transplant patient and high serum BKV antibody titer was seen at the same time.
Transmission mechanism
(1) Airborne transmission.
(2) A feco-oral transmission,
(3) Urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation)
(4) Blood transfusion and vertical transmission
Risk factors and pathogenesis
· The degree of immunosuppression
· Diabetes mellitus,
· Delayed graft function,
· Treated episodes of acute rejection, ureteral trauma,
· Use of anti-lymphocyte antibodies,
· Coinfection with Cytomegalovirus (CMV),
· Maintenance of steroid immunosuppression,
· Older age, white race/ethnicity,
· Presence of specific human leukocyte antigen (HLA) C loci.
· The presence of BKV antibody titers in donors
Clinical Picture of BK virus infection
(1) asymptomatic,
(2) slow and progressive increase of serum creatinine,
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Laboratory findings:
(1) elevated serum creatinine and
(2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
Diagnosis Overview
For a certain diagnosis of BKVN, a tissue (renal) biopsy is required, however patchy viropathic lesions could be overlooked. Tubulointerstitial nephritis and BKV viremia are identified by quantitative PCR.
Definitive diagnosis of BK virus nephropathy
Diagnosis of BKVN requires cytopathic changes and positive immunohistochemistry with 100% specificity.
Steps of BK Virus Infection in Renal Transplant Recipients
·Primary infection.
·Latent infection.
·Serologic evidence of infection.
·Virus detection.
·Viral disease.
Urine cytology findings for BK virus infections
· Urine examinations may reveal BKV-infected cells. BKV-infected cells have an enlarged nucleus with a single, large basophilic intranuclear inclusion.
Differential diagnosis
·CMV
·Herpes simplex virus,
·Adenovirus
Serology
Viral culture is not suitable for BKV detection outside the research setting as viral isolation from the clinical specimen can take weeks to months
Therapeutic interventions
·Immunosuppression reduction
·Cidofovir
·Brincidofovir (CMX001)
·Leflunomide
·Intravenous immunoglobulin
·Fluoroquinolone
Role of immunotherapy in the management of BKV infection
The idea of this approach depends on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
Conclusion:
·BK virus is a member of human polyomaviruses, which are DNA viruses;
·BKV infections lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplant population.
·There is a direct correlation between the incidence of BKV infection and the degree of immunosuppression, but not the drug itself.
·Other risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection episodes, and previous CMV infections.
·Clinical manifestations of BKV infection range from being asymptomatic to frank nephropathy with disturbed renal function and progressive increase of serum creatinine levels.
·Acute rejection is the main differential diagnosis of BKVN.
·Concomitant administration of agents with immunosuppression reduction is difficult to assess.
·Active screening every 3 months after renal transplant should reduce immunosuppression and follow-up with quantitative PCR and renal function tests.
·Newer options, including cellular immunotherapy, may carry potential hope for the treatment of BKV infection.
=============================================
What is the level of evidence provided by this article?
Level V.
I agree with your analysis, summary and level of evidence this article provides.I note that you consider adoptive cellular immunotherapy as a future potential.
Introduction:
BK virus belongs to the family of polyoma viridae. It is icosahedral double stranded DNA virus that causes disease in humans. The BK virus is a very ubiquitous virus that infects majority of the people at a very young age – 4-5 years. It was first discovered in a Sudanese transplant who had ureteric stenosis and was named after the patients initials. It mainly causes tubulointerstitial disease and ureteric obstruction in solid organ transplant patients and hemorrhagic cystitis in HSCT patients. It can lead to kidney graft failure in kidney transplant patients. The main risk factor is the degree of immunosuppression. There are 4 subtypes with subtype I being the most prevalent followed by subtype IV
Genome Structure:
It is a small – 40-50nm in diameter -, uncovered, icosahedral shaped virus with a double circular chain. The genome is about 5000 base pairs, contained in the histones derived from host cells. The genomic structure encodes 6 chief proteins divided into 3 regions: early encoding region, late encoding region and non-coding region
Transmission:
Primary BK viral infection occurs in early childhood, on average at 4-5 years. Posible routes of transmission include:
Primary infections are often clinically insignificant. The virus has a tropism for the renal tubular cells, parietal cells, transitional structures and Bowmans capsule. In the immunocompetent individuals, the BK virus does not cause any infection. It can lead to asymptomatic viral shedding in the urine in up to 20% of the immunocompetent individuals. The viruria incidence increase up to 60% in immunocompromised individuals.
Risk Factors and Pathogenesis:
The risk factors include:
Clinical Picture:
Majority of individuals (90%) will have had a BK virus infection. The BK virus enters into a latent phase and reactivates after SOT or HSCT. In SOT, it can cause BKVAN or ureteric stenosis while in HSCT patients, it can cause hemorrhagic cystitis.
Clinical manifestations are as follows:
Steps in BK viral infection:
BK virus does not cause symptoms
Diagnosis Overview:
A tissue (renal) biopsy is needed for the definitive diagnosis of BKVN. However, as the virus affects patch areas of the kidney and has a predilection for the medulla, the diagnosis may be missed.
Quantitative PCR is used to diagnose viremia, which demonstrates BK viral replication whether there is renal involvement or not.
A definitive diagnosis of BKVN requires characteristic cytopathic changes on the renal biopsy plus positive IHC which has a specificity of 100%. A diagnosis of BKV in a renal biopsy can be missed in 30% of cases because BK virus has a focal tropism for the medulla than the cortex.
In the absence of definitive criteria for BKVN diagnosis, a presumptive diagnosis can be made if there is sustained (> 2 week duration) urinary viral shedding and significant BK viral replication (plasma DNA PCR load > 10,000 copies/ml)
BKVN can be graded histologically into 3 subtypes based on the degree of fibrosis and viral replication
In BKVN, LM would show the following feature:
In BKVN, EM examination would show the following features:
Serology is not helpful in the diagnosis as because majority of the population have been infected by the BK virus and will have positive antibodies
Viral culture is rarely used as a method for BK viral infection outside the research setting
The differential diagnosis includes:
Therapeutic Intervention:
Immunosuppression reduction:
This is the mainstay of treatment of BKVN although it carries a high risk of developing rejection.
Cidofovir:
There have been case reports and single center studies showing efficacy of the use of cidofovir. However, there have been no RCTs and its use is limited by its nephrotoxicity profile
Brincidofovir:
This is a prodrug of cidofovir and has a lower incidence of nephrotoxicity than cidofovir. However, there have only been case reports of the use of brincidofovir. Large multi center RCTs are needed
Leflunamide:
This is an immunosuppressive drug that also has in vitro antiviral properties against BK virus. It is normally used in the place of mycophendlate. Several studies have shown beneficial effects when it replaces mycophendlate. However, it is not clear whether the beneficial effects are due to its antiviral effects or the reduced immunosuppression
IVIG:
IVIG contains neutralizing antibodies against BKV which would theoretically make it a good therapeutic intervention. However, there have only been case reports and no multi center RCTs
Fluoroquinolones:
These drugs can inhibit the replication of BKV and SV40 virus replication in vitro and have been used for treatment of BKVN and as prophylaxis. This is the only group of drugs that has had randomized trials which showed no benefit in renal transplant patients
Role of Adoptive cellular therapy:
There has been interest in developing T lymphocytes with activity against BKV and transfusing them into recipients with BKVN. Several techniques have been established to manufacture these T cells and one study showed beneficial effects in HSCT
Conclusion
BK virus is a member of the ubiquitous polyoma virus family. Majority of the human population are infected by the BK virus at a young age. It mainly affects SOT and HSCT and can lead to BKVN, ureteric stenosis and hemorrhagic cystitis. The main risk factor for BKVN is the degree of immunosuppression. A definitive diagnosis of BKVN is made by renal allograft biopsy using IHC and demonstrating characteristic cytopathic changes. In up to 30% of cases, the diagnosis can be missed due to the focal tropism for the medulla. ACR is the main differential diagnosis. The mainstay of treatment includes immunosuppression reduction. Newer option include cellular immunotherapy.
This is a systematic review: Level of evidence V
I note that you consider adoptive cellular immunotherapy as a future potential. I agree with your analysis, summary and level of evidence this article provides.
Please summarise this article.
# The objective:
To cover the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.
# Introduction:
*BKV is regarded as one of highly prevalent forms of polyomaviruses leading to infection particularly in immuno – compromised patients.
*In renal transplant recipients can lead to tubulointerstitial nephritis, ureteral stenosis and hemorrhagic cystitis in BMT patients.
* BKV viremia is mainly treated by reduction of immunosuppression (IS), regular follow-up of BKV (PCR) and renal functions to prevent BKV nephropathy that may result in graft failure, so there is challenging between avoiding the rejection which need to keep the IS at adequate level and at the same time it is lead to more BKV viremia and consequently BKVN.
# virology:
*BK virus is a member of the family Polyomaviruses
*Double-stranded DNA virus with icosahedral symmetry.
*It is detected serologically and genotypically into 4 groups with different virulence.
# Genome structure and transcription:
The genomic structure encodes 6 chief proteins divided into 3 regions:
1)Early encoding region
2)Late encoding region,
3)Non coding control region.
# Transmission mechanism:
*Primary BKV infection occurs at 4 to 5 years of age.
*The routes of transmission by:
1) Airborne route through air droplets.
2) A feco-oral route.
3) Urinary-oral route or seroconversion after SOT.
4) Blood transfusion and vertical transmission; as BKV DNA has been found in the placenta, brain, and renal tissue of aborted fetuses.
*Primary polyomavirus infections usually occur during childhood through respiratory or oral routes, it is insignificant; but the virus remains in the renal epithelium.
* In the immunocompetent population, BKV replication is manifested by asymptomatic viruria, and the incidence of shedding is 20%.
*In immunocompromised individuals, the risk of
shedding reaches 60% and the viruria is more common.
* Patients with impaired cell-mediated immunity have a particularly greater risk of BKV infection.
# Risk factors and pathogenesis:
The degree of (IS) mainly with heavy (IS).
*The type of (IS) protocols, more frequent with tacrolimus and MMF.
* Other risk factors but uncommon, DM, delayed graft function, treated episodes of AR, ureteral trauma, use of antilymphocyte antibodies, co-infection with CMV, maintenance steroid IS, older age, white race/ethnicity, and presence of specific HLA- C loci and presences of BKV antibody titers in donors.
*Both HLA and ABO-incompatible transplants have a higher risk of BKV nephropathy, and ABO incompatible are at a higher risk than HLA-mismatched due to higher rate of rejection and need more IS.
#The clinical Picture:
*90% of the people will become BKV seropositive during their life; which reactivates following SOT (BMT&KT).
*Clinical manifestations are:
1) asymptomatic
2) Slow and progressive increase of serum creatinine
3) An unsuspected finding of progressive renal damage (BKVN) on renal biopsy.
*No signs and symptoms are detected with BKV infection. (BKV infection occurs 10 to 13 months after transplant.
BKVN may occur earlier at week 1 or as late as 5 years after transplant).
# Laboratory findings :
1) Elevated serum creatinine.
2) Urine cytology (the presence of decoy cells increases the suspicion of BKV nephritis, the infected cells is an enlarged nucleus with a single, large basophilic intranuclear inclusion.
3)Urine electron microscopy: will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen
4) Quantitative PCR of blood preferable to urine.
5) Biopsy is needed for a definitive diagnosis of BKVN which requires characteristic cytopathic changes and positive IHC (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic.
# Differential diagnosis:
BK virus infection can be similar to other types of viral infections.
# Therapeutic interventions:
*Immunosuppression reduction:
Reduction of IS considered as keystone in the management of BKV infection, but it has a high risk of rejection that making this decision challenging.
*Cidofovir:
Assocated with nephrotoxicity, thus making the decision to use cidofovir unlikely.
*Brincidofovir (CMX001):
It is a prodrug of cidofovir that is administered orally.
Larger-scale clinical trials are needed to establish it is safety and efficacy.
*Leflunomide:
Studies showed association between leflunomide and decrease in BKV viral load; but, this does not reflect whether it is a result of IS reduction or antiviral properties of leflunomide.
Side effects of leflunomide include TMA, hepatitis, and BM suppression.
*Intravenous immunoglobulin:
It contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKV; however, no controlled studies have been reported.
*Fluoroquinolone:
In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV, but overall, the data suggest that fluoroquinolones do not currently have a clinically significant role in the management of BKV-related diseases.
*Cellular immunotherapy in the management:
Newer options, including cellular immunotherapy, may carry potential hope for treatment of BKV infection.
# What is the level of evidence provided by this article?
Level V
I agree with your analysis, summary and level of evidence this article provides.
I note that you consider adoptive cellular immunotherapy as a future potential
Update on the Management of BK Virus Infection
====================================================================
Please summarise this article.
Introduction
====================================================================
Virology
Properties
Historical aspects
Genome structure and transcription
Transmission mechanism
Risk factors and pathogenesis of BKV disease include
====================================================================
Clinical Picture of BK virus infection
Diagnosis Overview
Definitive diagnosis of BK virus nephropathy
Differential diagnosis of BKVN requires blood quantitative PCR and characteristically pathologic morphology results.
====================================================================
Urine cytology findings for BK virus infections
====================================================================
Quantitative polymerase chain reaction
====================================================================
Serology
viral culture
====================================================================
Urine electron microscopy
====================================================================
Therapeutic interventions
Immunosuppression reduction
Cidofovir
Brincidofovir
Leflunomide
Intravenous immunoglobulin
Fluoroquinolone
Role of cellular immunotherapy in the management of BKv infection
====================================================================
Conclusions
====================================================================
What is the level of evidence provided by this article?
The level of evidence provided by this article is V
I note that you consider adoptive cellular immunotherapy as a future potential
Yes
thank you very much Prof.Sharma
Please summarise this article.
BK virus is an important risk factor for graft dysfunction and renal failure. Currently prophylaxis and treatment for BK virus infection is not established. The main risk factors include immunosuppression , elderly recipients, prior rejection episodes, male sex, human leukocyte antigen mismatching, prolonged cold ischemia time, pretransplant BK virus serostatus, and ureteral stenting. Newer management options are being developed. The management options have been reduction of immune suppression, regular follow up and monitoring.
Virology
BK virus is double-stranded DNA virus with icosahedral symmetry divided into four groups.
Transmission mechanisms
· Airborne transmission
· Feco-oral transmission
· Urinary-oral route
· Seroconversion after solid-organ transplant
· Blood transfusion and vertical transmission
Risk factors and pathogenesis
The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used. Other risk factors are diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci.
Clinical Picture
· Graft dysfunction and failure
· Asymptomatic
· Slow and progressive increase of serum creatinine
· An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy
Diagnosis
Renal Biopsy
Quantitative PCR
Decoy cells in urine
Suspect BK virus in tubulointerstitial nephritis
Definitive diagnosis of BK virus nephropathy
It requires cytopathic changes on the renal biopsy plus positive immunohistochemistry against BKV or against SV40 large T antigens.
Differential diagnosis
Differential diagnosis BK virus infection can be similar to other types of viral infections (CMV, herpes simplex virus, adenovirus)
Urine cytology findings for BK virus infections
The infected cells is an enlarged nucleus with a single, large basophilic intranuclear inclusion- Decoy Cells
Other test
Quantitative polymerase chain reaction
Viral serology
It is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection because positivity for these antibodies is quite common in the general population
Urine electron microscopy
It will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen
Therapeutic interventions
immunosuppression reduction
The reduction of immunosuppression has been the cornerstone in the management of BKV infection, it also carries a higher risk of rejection, making this decision challenging.
Cidofovir
Limitations of this approach is nephrotoxicity, thus making the decision to use cidofovir unlikely
Brincidofovir (CMX001)
Larger-scale clinical trials are needed to establish the safety and efficacy of brincidofovir in the management of BKVN p
Leflunomide
intravenous immunoglobulin
In patients with hypogam – maglobulinemia, IVIG therapy was beneficial with regard to anti-BKV immunity; the immunomod ulatory effects of IVIG may guard against allograft rejection.
Fluoroquinolone
Data suggest that fluoroquinolones do not currently have a clinically significant role in the management of BKV-related diseases
Conclusions
· There is a direct correlation between the incidence of BKV infection and the degree of immunosup – pression, but not the drug itself
· The risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection episodes, and previous CMV infections.
· Clinical manifestations of BKV infection range from being asymptomatic to frank nephropathy with disturbed renal function and progressive increase of serum creatinine levels
· Acute rejection is the main differential diagnosis of BKVN
· There are no available antiviral medications for BKV infections
· The common approach for BKV infection management is active screening every 3 months after renal transplant; with any levels of BKV viremia, immunosuppression should be reduced
· Newer options, including cellular immunotherapy, may carry potential hope for treatment of BKV infection
What is the level of evidence provided by this article?
Level V
I agree with your analysis, summary and level of evidence this article provides.
Please summarise this article.
Human Polyomavirus HPvY has been associated with development of malignancies. HPyY has been associated with skin cancer and , Merkel cell carcinoma (MCC). This review is about the BK virus BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
Tropism and epidemiology
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old.
Following primary infection, BKPyV persists in the kidneys. If the host becomes immunosuppressed, the virus causes significant morbidity.
Transmission can be feco oral, trnasplacental or by vertical route.
Currently there no significant evidence of association with BKPyV and malignancy.
Role in development of malignancy
The oncogenic properties of BKPyV are welldemonstrated in in vitro and in vivo
Two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg)
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase
Transforming ability of BKPyV is welldocumented in experimental rodent models, definitive transforming activity is not always observed in human
Inactivation of tumour suppressor gene has a role .
Alteration in chromosomal activity
Main association with bladder and prostate cancer.
Conclusion
· At the moment there is no conclusive evidence of role of BKPyV in the development of cancer
· The investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumours are required
I am sorry . This is journal club 2 . Posted here by mistake. Apologies
No worries
1. Summary:
Update on the Management of BK Virus Infection
Introduction
▪︎BK polyomavirus (BKV) is one of the highly prevalent forms of polyomaviruses
causing infection in immuno -compromised patients. It can lead to tubulointerstitial nephritis and ureteral stenosis in renal transplant recipients.
▪︎The current consensus on management of BKV viremia is:
1. Decrease immunosuppression (IS)
2. Regular follow-up of BKV polymerase chain reaction (PCR),
3. Continuous monitoring of renal functions
▪︎The challenging part in the management of BKV infection is the balance between the fear of rejection due to reduction of IS and the maintenance of IS at the same level, which can lead to BKV viremia and so BKVN.
Virology
BK virus is a member a double-stranded DNA Polyomaviruses
Transmission mechanism
▪︎Primary BKV infection occurs on average at 4 to 5 years of age.
▪︎Possible routes include the following:
(1) airborne transmission through air droplets
(2) a feco-oral transmission
(3) urinary-oral route or seroconversion after solid-organ transplant.
(4) blood transfusion and vertical transmission.
Risk factors and pathogenesis
The degree of immunosuppression rather than the type of immunosuppression used. Immunosuppressive agents can affect T cells, which can lead to increased BKV replication.
Clinical Picture of BK virus infection
In kidney transplant recipients, reactivation may lead to BKVN, which may end with graft dysfunction and failure by causing tubulointerstitial nephritis and/or ureteral obstruction.
▪︎Clinical manifestations:
(1) asymptomatic, (2) slow and progressive increase of serum creatinine, and (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance
renal allograft biopsy. Importantly, no signs and symptoms are identified with BKV infection.
▪︎Laboratory findings:
(1) elevated serum creatinine.
(2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts.
However, these results could be normal.
Diagnosis Overview
1. A renal biopsy for a definitive diagnosis.
2. Quantitative PCR to diagnose BKV viremia
▪︎BK virus nephritis is suspected when the clinical diagnosis of tubulointerstitial
nephritis is suspected.
▪︎The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis, which should be followed by quantitative PCR of blood preferable to urine.
Definitive diagnosis of BK virus nephropathy
▪︎Requires:
Characteristic cytopathic changes on the renal biopsy pluse positive IHC.
▪︎In the absence of definitive criteria, a presumptive diagnosis can be done if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction.
▪︎BKVN can be graded into 3 grades using Banff criteria according to the percentage of fibrosis and the amount of viral replication.
▪︎Light microscopy and electron microscopy examinations; which will show features of BKV nephropathy.
Differential diagnosis
Other types of viral infections (CMV, herpes simplex virus, adenovirus).
▪︎ To confirm a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100
BKV copies plus characteristically pathologic morphology results are needed.
Urine cytology findings for BK virus infections
▪︎Urine examinations may reveal BKV-infected cells (an enlarged nucleus with a single, large basophilic intranuclear inclusion which have been called decoy
cells)
▪︎Viral replication in the urine is demonstrated by either decoy cells or BKV urine quantitative PCR.
▪︎Quantitative PCR analyses
▪︎Serology is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection
▪︎Viral culture is rarely used
▪︎Urine electron M will show Haufen
◇ Therapeutic interventions
▪︎The usual approach in the management of BKV viremia or BKVN in renal transplant recipients is the reduction of immunosuppression and continuous monitoring of BKV viremia levels using quantitative PCR.
▪︎Other therapeutic options:
– Cidofovir: one of the limitations is nephrotoxicity, thus making the decision to use cidofovir unlikely.
– Leflunomide & Brincidofovir larger-scale clinical trials are needed to establish their safety and efficacy.
– Intravenous immunoglobulin:
contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKVN.
– Fluoroquinolone (immunosuppression rather than augmentation as in cases of rejection.
-There is a possibility of management of BKV infection using the adoptive transfer of BKV-reactive T cells.
◇ Conclusions
▪︎There is a direct correlation between the incidence of BKV infection and the degree of immunosuppression, but not the drug itself. Other risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection
episodes, and previous CMV infections.
▪︎Clinical manifestations of BKV infection range from being asymptomatic to frank nephropathy.
▪︎ A definitive diagnosis of BKVN is made by renal allograft biopsy using immunohistochemistry, which cross-react with the BKV, specifically SV40 large-T antigen part of the virus.
▪︎BK virus nephropathy could be missed in about one-third of patients; therefore, 2 core biopsies are needed for confirmation, preferably including the medulla.
▪︎ Renal transplant recipients are usually monitored by serum and urine quantitative PCR for BKV DNA.
▪︎Acute rejection is the main differential diagnosis of BKVN.
▪︎There are no available antiviral medications for BKV infections.
▪︎The common approach for BKV
infection management is active screening every 3 months after renal transplant; with any levels of BKV viremia, IS should be reduced and there should be continuous follow-up of BKV viremia levels using quantitative PCR and RFTs.
▪︎ Newer options, including cellular
immunotherapy, may carry potential hope for treatment of BKV infection
2. What is the level of evidence provided by this article? Level V
I agree with your analysis, summary and level of evidence this article provides.
Update On the Management Of BK Virus Infection
Summary Of This Article:
Virology:
Transmission Mechanisms:
· Primary Polyomavirus Infections Usually Occur During Childhood Through
Respiratory Or Oral Routes.
It Is Usually Asymptomatic And The Virus Remain In Renal Epithelium (Tubules)
Risk Factors:
Clinical Features:
Diagnosis:
Serology:
Treatment:
Level Of Evidence Is V (Narrative review)
I agree with your analysis, summary and level of evidence this article provides.
Introduction
It is a polyomavirus with latency mainly in renal tubules that can be reactivated with immunosuppression mainly in kidney and bone marrow transplants
Level of evidence
Narrative review – Level V
Transmission
1. Fecal Oral
2. Airborne droplets
3. D+/R- transplant
4. Vertical
Risk factors
– D+/R-
– Combined CNI and MMF immunosuppression
– Use of rATG for induction
– Coinfection with CMV
– Advanced age
– acute rejection
– HLA mismatch
– Caucasians
Clinical presentations
– Asymptomatic
– Slow progression of creatinine levels
– Occasional biopsy finding of nephropathy
– Investigation of kidney damage (nephropathy)
Diagnosis
– Biopsy is the most appropriate, including graduations in A, B or C
– Viruria and viremia.
– Presence of decoy cells in the urine
Treatment
There is no specific treatment and adequate studies are lacking to establish an effective treatment. Decreasing current immunosuppression is still the most effective way to treat the patient.
New models of immunotherapy with positive donor blood using CART cells may be a more effective answer in the future, but studies need to be carried out.
I like your summary.
Summary review Update on the Management of BK Virus Infection 2020
This article address, the diagnosis, screening, diagnostic tools, and updated management of BK virus infections.
Introduction:
Transmission:
Risk factors:
Clinical Picture of BK virus infection
Diagnosis Overview
Definitive diagnosis of BK virus nephropathy
Recommendations for BK Virus Screening:
Management of BKVN:
Adoptive T-cell therapy to restore antiviral immunity in immunocompromised patients may carry potential hope for treatment of BKV infection.
Level of evidence: level v
I agree with your analysis, summary and level of evidence this article provides.
Introduction
BK virus is DNA polyoma virus that infects human especially immunocompromized individuals. It was first isolated in 1971 in a renal transplant recipient. BK virus may cause Tubulointerstitial, nephritis, ureteric stricture and associated with risk of graft rejection. There are four serotypes, among which serotype 1 is most prevalent.
Mode of transmission;
Primary BKV occurs in first decade of life and tends to be dormant. It is transmitted via air droplets, fecal –oral and blood transfusion or solid organ transplant. BKV infection occurs during immunosuppression phase and viruria occurs in up to 60% patients. BKVN prevalence is reported in 5% patients of kidney transplants.
Risk factors for BKV;
· Mainly the degree of immunosuppressant and immunosuppressive drugs like ATG, MMF and Tacrolimus.
· History of Diabetes mellitus
· DGF
· HLA mismatch
· ABO incompatibility and
· Allograft rejection.
Presentation
· Asymptomatic
· Slowly raising creatinine
· Progressive renal damage on surveillance biopsy.
Diagnosis:
Kidney Biopsy is definitive diagnostic tool but can miss diagnosis in 30% due to focal tropism in medulla. Usual biopsy finding are
1. Cytopathic changes with immunohistochemistry (SV 40)
2. Basophilic Viral inclusion on EM
Other diagnostic tests are:
· DNA PCR plasma
· DNA PCR urine
· Decoy cells in urine
Differential diagnosis
· CMV infection
· Adenovirus and
· HSV infection
Therapeutic intervention;
Ø There is no specific treatment available so for against BKV, although there are reports on the use of some medications. The key intervention is reduction of immunosuppression some time stopping it altogether with greater risk of rejection.
Ø Cidofovir ———-risk of nephrotoxicity
Ø Brancidofovir———-In phase III trial
Ø Lefulonmide——–Risk of TMA and marrow suppression
Ø IVIG —————No controlled study only case reports
Ø Flouroquinolone —-no evidence
Ø Immunotherapy ——adoptive immunotherapy with positive results.
Conclusion:
BKV is a human polyomavirus with incidence of 10% in renal transplant patients depending on in immunosuppression dosage and other risk factors like diabetes, old age recipient, HLA mismatches, ABO incompatibility, Male gender, acute rejection and delayed graft function. The choice of investigation in kidney biopsy and mainstay of treatment is reduction of immunosuppression.
Level of evidence
Level -V
I agree with your analysis, summary and level of evidence this article provides.
classification of infections:
1.primary infection:
2.latent infection
3.serologic evidence of infection
4.viral activation
5.viral disease
Risk factors:
clinical picture:\
DIAGNOSIS:
2 . PCR urine and blood (preferable)
3.biopsy (definitive)…IHC SV40 large T antigen/ require 2 core biopsy including medulla, 100% specific
stages of infection:
DDX.:
BKVN biopsy can be classified :
Treatments:
I agree with you analysis of this article provides.
Please summarize this article.
Introduction
Transmission
Risk factors:
Clinical picture:
Diagnosis:
BKVN IN 30% of cases is focal disease in nature and it may involve the medulla
only rather than the cortex diagnosed on histopathology.
Differential diagnosis:
Treatment:
Conclusion
-What is the level of evidence provided by this article?
I agree with you analysis, summary and level of evidence this article provides.
Summary of the Article:
Introduction:
Virus properties:
Transmission:
Primary infection happens during childhood during at 4-5 years of life and is deposited in the organs and tissues (epithelial cell in the tubules and Bowmanes capsule), manifested as asymptomatic viruria and shedding is about 20%, rising up to 60% in immunocompromised patients.
Risk factors:
Clinical manifestation:
Usually, BK infection occurs in 1st 10-13 months post-transplantation, but it can occur as earlier as 1st week and as late as 5 years postTx.
Diagnosis:
1. Basophilic intranuclear viral inclusions without a surrounding halo.
2. Anisonucleosis, hyperchromasia, and chromatin clumping of infected cells.
3. tubular damage.
4. Tubular injury.
5. Tubulitis with lymphocyte invasion to the BM of the tubular epithelium.
1. Viral inclusions.
2. Tubular damage.
Banff Grading of BK virus nephritis:
Steps of infection of BKV:(European Society Of Organ Transplantation 2006):
Differential Diagnosis:
Management:
1. Switch from TAC to CsA.
2. Switch MMF to mTORi.
Follow-up response:
Conclusion:
BK viral infection is causing TIN and ureteral strictures, with an average incidence of about 10% in transplanted patients.
Incidence and viral reactivation and replication depend on an intensive immunosuppressant regimen.
Risk factors associated with BKV infection should be considered.
BKV infection may be manifested as asymptomatic to invasive disease.
Allograft biopsy-based diagnosis, with pathognomic immunohistochemistry against SV40 large T antigen.
BKV infection should be differentiated from acute rejection.
No specific antiviral medication proven till now, and concomitant use with IS reduction has been studied only in uncontrolled retrospective observational studies.
Level of evidence:
Level ((V))
I agree with you analysis, summary and level of evidence this article provides.
1. Please summarise this article.
Introduction
Risk factors include:
Clinical manifestations of BKV infection:
Diagnosis:
Treatment
Commonly used options:
Newer options:
Cellular immunotherapy:
============================
2. What is the level of evidence provided by this article?
Level V (Review article)
I agree with you analysis, summary and level of evidence this article provides.
1-Please summarise this article?
Introduction;.
-BK virus is a member of human polyomaviruses, which are DNA viruses
-BKV infections lead to tubulointerstitial nephritis and ureteral stenosis in the renal transplant population.
Incidence;.
-The average incidence is about 10% of the renal transplant population.
-There is a direct correlation between the incidence of BKV infection and the degree of immunosuppression, but not the drug itself.
Risk Factors;.
-The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used.
-Transplant physicians consider BKV infection as a marker of heavy immunosuppression.
-Other risk factors include diabetes mellitus, elderly patients, male patients, delayed graft function, acute rejection episodes, and previous CMV infections.
Clinical Picture of BK virus infection;.
-About 90% of the population will become BKV seropositive during their life,
-Clinical manifestations of BKV infection range from being asymptomatic to frank nephropathy with disturbed renal function and progressive increase of serum creatinine levels.
-Urine analysis may show hematuria, pyuria, and cellular casts.
-Urine microscopy shows decoy cells that are BKV-infected cells.
Diagnosis Overview;.
-A definitive diagnosis of BKVN is made by renal allograft biopsy using immunohistochemistry, which cross-react with the BKV, specifically SV40 large-T antigen part of the virus.
-BK virus nephropathy could be missed in about one-third of patients; therefore, 2 core biopsies are needed for confirmation, preferably including the medulla.
-Renal transplant recipients are usually monitored by serum and urine quantitative PCR for BKV DNA.
-Viral replication goes through stages, with viruria preceding viremia by about 4 weeks and nephropathy by 12 weeks.
-Acute rejection is the main differential diagnosis of BKVN. BK virus nephropathy could be differentiated with BKV inclusions and immunohistologic analyses.
-In addition, it is important to correlate histologic findings with PCR evidence of viremia.
Treatment;.
-There are no available antiviral medications for BKV infections, and there are few controlled studies available on management of BKV infection in renal transplant recipients.
-The concomitant administration of these agents (Cidofovir , Brincidofovir , Leflunomide , Intravenous immunoglobulin (IVIG) , Fluoroquinolone) with immunosuppression reduction has been reported in only uncontrolled retrospective observational studies; therefore, it is difficult to make firm conclusions about their therapeutic efficacy.
-The common approach for BKV infection management is active screening every 3 months after renal transplant; with any levels of BKV viremia, immunosuppression should be reduced and there should be continuous follow-up of BKV viremia levels using quantitative PCR and renal function tests.
-Newer options, including cellular immunotherapy, may carry potential hope for treatment of BKV infection.
2. What is the level of evidence provided by this article?
(level V evidence)
I agree with you analysis, summary and level of evidence this article provides.
Update on the Management of BK Virus Infection:
This article address the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.
BK virus is common infection post transplant due to use of heavy immunosuppressive therapy and carrying risk for graft rejection and loss.
Risk factors of BK virus:
There’s no specific treatment for BK virus but serial monitoring of BKV polymerase chain reaction (PCR) and screening for BK virus important to prevent infection.
Cellular immunotherapy is new modality promised to treat infection and also reducing dose of immunosuppressive drug help to treat infection.
Introduction:
Polyomaviruses are small DNA viruses that can infect humans and animals.
It’s can lead to interstitial nephritis and ureteral stenosis and haemorrhagic cystitis in bone marrow transplant.
Mode of Transmission:
Transmitted by placenta to neonatal and it’s found in brain and renal tissue of aborted foetus.
Clinical picture of BK virus:
Around 90% of population developing BK virus from childhood and reactivated if patient gets compromised or post kidney transplant.
It’s manifested by slow progress of disease and raised creatinine level and unexplained graft kidney failure.
Laboratory studies shows elevated serum creatinine and urine analysis shows pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
Diagnosis:
Presence of decoy cells indicates of BK virus.
Definitive diagnosis by renal biopsy //
Light microscopy examinations shows basophilic intranuclear viral inclusions without a surrounding halo/ anisonucleosis, hyperchromasia, and chromatin clumping of infected cells and areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates // tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining and tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
Extensive BK virus shows evidence of graft rejection.
Electron microscopy examinations shows viral inclusions with diameter size ranging from 30 to 50 nm and tubular damage and cell necrosis.
Absence of decoy cell does not exclude the disease.
Confirm diagnosis by PCR of BK virus.
The onset of viremia occur after 6 months post transplant, and it’s can detected in urine and plasma.
Serology:
Anti-BKV antibodies are not helpful in diagnosis of BKV infection.
During BKV infection, there are high levels of BKV IgG titers during the first 6 weeks of infection or 2 years after primary infection.
Virus culture is rarely done in diagnosis of BKV.
Treatment:
immunosuppression reduction:
But It’s carry risk of rejection. One study suggested that patients with persistent sustained BKV viremia are prone to the development of de novo donor-specific anti-HLA antibodies.
Cidofovir:
It’s unlikely to use because it’s nephrotoxic and no randomized control studies to support this approach.
Brincidofovir (CMX001):
It’s prodrug of cidofovir and it’s bring successful outcome in treatment of BKV with brincidofovir.
Leflunomide:
There’s good link between leflunomide and decrease in BKV viral load. Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression.
intravenous immunoglobulin:
It’s good choice in treatment of BKV.
Fluoroquinolone:
It’s inhibit replication of BKV.
Role of cellular immunotherapy in the management of BKv infection:
There’s no specific management to treat BKV. However cellular immunotherapy, may carry potential hope for treatment of BKV infection.
Level V
I agree with you analysis, summary and level of evidence this article provides.
Please summarise this article.
Introduction
BKV are small DNA viruses (Polyomaviruses family)
It can cause tubulointerstitial nephritis, ureteral stenosis, and hemorrhagic cystitis
The main step in the management is to decrease immunosuppressione
Aim of the study: address the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections
Virology
Polyomaviruses are small (40-50 nm in diameter), uncovered, icosahedrals, with a double circular chain
Primary infection occurs early (4-5 years of age)
Transmission:
1. Airborne through air droplets
2. Feco-oral
3. Urinary-oral route or seroconversion after solid-organ transplant
4. Blood transfusion and vertical transmission
Prevalence of BKVN in renal transplant recipients is 5%
Risk factors:
1. Degree of immunosuppression (the most important cause)
2. Others include diabetes mellitus, DGF, treated episodes of acute rejection, ureteral trauma, use of ATG, coinfection with CMV, maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci
Clinical Picture
Usually, BKV infection occurs 10 to 13 months posttransplant (may occur earlier at week 1 or as late as 5 years)
Clinical manifestations:
1. Asymptomatic
2. Slow and progressive increase of serum creatinine
3. Unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy
Laboratory:
1. Elevated serum creatinine
2. Urine analysis (pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells)
Diagnosis
A tissue biopsy is the definitive diagnosis (may be missed as the lesions are patchy)
Cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens)
Diagnosis in a renal biopsy may be missed in 30% (It could be patchy or isolated to the medulla)
Presumptive BKVN: sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction
Specific Histologic Findings of BK Virus Nephropathy:
1. Pattern A (Cytopathic/cytolytic changes with absent or minimal inflammation)
2. Pattern B (Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy)
3. Pattern C (Graft sclerosis)
Banff Grading of BK Virus Nephritis:
1. Grade 1( minimal viral replication in < 1% of biopsy with < 25% fibrosis)
2. Grade 2 (any between grades 1 and 3)
3. Grade 3 (marked virus replication in > 10% of cores with > 25% fibrosis)
Electron microscopy:
1. Viral inclusions with diameter size ranging from 30 to 50 nm
2. Tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts
Differential diagnosis
CMV, herpes simplex virus, and adenovirus
Urine cytology
Decoy cells (infected cells with an enlarged nucleus with a single, large basophilic intranuclear inclusion). Strongly suggestive of PKV infections, but not specific, sensitive, and their absence does not exclude the disease
Quantitative PCR
· Urine or plasma
· Sensitivity and specificity is 100% and 88% (plasma)
· Viruria precede viremia by 4 weeks
· During the first 6 months, 10-30% of patients show levels of BKV viremia (decrease later to 5% to 10%)
· Patients with a higher viruria level are highly prone to developing BKV viremia, and patients with high sustained viremia are susceptible to BKVN
Serology
Not helpful:
1. Common in the general population
2. During infection, there are high levels of BKV titers during the first 6 weeks of infection or 2 years after primary infection
Viral culture
Not clinically applicable
Urine electron microscopy
Show cast-like 3-dimensional polyomavirus aggregates (Haufen). It is 100% sensitivity and 99% specificity. Correlated with viremia, AKI and BKVN
Therapy
immunosuppression reduction
Carries a higher risk of rejection and a higher incidence of longterm chronic rejection
Cidofovir
Limited with nephrotoxicity
Brincidofovir (CMX001)
A prodrug of cidofovir that is administered orally
Less nephrotoxic
Leflunomide
Immunosuppressant and antiviral effects
Side effects include thrombotic microangiopathy, hepatitis, and bone marrow suppression
The active metabolite (known as teriflunomide or A771726) can be measured
Intravenous immunoglobulin
Contains neutralizing antibodies against BKV (good choice in the management of BKVN)
Fluoroquinolone
Inhibit replication of BKV or SV40 polyomavirus replication in vitro
Cellular immunotherapy
Transfer of primed BKV-reactive T cells
Interferon-capture technology or major histocompatibility complex multimers
What is the level of evidence provided by this article?
Level V (narrative review)
I agree with you analysis, summary and level of evidence this article provides.
Update on the Management of BK Virus Infection
Review article published in Experimental and Clinical Transplantation (2020)
base of evidence V
Polyoma viruses are DNA viruses infects humans and animals and BK is one of the most common viruses which affect immunocompromised patients like solid organ transplant patients.
file:///C:/Users/ramya/AppData/Local/Temp/msohtmlclip1/01/clip_image002.jpg
BK is latent virus which activate in 10-20% of cases post-transplant causing viruria in 40% which associated with decoy cells in 30% of cases and progress to viremia after 4w in 20% of cases and finally BKVN in 10% of cases only after 12w.
Diagnosis can be made by (as showen in figure 1)
1. PCR in urine if viral load more than 9 log which mean high viral load which probably will progress to viremia with sensitivity 90% and specificity 60%
2. Decoy cells in urine but its not specific as it can occur with other viral infections like herpes and CMV.
3. Urine electron microscopy: 3-dimensional polyomavirus aggregates, which are called Haufen with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients but limited still because need expert pathologist and it can’t diagnosis rejection.
4. PCR in serum which occurs in 20% of cases only who developed viruria with sensitivity 90% and specificity around 95% and if not treated it may progress to BKVN.
5. Kidney biopsy: BK patchy infiltrate tubule-interstitial cell so 30% maybe missed. BKV can lead to tubule-interstitial nephritis and ureteral stenosis. Interstitial inflammation giving picture similar to rejection and difficult to be differentiate and needs immune-histological examination using specific staining to differentiate with adequate sampling including medullary tissue.
Specific Histologic Findings of BK Virus Nephropathy
Pattern Characteristics (The presence of characteristic cytopathologic changes in infected cells (which have been called decoy cells due to their similarity to renal carcinoma cells) is strongly suggestive of polyomavirus infections.)
Pattern A Cytopathic/cytolytic changes with absent or minimal inflammation (Figure 3)
Pattern B Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy
Pattern C Graft sclerosis
Banff criteria
BKVN can be graded into 3 grades according to the percentage of fibrosis and the amount of viral replication.
Grade 1 Minimal viral replication in < 1% of biopsy with < 25% fibrosis
Grade 2 Any between grades 1 and 3
Grade 3 Marked virus replication in > 10% of cores with > 25% fibrosis
Treatment approach (as shown in figure 2)
There is no specific treatment and evidence based on retrospective studies and case series and include
· -decrease of immunosuppression 30%-50% with follow up of viral log in serum after 4w with further decrease if needed according to response
· -cidovir
· -baricidovir
· -leflenomide
· -IVIG
· -qunolonesfile:///C:/Users/ramya/AppData/Local/Temp/msohtmlclip1/01/clip_image004.gif
figure 2
I agree with you analysis, summary and level of evidence this article provides.
SUMMARY.
Introduction.
BK is one of the prevalent forms of polymaviruses. In transplant recipients it causes tubulointerstitial nephritis and ureteral stenosis in kidney transplant recipients and hemorrhagic cystitis in bone marrow recipients.
Current consensus on management is to reduce immunosuppression, monitor renal functions to avoid allograft nephropathy and followup BK virus PCR.
Transmission
Primary infection occurs in the first decade of life, average at 4-5 years of life.
Modes of transmission:
Primary infection occurs through oral and respiratory route, it’s mainly clinically asymptomatic. It then remains dormant in the kidneys-tubular, parietal, transitional structures and Bowman’s capsule.
Immunocompetent individuals BKV replication is manifested by asymptomatic viruria with 20% incidence of shedding. While the immunocompromised have 60% incidence.
Risk factors
Clinical manifestations
Includes:
Diagnosis
A renal biopsy required for definitive diagnosis, however may be missed because the lesions are patchy.
Diagnosis requires characteristic cytopathic changes plus positive immunohistochemistry against BKV or SV40 large T antigens.
May miss 30% of cases due to focal tropism in the medulla thus initial biopsy is not enough to rule out highly suspicious cases.
Presumptive diagnosis is made when there is persistent viruria (more than 2 weeks) and significant viral replication(plasma DNA PCR>10,000copies/ml).
Serology for antibodies: Not found to be helpful since they are not protective.
Viral culture: takes weeks to months to isolate a specimen thus not routinely done outside research.
Urine electron microscopy: Haufen bodies have 100% sensitivity and 99% specificity for detection of biopsy proven BKVAN. Thus it’s a non-invasive method of differentiating BKVAN and BKV infection. However it doesn’t differentiate between BKVAN and rejection and requires sophisticated analysis and tedious interpretation by pathologists.
Treatment
No antivirals approved.
Cornerstone of management is reduced immunosuppression that carries a risk of rejection.
Cidofovir: No RCT to support its use and its nephrotoxic.
Brincidofovir: Prodrug of cidofovir that is oral. Less nephrotoxic. Larger clinical trials needed to establish its use.
Leflunomide: Immunosuppressive drug with antiviral properties. RCT required to confirm its safety and efficacy.
IVIG: Its immunomodulatory effect may guard against rejection in context of reduced immunosuppression. No RCT
Fluoroquinolone: Retrospective studies had shown a role in prophylaxis against BKV infection. However prospective studies have shown no benefit. Further studies required.
Cellular immunotherapy: Based on transfer of primed BKV T cells to control the replication.Studies are still in the early stages.
Level of evidence: This is a narrative review hence level V.
I agree with you analysis, summary and level of evidence this article provides.
Update on the Management of BK Virus Infection.
Introduction.
It is considered small DNA virus that infect humans who are immunocompromised such as post kidney transplant which may affect graft survival and lead to many co-morbidities such as tubulointerstitial nephritis and ureteral stenosis; it can also lead to hemorrhagic cystitis, and it is management mainly depends on Immunosuppression medications reduction with balance to avoid the risk of rejection.
Genome structure and transcription.
Polyomaviruses are small (40-50 nm in diameter), uncovered, icosahedral, with a double circular chain, serologically and genotypically into 4 groups (I to IV).
Route of transmission:
Multiple Faeco-oral, Respiratory, Organ transplantation and Transplacental.
Risk factors and pathogenesis.
Primary infection occurred in childhood and then latent infection in renal tubules and urothelial cells, reactivation, mostly asymptomatic viruria, with decoy cells in urine and when lyses of the infected tubular cells releases the virus into the tubules, the BKV can leak back into the interstitium, hence the capillaries causing viremia.
The most important risk factor is degree of immunosuppressive status and others such as diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci.
Clinical Picture of BK virus infection.
Clinical manifestations are as follows: (1)asymptomatic, (2) slow and progressive increase of serum creatinine, and (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy. There are no signs and symptoms are identified with BKV infection. Usually, BKV infection occurs 10 to 13 months post transplant. BK virus nephropathy may occur earlier at week 1
post transplant or as late as 5 years posttransplant.3
Diagnosis Overview.
Renal biopsy is considered the gold standard for diagnosis of BKN, plus positive immunohistochemistry (against BKV or against SV40 large T antigens) and BK PCR and detection od Decoy cell in urine increase suspicion for diagnosis, but diagnosis of BKV in a renal biopsy could be missed in about 30% of cases because BKV has a focal tropism in the medulla rather than in the cortex.
Differential diagnosis
BK virus infection can be similar to other types of
viral infections (CMV, herpes simplex virus, adenovirus). Therefore, to confirm a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed and decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients.
Quantitative polymerase chain reaction.
PCR analyses in detecting BKV DNA were about 100% and 88%, respectively, viruria precede viremia by 4 weeks, serology not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection.
Urine electron microscopy.
Show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen (Figure 8).57 In a retrospective single-center study, Haufen presence was shown to be associated with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients.
Therapeutic interventions.
1-immunosuppression reduction.
It is considered the cornerstone in the management of BKV
infection, it also carries a higher risk of rejection, making this decision challenging.
2-Cidofovir.
There is no randomized controlled trials are available to support
this approach, and one of the limitations of this approach is nephrotoxicity.
Brincidofovir (CMX001).
is a prodrug of Cidofovir but lower incidence of nephrotoxicity.
Leflunomide.
is an immunosuppressant agent that also has antiviral properties against BKV in vitro and association between leflunomide and decrease in BKV viral load, side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression.
Intravenous immunoglobulin.
In patients with hypogammaglobinemia, IVIG therapy was beneficial with regard to anti-BKV immunity; the immunomodulatory effects of IVIG may guard against allograft rejection in the context of reduced immunosuppression.
Fluoroquinolone.
Inhibit replication of BKV or SV40 polyomavirus replication in vitro.
Role of cellular immunotherapy in the management
of BKv infection.
The idea of this approach depends on the transfer of primed BKV reactiveT cells, which may help in controlling the BKV-associated disease.
Conclusions.
BK virus infection one of the most common infection post kidney transplant recipient that mainly due to heavy immunosuppreive status which lead to reactivation of the dominant infection and lead to BKVN, hemorrhagic cystitis and or ureteric obstruction, the corner stone of treatment is reduction of immunosuppression drugs and there are no available antiviral medications for BKV infections, and there are few controlled studies available on management of BKV infection in renal transplant recipients.
Level of evidence: V (narrative review).
I agree with you analysis, summary and level of evidence this article provides.
Introduction
· BK virus is a member of the family Polyomaviruses. This family is a double-stranded DNA virus
· BK virus has been categorized into 4 groups (I to IV),
· About 90% of the population will become BKV seropositive during their life
it reactivates after solid-organ transplant, especially in bone marrow or kidney transplant recipients
· Usually, BKV infection occurs 10 to 13 months posttransplant.
BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
· BKV can lead to tubulointerstitial nephritis and ureteral stenosis; it can also lead to hemorrhagic cystitis in bone marrow transplant patients.
Risk factors and pathogenesis
· the degree of immunosuppression rather than the type of immunosuppression used.
· Other risk factor include
diabetes mellitus,
delayed graft function,
treated episodes of acute rejection,
ureteral trauma,
use of antilymphocyte antibodies,
coinfection with Cytomegalovirus (CMV),
maintenance steroid immunosuppression,
older age, white race/ethnicity,
Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy,
Clinical manifestations
(1) may be asymptomatic
(2) slow and progressive increase of serum creatinine
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Laboratory findings
(1) elevated serum creatinine and
(2) urine analysis with pyuria, hematuria , findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. However, these results could be normal
Diagnosis
· Quantitative PCR is used to diagnose BKV viremia
· BK virus nephritis is suspected when the clinical diagnosis of tubulointerstitial nephritis is suspected
· The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis (an enlarged nucleus with a single large basophilic intranuclear inclusion )
· (decoy cells) are suggestive but not specific, sensitive, or definitive for BKV infection because
(1) decoy cells can be present in other renal viral infections (such as CMV or adenovirus
(2) decoy cells correlate poorly with biopsy-proven BKVN in renal transplant recipients.
(3) their absence does not exclude the disease.
· the definitive diagnosis of BKVN the presence of
1-cytopathic changes on the renal biopsy plus
2-positive immunohistochemistry which cross-react with the BKV, specifically SV40 large-T antigen part of the virus.
has a specificity of 100%, however in 30 % of cases diagnosis could be missed (pathchy lesion in medulla )
· a presumptive diagnosis
sustained (more than 2-week duration) urinary viral shedding and significant BKV replication ((plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction
· BKVN, light microscopy examinations
(1) basophilic intranuclear viral inclusions without a surrounding halo
(2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells
(3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates
(4) tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining
(5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
When extensive, it is difficult to differentiate between BKVN and allograft rejection
· In BKVN, electron microscopy examinations
(1) viral inclusions with diameter size ranging from 30 to 50 nm and
(2) tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
· Pattern of BKVN
Pattern A
Cytopathic/cytolytic changes with absent or minimal inflammation
Pattern B
Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy
Pattern C
Graft sclerosis
· Banff grading of BKVN
Grade 1-Minimal viral replication in < 1% of biopsy with < 25% fibrosis
Grade 2- Any between grades 1 and 3
Grade 3 -Marked virus replication in > 10% of cores with > 25% fibrosis
Therapeutic interventions
immunosuppression reduction
· the reduction of immunosuppression is the cornerstone in the management of BKV infection BUT it carry high risk of rejection
· Histologically, there is a similar feature between rejection and BKVN,.modification of immunosuppression to treat BKV infection carries a higher incidence of long- term chronic rejection.
.
Cidofovir
no ran- domized controlled trials are available to support . nephrotoxic
Brincidofovir
Successful outcomes in renal and hematopoietic transplant have been described in multiple case reports after treatment of BKVN with brincidofovir
Leflunomide
· Has immunosuppressant and antiviral properties against BKV.
· Side effects thrombotic microangiopathy, hepatitis, and bone marrow suppression. The active metabolite of leflunomide (known as teriflunomide or A771726) can be measured, level of 50 to 100 g/mL of teriflunomide was associated with a reduction of BKV viral load,
intravenous immunoglobulin
· (IVIG) contains neu- tralizing antibodies against BKV,
· The evidence of using IVIG as adjunctive therapy for BKVN has been described in multiple case reports and case
· the immunomodulatory effects of IVIG may guard against allograft rejection in the context of reduced immunosuppression.
Fluoroquinolone
· In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication
· No data suggest that fluoroquinolones have a clinically significant role in the management of BKV-related diseases.
Level of evidence
5
I agree with you analysis, summary and level of evidence this article provides.
SUMMARY
Introduction
BK polyomavirus is a DNA virus that has affects humans,s especially those with an immunocompromised state like solid organ transplantation. it usually affects the kidney allograft with a clinical presentation like tubulointerstitial nephritis, ureteral stenosis, and hemorrhagic cystitis. The risk of graft loss could be high when trying to treat the infection because of the need to reduce the immunosuppressive medications in the recipients.
Transmission mechanism
Risk factors for BKV
Clinical Picture of BK virus infection
Diagnosis
-characteristic cytopathic change with immunohistochemistry against BKV OR SV40 large T antigen (note, this could be missed in 30% of case)
Differential Diagnosis
Therapeutic intervention
There is no available potent antiviral agent against BKV, although few report has been published on use of few medications.
The key in the management is reduction of immunosuppressive medication and sometimes stopping some completely
Immunotherapy
Conclusion
The BKV is a member of human polyomal viral that is primary acquired by about 9)5 of general population and usually remain dormant in kidney tissue (medulla) until reactivated by immunosuppressive state like after kidney transplantation. Diagnosis requires persistent rising PCR DNA of BKV and a kidney tissue containing medula.
The main stay of treatment with some consistent result remain reduction of immunosuppression, but this could be accompanied by unintended allograft loss.
Level of evidence is 5
I agree with you analysis, summary and level of evidence this article provides.
Introduction
It was first discovered as a cause of ureteric stricture following transplantation in early 1971.
BK A tiny, double-stranded, non-enveloped DNA virus is known as a polyomavirus. There are four serotypes; serotype 1 is the most prevalent. Six viral proteins, two early, one non-coding, and three late, are encoded by its genome.
The majority of people (around 90% of people globally by the age of 4) are infected by the time they are 4 years old, and infection is typically acquired in childhood through either a feco-oral, respiratory, or transplantation with the graft route. Infection remains lifetime.
In people with a functioning immune system, the infection is typically benign and asymptomatic. Only 20 percent of the virus sheds.
In immune-compromised renal transplant recipients, infection can be acquired through the reactivation of latent infection or newly transmitted from the donor kidney. Infections can be subclinical or symptomatic, leading to BK nephropathy, graft dysfunction, and likely graft loss. Shedding of the virus increases to 60% in the transplant setting.
Viremia risk is related to following contributors:
The degree of immunosuppression
The stronger the immunosuppression being used, in ABO and HLA incompatible transplants, the higher the risk of BKPyVN.
Patients with DGF and those who experience recurrent rejection episodes are more likely to experience it.
No individual medication has been connected to infection, but a tacrolimus plus MMF protocol may be associated with higher risk comparing to cyclosporine-based regimen.
When it comes to donor’s factors BK serostatus is of great value, such as kidney transplantation from a donor who is BK+ to a recipient who is BK-.
Viruria in the donor before transplantation increases the risk of viruria and viremia in the recipient post-transplantation.
C: Recipient variables
Older males
The prevention of ureteric leaks through the application of ureteric stents
Kidney transplantation-related ischemia or rejection damage
Routes of transmission
Airborne transmission via an air droplet is one of the transmission routes.
Transmission through the feces.
Oral and urinary routes
Vertical transmission and blood transfusion.
Clinical picture
Ninety percent of the population develops seropositivity during the course of their lifetime.
The manifestations seen in solid organ transplantation include tubulointerstial nephritis, uretric stricture, and graft malfunction.
Hemorrhagic cystitis in recipients of bone marrow transplants.
BKV, which is typically asymptomatic and manifests in the first year following a kidney transplant, can cause progressive elevations in serum creatinine or progressive kidney damage that can be verified by a kidney biopsy (BKVN).
Increased creatinine, sham cells, pyuria, hematuria, and cellular casts in urine are some of the laboratory results.
Diagnosis
Kidney biopsy is required for a conclusive diagnosis of BKVN; however, because viropathic lesions are patchy, a diagnosis may be missed in the tissue collected. In addition, the tropism of BKV is the medulla, not the cortex, which may enhance the possibility of missing viropathic lesions. In around 30% of instances, a BKV diagnosis could be missed in a kidney biopsy.
BKV viremia is diagnosed by quantitative PCR, which demonstrates BKV replication regardless of renal dysfunction.
BK viral nephritis is suspected when tubulointerstitial nephritis is suspected; however, there are no tubulointerstitial nephritis clinical characteristics that are unique to BKVN.
The presence of decoy cells in a urine examination raises the suspicion of BKV nephritis, which should be confirmed by quantitative PCR on blood rather than urine.
Since BKV-positive serology is frequent, it cannot be used for diagnosis.
BKV Ig G titers are elevated from six weeks to two years after primary infection.
It is debatable if BKV serology investigations before and after transplants are beneficial.
Approach of treatment
Decrease in immunosuppression
Immunosuppression reduction is the initial step in managing BKPyVN. Treatment begins with reduction in the dose of MMF by 50%, and followup on viremia titers every week. Alternative approach is to lower CNI dose to acheive lower trough levels 4-6 ng/ml. MMF can be dropped from the management of no improvement in the followup, and the risk of rejection is low.
Histologically, BKVN and rejection can be identical, making it difficult to diminish immunosuppression, which is the primary treatment for BKVN.
In addition, altering immunosuppression to treat BKV infection increases the incidence of chronic long-term rejection.
Cidofovir
It was tested in conjunction with RI, but nephrotoxicity prevents its usage.
Brincidofovir
Is an oral prodrug of cidofovir with a reduced risk of nephrotoxicity.
Leflunamide
Is an immunosuppressant with antiviral properties; studies have demonstrated its association with viral load decrease; nonetheless, it is associated with thrombotic microangiopathy, hepatitis, and suppression of bone marrow.
IVIG
It had anti-BKV immunity in hypogammaglobulinemia, and the immunomodulatory effects of IVIG can protect against allograft rejection.
Fluoroquinolone
Can inhibit BKV or SV40 polyomavirus replication in vitro; it has also been hypothesized to play a function in preventing BKV infection.
There is currently no evidence to suggest its significance in BKV treatment.
Immunocellular treatment
Utilize BKV-reactive T lymphocytes primed for therapy.
A study utilized pools of overlapping peptides derived from all five BKV antigens to expand BKV-specific T lymphocytes in humans.
Positive results were observed in research evaluating the efficacy of the
Transfer of BKV-reactive T cells adoptively.
In conclusion, Polyomaviridae BKV is acquired in childhood. Renal transplant recipients are at risk of allograft loss because of BK virus . Over-immune suppression is the great concern. Biopsy and immunohistochemistry (SV 40) determine the diagnosis, but one-third of patients have negative biopsies. BKV viremia and urine decoy cells aid diagnosis. The treatment approach consists primarily of Immune suppression reduction and monitoring for response or rejection. Antibiotics and other adjunct medicines need more research.
I agree with you analysis of this article provides.
Please summarise this article.
BK Virus :
Is a polyomavirus, small non enveloped DNA virus, affects immunocompromised patients, supposed to be due to heavy immunosuppression( ATG,Tacrolimus and MMF), 4 gdenotypes has been identified.
RISK FACTORS:
Diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci, ABO I transplants, and D+/R- (Serostatus of donor and recipient).
Routes of transmission:
Airborne transmission through air droplet.
Feco-oral transmission.
Urinary-oral route.
Blood transfusion and vertical transmission.
Clinical Picture of BK virus infection:
90% of population become seropositive during their life.
Tubulointerstial nephritis, uretric stricture and graft dysfunction are the presentations in solid organ transplantation.
Hemorrhagic cystitis in bone marrow transplant patients.
In kidney transplant BKV present in the first year post tratnsplantation, mostly asymptomatic, can present with progressive elevation of serum creatinine, or progressive kidney damage proved by kidney biopsy (BKVN).
Laboratory findings: elevated creatinine, decoy cells, pyuria, hematuria, and cellular casts in urinalysis.
Diagnosis of BKV :
– Kidney biopsy is the gold standard definitive diagnostic tool.
Light microscopy:- : (1) basophilic intranuclear viral inclusions. (2) anisonucleosis, hyperchromasia, and chromatin clumping of infected cells. (3) areas of tubular damage showing interstitial mononuclear or polymorphonuclear cell infiltrates. (4) tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining. (5) tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
Electron microscopy:- (1) viral inclusions with diameter size ranging from 30 to 50 nm. (2) tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts.
Patterns of BKVN : Pattern A= Cytopathic/cytolytic changes with absent or minimal inflammation. Pattern B= Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy. Pattern C= Graft sclerosis.
– Quantitative blood BKV PCR. >60-100 copies/ml + pathological findings.( sensitivity 100%, specificity 88%).
– Urinary BKV PCR > 10000 copies/ml.(sensitivity 70%, specificity 70%).
– Anti BKV can increase in both primary infections and reactivation of infections.
– Viral culture takes long time so clinically inapplicable.
– Haufen/urine electron microscopy, a cast-like 3-dimensional polyomavirus aggregates.(sensitivity 100%, specificity 99%). The study cannot discriminate between rejection and BKVN.
Differential diagnosis:
Other viral infections: CMV, HSV, and adenovirus.
Acute rejection.
Patients with a higher viruria level are highly prone to developing BKV viremia, and patients with high sustained viremia are susceptible to BKVN.
Therapeutic interventions:
The gold standard approved therapeutic intervention is immunosuppression reduction by 50% or more of both antimetabolites and CNI, and reduction of steroids as well.
Cidofovir, Leflunomide, are of limited evidence needs further studies.
Intravenous immunoglobulins, are of limited evidence may be used.
Fluoroquinolone, in vitro there is some inhibitory effects, in vivo no evidence, but may be protective of BK virema.
Adoptive immunotherapy, is a possible premature treatment option.
Conclusion:
BKV is a DNA virus from, a human polyomavirus, with incidence of 10% in renal transplant patients, depends on the immunosuppression dosage, other risk factors includes, DM , old age recipients, male, old CMV infection, HLA missmatch and ABOi transplants, acute rejection, and delayed graft function.
The gold standard diagnostic tool is kidney biopsy, and reduction of immunosuppression is the treatment of choice up till now.
What is the level of evidence provided by this article?
Level of evidence V – review article.
I agree with you analysis, summary and level of evidence this article provides.
Introduction
Risk factors for viremia
A- The intensity of immunosuppression
B- Donor factors
C- Recipient factors
Clinical presentation 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
And
B- Positive IHC test for SV40 antigen
BK nephropathy is classified into 3 classes
NB : pvl 1 (tubulitis <1%), pvl 2( tubulitis 1-10%), pvl 3 (tubulitis > 10%)
Treatment
What is the level of evidence provided by this article?
I agree with you analysis, summary and level of evidence this article provides.
Summary
BKV infection occurs 10 to 13 months post transplant. BK virus nephropathy may occur earlier at week 1 posttransplant or as late as 5 years posttransplant.
The mean prevalence of BKVN in renal transplant recipients is 5%
The viruria in a potential donor can be considered as a predictor for posttransplant BKV infection.
Graft dysfunction – failure risk factors
heavy immunosuppression the main risk factor most commonly tacrolimus and mycophenolate mofetil based- immunosuppressive agents can affect T cells, use of antilymphocyte antibodies,maintenance steroid immunosuppression,
Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy, possibly due to heavy immunosuppression (whether due to induction or maintenance immunosuppression or episodes of rejection).
elderly recipients male sex -white race/ethnicity,
prior rejection episodes- prolonged cold ischemia time
human leukocyte antigen mismatching-delayed graft function, treated episodes of acute rejection, and presence of specific human leukocyte antigen (HLA) C loci.
ureteral stenting.ureteral trauma
pretransplant BK virus serostatus- coinfection with Cytomegalovirus (CMV)
diabetes mellitus
Laboratory findings
(1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.However, these results could be normal
Diagnosis
A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN; however, a diagnosis may be missed in the tissue obtained because viropathic lesions are patchy. In addition, for BKV, tropism is medulla, not the cortex, which may increase the risk of missing the viropathic lesions.
Quantitative PCR is used to diagnose BKV viremia, which demonstrates BKV replication whether there is renal involvement or not.
Definitive diagnosis of BK virus nephropathy A definitive diagnosis of BKVN requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection
Anti-BKV antibody does not seem to be protective; therefore, it can increase in both primary infections and reactivation of infections.
The utility of conducting BKV serology examinations before and after transplant is controversial because it is not entirely clear which antibodies are neutralizing.
The risk of developing a clinically significant BKV infection is high when transplant is performed between a positive BKV donor and a negative recipient viral culture
Viral culture is rarely used as a method for BKV infection detection outside the research setting.
Viral isolation from the clinical specimen can take weeks to months; therefore, this method is not clinically applicable.
Urine electron microscopy Urine examinations using negative-staining electron microscopy for patients with BKV infection will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen
In a retrospective single-center study
Haufen presence was shown to be associated with 100% sensitivity and 99% specificity for biopsy-verified BKVN in kidney transplant recipients.
In addition, a relationship was reported among Haufen, high-level BKV viremia (median copy 1 206 325 copies/mL), and the occurrence of acute kidney injury and BKVN.
However, urine analyses in patients with a low viremia (median of 26 959 copies/mL) did not show Haufen bodies. Thus, urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis in renal transplant recipients.
This diagnostic technique is of a great utility, especially in differentiating between BKVN and asymptomatic BKV infection. However, it remains to be determined whether this method can be used for diagnosis as it depends on a sophisticated analysis and it also requires a meticulous interpretation by pathologists. In addition, the study did not determine whether urine electron microscopy can discriminate between rejection and BKVN.
Management of BKV viremia
decrease immunosuppression
regular follow-up of BKV polymerase chain reaction (PCR)
continuous monitoring of renal functions in an attempt to prevent allograft
Currently, there are no available antiviral medications against BKV.
cellular immunotherapy
the idea of this approach depends on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
Identifying viral immunogenic antigens is necessary for successful generation of virus-specific T cells.
Brincidofovir a prodrug of cidofovir that is administered orally.
Leflunomide has antiviral properties against BKV in vitro.
Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression. The active metabolite of leflunomide (known as teriflunomide can be measured, which can be helpful in continuous monitoring of the level of leflunomide and avoid toxicity.
Further prospective controlled studies of leflunomide are needed to confirm the efficacy and safety of this drug against BKV infection
intravenous immunoglobulin contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKVN.
The evidence of using IVIG as adjunctive therapy for BKVN has been described in multiple case reports and case series however, no controlled studies have been reported.
fluoroquinolone antibiotics have been considered as potential agents for controlling BKV infection in renal transplant recipients
In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication in vitro
What is the level of evidence provided by this article?
Level III Evidence – other studies with essentially minimal design, ‘descriptive’ and lowest level of evidence
Why level 3?
Case-control study (therapeutic and prognostic studies); retrospective comparative study
honestly level of evidence not under stood if there is referrence
I will be grateful
THANKS
Virology Properties;
————————————————————————————
BK virus is a member of the family Polyomaviruses. This family is a double-stranded DNA virus with icosahedral symmetry. BK virus has been categorized serologically and genotypically into 4 groups (I to IV), with each one having a different virulence .
Transmission mechanism;
————————————————————————–
Primary BKV infection occurs in the first decade of life, on average at 4 to 5 years of age. Possible routes include the following:
(1) Airborne transmission through .
(2) Feco-oral transmission .
(3) Urinary-oral route or seroconversion after solid-organ transplant .
(4) Blood transfusion and vertical transmission .
Risk factors
——————————————————————————
1-The most important risk factor for developing BKV disease is the degree of immunosuppression rather than the type of immunosuppression used.
2-Diabetes mellitus.
3- Delayed graft function .
4-Treated episodes of acute rejection .
5-Ureteral trauma .
6-Use of antilymphocyte antibodies .
7- Coinfection with Cytomegalovirus (CMV) .
8- maintenance steroid immunosuppression .
9-older age .
10-white race/ethnicity .
11-Both HLA and ABO-incompatible transplants carry a higher risk of BKV nephropathy.
Clinical Picture of BK virus infection;
———————————————————————–
Clinical manifestations are as follows:
(1) Asymptomatic .
(2) slow and progressive increase of serum creatinine .
(3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Usually, BKV infection occurs 10 to 13 months post transplant.
BK virus nephropathy may occur earlier at week 1 post transplant or as late as 5 years post transplant.
Diagnosis Overview;
——————————————————————————
1-A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN; however, a diagnosis may be missed in the tissue obtained because viropathic lesions are patchy. In addition, for BKV, tropism is medulla, not the cortex, which may increase the risk of missing the viropathic lesions. A diagnosis of BKV in a renal biopsy could be missed in about 30% of cases .
2-Quantitative PCR is used to diagnose BKV viremia, which demonstrates BKV replication whether there is renal involvement or not.
3-BK virus nephritis is suspected when the clinical diagnosis of tubulointerstitial nephritis is suspected; however, there are no clinical features of tubulointerstitial nephritis that are unique to BKVN.
4-The presence of decoy cells in the urine analysis increases the suspicion of BKV nephritis, which should be followed by quantitative PCR of blood preferable to urine.
A definitive diagnosis of BKVN requires;
————————————————————————–
A-Characteristic cytopathic changes on the renal biopsy .
B- Positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection .
In the absence of definitive criteria for BKVN diagnosis ;
—————————————————————————————–
a presumptive diagnosis can be done if there is ;
1-Sustained (more than 2-week duration) urinary viral shedding .
2-Significant BKV replication (plasma DNA PCR load > 10 000 copies/mL), as detected using a specific assay with or without kidney dysfunction .
BKVN can be graded into 3 grades using Banff criteria according to the percentage of fibrosis and the amount of viral replication .
—————————————————————————————————–
Grade 1 Minimal viral replication in < 1% of biopsy with < 25% fibrosis
Grade 2 Any between grades 1 and 3
Grade 3 Marked virus replication in > 10% of cores with > 25% fibrosis
Specific Histologic Findings of BK Virus Nephropathy;
————————————————————————————————–
1-Pattern A Cytopathic/cytolytic changes with absent or minimal inflammation .
2-Pattern B Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy
3-Pattern C Graft sclerosis .
Differential diagnosis ;
———————————————————————————
BK virus infection can be similar to other types of viral infections (CMV, herpes simplex virus, adenovirus).
Therefore, to confirm a diagnosis of BKVN, a blood quantitative PCR showing > 60 to 100 BKV copies plus characteristically pathologic morphology results are needed.
Urine cytology findings for BK virus infections;
———————————————————————————
Urine examinations may reveal BKV-infected cells. The most characteristic abnormality of infected cells is an enlarged nucleus with a single, large basophilic intranuclear inclusion .
The presence of characteristic cytopathologic changes in infected cells (which have been called decoy cells due to their similarity to renal carcinoma cells) is strongly suggestive of polyomavirus infections.
Quantitative polymerase chain reaction;
—————————————————————————————
1-Sustained high viral DNA levels in the plasma of renal transplant recipients who have an appropriate clinical picture can suggest BKVN.
2- Patients with a higher viruria level are highly prone to developing BKV viremia, and patients with high sustained viremia are susceptible to BKVN.
3- BK virus DNA levels can alter weekly by 1 to 2 log-folds depending on the commercially available PCR assay. It is recommended that medical decisions, especially those with regard to alterations of immunosuppression, be made on the basis of trends in quantitative DNA levels rather than on a single measurement.
Serology;
————————————————————
1-It is not helpful to examine serum for anti-BKV antibodies for a definitive diagnosis of BKV infection because positivity for these antibodies is quite common in the general population.
2- Anti-BKV antibody does not seem to be protective; therefore, it can increase in both primary infections and reactivation of infections.
Viral culture;
———————————————–
Viral isolation from the clinical specimen can take weeks to months; therefore, this method is not clinically applicable.
Urine electron microscopy;
—————————————————–
1-Urine examinations using negative-staining electron microscopy for patients with BKV infection will show cast-like 3-dimensional polyomavirus aggregates, which are called Haufen .
2- It depends on a sophisticated analysis and it also requires a meticulous interpretation by pathologists.
3- The presence of a high load of Haufen with equivocal biopsy would highly support the possibility of BKVN rather than rejection as a cause of allograft dysfunction, which could support medical decisions of reduction of immunosuppression rather than augmentation as in cases of rejection.
Therapeutic interventions;
————————————————-
1-immunosuppression reduction.
——————————————————————————-
Despite the fact that reduction of immunosuppression has been the cornerstone in the management of BKV infection, it also carries a higher risk of rejection, making this decision challenging.
2- Cidofovir;
———————————————————-
One of the limitations of this approach is nephrotoxicity, thus making the decision to use cidofovir unlikely.
3- Brincidofovir (CMX001);
———————————————————-
Because of the nephrotoxicity with cidofovir, scientists had developed brincidofovir, which is a prodrug of cidofovir that is administered orally. Phase 3 clinical trials have shown a lower incidence of nephrotoxicity with brincidofovir.
4- Leflunomide;
———————————————————-
Leflunomide is an immunosuppressant agent that also has antiviral properties against BKV in vitro. Side effects of leflunomide include thrombotic microangiopathy, hepatitis, and bone marrow suppression.
5-intravenous immunoglobulin;
———————————————————————-
Intravenous immunoglobulin (IVIG) contains neutralizing antibodies against BKV, which makes it a good choice in the management of BKVN. The immunomodulatory effects of IVIG may guard against allograft rejection in the context of reduced immunosuppression.
6- Fluoroquinolone;
———————————————————————
In vitro studies have shown that fluoroquinolone antibiotics can inhibit replication of BKV or SV40 polyomavirus replication in vitro; therefore, fluoroquinolone antibiotics have been considered as potential agents for controlling BKV infection in renal transplant recipients.
Role of cellular immunotherapy in the management of BKv infection;
—————————————————————————————————
Therefore, the idea of this approach depends on the transfer of primed BKV-reactive T cells, which may help in controlling the BKV-associated disease.
Research on treating BKV-associated diseases using immunotherapeutic approaches is still in the early stages, and data on immunodominant BKV epitopes for T-cell priming are limited.
What is the level of evidence provided by this article?
Level V .
I agree with you analysis, summary and level of evidence this article provides.
I- Summary:
Virology:
– One of the polyomaviruses (double-strand DNA)
– KK virus has 4 genotypes (I-IV).
Transmission mechanisms:
1- Airborne transmission through air droplets
2- A feco-oral transmission.
1- Urinary-oral.
2- Blood transfusion and vertical transmission; as BKV DNA has been found in the placenta, brain, and renal tissue of aborted fetuses
· Primary polyomavirus infections usually occur during childhood through respiratory or oral routes.
· It is usually asymptomatic and the virus remain in renal epithelium (tubules)
· It becomes reactivated in immunocompromised patients.
Risk factors:
1- The degree of immunosuppression.
· Most common with tacrolimus and mycophenolate mofetil based IS.
· Immunosuppressive agents can affect T cells, which can lead to increased BKV replication.
2-Other risk factors: DM, delayed graft function, treated episodes of acute rejection, ureteral
trauma, coinfection with CMV, maintenance steroid use, older age and white
race/ethnicity.
3- Transmitted infection from the donor (the risk is high with D+ and R-)
4- ABO and HLA incompatible transplantation.
Clinical picture:
– About 90% of the population will become BKV seropositive during their life.
– It reactivates after bone marrow and renal transplantation
– In kidney transplant recipients, reactivation may lead to BKVN, which may end with graft dysfunction and failure by causing tubule-interstitial nephritis and/or ureteral obstruction.
– In bone marrow transplant recipients, BKV can lead to hemorrhagic cystitis.
– Usually, BKV infection occurs 10 to 13 months post-transplant. BK virus nephropathy may occur earlier at week 1 post-transplant or as late as 5 years post-transplant
Clinical manifestations are
1- Asymptomatic
2- slow and progressive increase of serum creatinine
3- An unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Laboratory findings: (may be normal)
a- Elevated serum creatinine
b- Urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells.
Diagnosis of BK virus infection:
1- Renal biopsy:
· Basophilic intra-nuclear viral inclusions.
· Anisonucleosis, hyperchromasia, and chromatin clumping of infected cells.
· Areas of tubular damage showing interstitial mononuclear or polymorphonuclear
cell infiltrates.
· Tubular injury: tubular cell apoptosis, desquamation, and flattened epithelial lining.
· Tubulitis with lymphocyte invasion to the basement membrane.
2- Presence of urine decoy cells (infected cells with an enlarged nucleus with a single, large basophilic intranuclear inclusion) and viral shedding.
N.B: decoy cells is not specific to BKV infection ( can be present with CMV or other polyoma viruses) and poorly correlated with BKVN.
3- Confirmed by quantitative PCR ( in blood is preferred) > 10000 copies/ml (sensitivity 100% and specificity 80%)
Both can diagnose infection in case with normal biopsy.
4- Serology:
Not recommended to test for BK virus antibodies.
DD: CMV infection, adenovirus and HSV.
Therapeutic intervention:
II- level of evidence: V
I agree with you analysis, summary and level of evidence this article provides.
Introduction:
Virology:
Clinical features:
Diagnosis:
Treatment:
Level of evidence is 5
I agree with you analysis, summary and level of evidence this article provides.
Introduction
BK polyomavirus (BKV) is highly prevalent in immunocompromised patients. The average incidence is
about 10% KTRs.
Virology
It is a ds-DNA virus, a member of the family Polyomaviruses, and has genotype (I to IV) with different virulence.
Transmission mechanism:
*Route of transmission:
– Airborne transmission
– Feco-oral or urinary-oral transmission.
– Blood transfusion
– Vertical transmission.
*Primary BKV infection occurs early in life during childhood and often clinically insignificant.
*Latent infection: followed the 1ry infection) the virus stays in the renal epithelium and becomes dormant until it is reactivated
* BKV replication in immunocompetent population; asymptomatic viruria, ( viral shedding 20%)
*immunocompromised individuals, shedding reaches 60% and the viruria is more common.
Risk factors and pathogenesis
– Impaired cell-mediated immunity increase the risk of BKV.
-The degree of immunosuppression rather than the type used ( The most important risk factor ).
– Others; diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of rATG, coinfection CMV, maintenance steroid IS, older age, white race/ethnicity, and presence of specific (HLA) C loci.
– High donor BKV antibody titers, donor viruria is a predictor for posttransplant BKV infection.
– HLA and ABO-incompatible transplants.
Clinical Picture of BK virus infection:
– BKV infection occurs as early as 1 week or as late as 5 years posttransplant
– Asymptomatic, no signs and symptoms.
– Slow and progressive increase of serum creatinine.
– BKVN on surveillance biopsy may end with graft dysfunction and failure by causing tubulointerstitial nephritis and/or ureteral obstruction.
– In HSCT, BKV can lead to hemorrhagic cystitis.
Laboratory findings
– elevated serum creatinine and
– urine analysis with pyuria, hematuria, and findings of interstitial nephritis as cellular casts
Diagnosis Overview
-A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN; might be missed in 30 % as virus tropism is patchy and affect medulla. therefore, 2 core biopsies are needed for confirmation.
– PCR is used to diagnose BKV viremia. sensitivity and specificity about 100% and 88%,
– Characteristic; decoy cells in the urine analysis increases the suspicion of BKV nephritis.
– Serology anti-BKV antibodies: It is not helpful.
– viral culture not clinically applicable , only in research settin.
– Urine electron microscopy; urinary Haufen bodies can act as a noninvasive method for BKVN diagnosis.
Definitive diagnosis of BKVN;
-Requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens)
Presumptive diagnosis
if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication
(plasma DNA PCR load > 10 000 copies/mL), with or without kidney dysfunction.
– Different pathological patterns and associations with BKV infection
– Specific Histologic Findings of BK Virus Nephropathy
– BKVN can be graded into 3 grades using Banff criteria according to the percentage of fibrosis and the amount of viral replication.
Differential diagnosis
– BK virus nephropathy can be similar to cellular rejection, IHC and in situ hybridization used to differentiate
-It can be similar to other types of viral infections (CMV, herpes simplex virus, adenovirus).
Therapeutic interventions.
*Currently, there are no available antiviral medications against BKV.
*Approach in the management of BKV viremia or BKVN in renal transplant recipients is reduction of IS and continuous monitoring of BKV viremia level via PCR.
– Immunosuppression reduction; cornerstone, carries a higher risk of rejection.
Other agents used with reducing IS:
– Cidofovir; No RCT, associated with nephrotoxicity
– Brincidofovir; prodrug, less nephrotoxic, successful outcomes in renal and HSCT.
– Leflunomide; IS and antiviral properties.
– Intravenous immunoglobulin; neutralizing antibodies, used as adjunctive therapy, immunomodulatory
effects may guard against allograft rejection in the context of reducing IS.
– Fluoroquinolone; inhibit replication of BKV or SV40.
– Adoptive cellular immunotherapy; may carry potential hope
Level of evidence; narrative review level 5.
I agree with you analysis, summary and level of evidence this article provides.
Introduction
BK polyomavirus is DNA virus, highly prevalent causing infection in immunocompromised patients. BKV can cause tubulointerstitial nephritis and ureteral stenosis in renal transplant cases ; and in bone marrow transplant cases it can lead to haemorrhagic cystitis. BKV viremia main treatment is reduction of immunosuppression that can preserve allograft function, and follow up BKV PCR and renal function.
Balancing between rejection avoidance due to Immunosuppression reduction and immunosuppression continuation at the same level that can lead to BK viremia and BKV nephropathy.
Virology
Properties BK polyomavirus is divided into 4 groups of variable virulence.
Histological aspect It was detected in the ureteric lining of a Sudanese renal transplant recipient presented with urinary obstruction ,whom the virus was named from his initials
The Genome has nearly 5000 base pairs, which is stable at high temperature rendering it a virulent virus , it encodes 6 main proteins divided into 3 regions: early encoding region, late encoding region, and noncoding control region.
Transmission mechanisms
It usually occurs in the first decade of life transmitted through airborne ,feco-oral ,urinary -oral route or seroconversion after SOT ,through blood transfusion and vertical transmission.
Virus stays in the renal tubular, parietal, and transitional structures and in Bowman’s capsule. In
immunocompromised individuals, the risk of shedding reaches 60% and the viruria is more
common than in immunocompetent .
The risk of the infection increases in patients with impaired cell mediated immunity.
Risk factors and pathogenesis
Immunosuppression degree is the most important risk factor which is considered a marker of heavy immunosuppression possibly particularly associated with Tac( through a mechanism involving FK-binding protein) and MMF.
Other less common risk factors are diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with CMV, maintenance steroid , older age, white race ,specific HLA C loci , BKV Ab titers in donors , and HLA and ABO-incompatible transplants have a higher risk of BKV nephropathy specially ABO incompatible due to higher rejection risk.
Clinical presentation
90% of the population are BKV seropositive ,which is reactivated when a candidate is immunosuppressed as in kidney and bone marrow transplant recipients while it’s reactivation is rare in other immunocompromised cases.
In kidney transplant recipients, reactivation may lead to BKVN, graft dysfunction ,tubulointerstitial nephritis ,ureteric obstruction and failure .
In bone marrow transplant recipients, BKV can lead to haemorrhagic cystitis.
CP varies from being asymptomatic to gradual worsening of kidney function
BK virus nephropathy can occur early during first week of transplant or 5 years posttransplant.
Laboratory findings are variable ,urine analysis can show decoy cells which raises the suspicion of BKV nephritis.
A renal biopsy is mandatory for diagnosis presented by non specific tubulointerstitial lesions meanwhile the patchy nature of the virus and it’s involvement of the medulla increases the possibility of missing the diagnosis.
Quantitative PCR to detect BKV viremia and replication whether kidney is involved or not.
Definitive diagnosis of BK virus nephropathy represent pathognomonic cytopathic changes on the renal biopsy along with positive immunohistochemistry (against BKV or against SV40 large T antigens).
Presumptive diagnosis is done if there is sustained urinary viral shedding and significant BKV replication in the absence of definitive criteria for BKVN diagnosis .
BKVN can be divided into 3 grades using Banff criteria according to fibrosis percent
and the degree of viral replication.
BKV LM examination:
-basophilic intranuclear viral inclusions without a surrounding halo,
-anisonucleosis, hyperchromasia, and chromatin clumping of infected cells,
– areas of tubular damage with interstitial mononuclear or polymorphonuclear cell infiltrates -tubular injury in the form of tubular cell apoptosis, desquamation, and flattened epithelial lining,
-tubulitis with lymphocyte invasion to the basement membrane of the tubular epithelium.
– Differentiate between BKVN and allograft rejection.
BKVN, EM examinations :
-viral inclusions with diameter ( 30 to 50 nm )
-tubular damage, including tubular cell necrosis, prominent lysosomal inclusions, and luminal protein
and cellular casts.
BK virus nephropathy can mimic cellular rejection, in situ hybridization or immunohistologic methods are used to differentiate between both.
Differential diagnosis
BK virus infection can be similar to other types of viral infections
Urine cytology findings for BK virus infections
Urine analysis reveal BKV-infected cells, it is an enlarged nucleus with a single, large basophilic
intranuclear inclusion the decoy cells which is neither specific nor sensitive to BKV, quantitative urine PCR can be done as well.
Quantitative PCR
It is 100% sensitive and 88% specific in detecting BKV DNA .
Decreasing immunosuppression ,lead to disappearance of the virus DNA.
Viral replication in the urine as detected by urine cytology or demonstration of the virus by quantitative PCR .
During the first 6 months viremia can be detected and latter can decrease.
Cases having high viruria levels are more liable to have viremia and subsequently BKVN.
Since BKV level varies ,the decision of immunosuppression reduction need to be built on the basis of trends in quantitative DNA levels rather than a single measurement.
Serology
Positivity of BKV Ab is common therefore it cannot be used for diagnosis .
BKV Ig G titers are high during the first 6 weeks till 2 years after primary infection
The benefit of BKV serology examinations before and after transplant is controversial.
Viral culture is non applicable
Urine EM
It shows cast-like 3-dimensional polyomavirus aggregates (Haufen) it is highly sensitive and specific for BKVN.
It is relate to high BK viremia level, BKVN ,AKI.
It can differentiate between asymptomatic BKVN and asymptomatic BKV infection.
high level of Haufen along with equivocal biopsy can increase BKVN possibility rather than
rejection.
Treatment
Reduction of immunosuppression(RI)
The BKVN and rejection are can be similar histologically therefore treatment is challenging to reduce the immunosuppression which is the main treatment for BKVN.
In addition , immunosuppression alteration as a treat BKV infection increases the incidence of long term chronic rejection.
Cidofovir
It was studied with RI in the therapy but nephrotoxicity is a limitation for it’s use.
Brincidofovir
Is a prodrug of cidofovir orally taken with lower risk of nephrotoxicity.
Leflunamide
Is an immunosuppressive with antiviral role, Studies revealed it’s relation to viral load reduction but it’s drawbacks are thrombotic microangiopathy, hepatitis, and bone marrow suppression.
IVIG
In hypogammaglobulinemia, it had anti-BKV immunity; also it’s immunomodulatory effects of IVIG can guard against allograft rejection
Fluoroquinolone
Can inhibit replication of BKV or SV40 polyomavirus replication in vitro,also it was proposed to have a role in prevention of BKV infection.
At the time being there is no data to support it’s important role in BKV treatment
Cellular immunotherapy
Involve using primed BKV-reactive T cells for treatment.
A study used overlapping peptide pools from all 5 BKV antigens to expand BKVspecific human T cells.
There was positive outcomes for studies regarding the treatment of BKV infection using the
adoptive transfer of BKV-reactive T cells.
Conclusion
It’s diagnosis is challenging .BK virus nephropathy can be detected with BKV inclusions and immunohistologic analyses along with correlation of histologic findings with BKV PCR .
BKV infection treatment is active screening every 3 months after renal transplant, immunosuppression should be reduced along with continuous monitoring of BKV viremia levels using quantitative PCR and renal function test.
Cellular immunotherapy is under studies
-level of evidence is V
I agree with you analysis, summary and level of evidence this article provides.
This article discusses BK virus, starting from virology, and historical aspects to management.
Virology: BK virus is a member of the family Polyomaviruses. This family is a double-stranded DNA virus.
Transmission through: (1) airborne transmission through air droplets
(2) feco-oral transmission.
(3) other mechanisms, including urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation)
(4) both through blood transfusion and vertical transmission.
Risk factors:
· Importantly, the Degree of immunosuppression, commonly tacrolimus and mycophenolate mofetil based.
· Other risk factors that could be involved, although not common, include diabetes mellitus, delayed graft function, treated episodes of acute rejection, ureteral trauma, use of antilymphocyte antibodies, coinfection with Cytomegalovirus (CMV), maintenance steroid immunosuppression, older age, white race/ethnicity, and presence of specific human leukocyte antigen (HLA) C loci.
Clinical Picture of BK virus infection:
Clinical manifestations are as follows: (1) asymptomatic, (2) slow and progressive increase of serum creatinine, and (3) an unsuspected finding of progressive renal damage (BKVN) on surveillance renal allograft biopsy.
Usually, BKV infection occurs 10 to 13 months posttransplant.
Laboratory findings in patients with BKV infection are as follows: (1) elevated serum creatinine and (2) urine analysis with pyuria, hematuria, and findings consistent with interstitial nephritis as cellular casts composed of renal tubular cells and inflammatory cells. However, these results could be normal.
Diagnosis:
· A tissue (renal) biopsy is needed for a definitive diagnosis of BKVN; however, a diagnosis may be missed in the biopsied tissue.
· Urine examinations may reveal BKV-infected cells (decoy cells). The most characteristic abnormality of infected cells is an enlarged nucleus with a single, large basophilic intranuclear inclusion.
· High viral DNA PCR levels in the plasma of renal transplant recipients.
· Viral culture is rarely used as a method for BKV infection detection outside the research setting.
· Urine electron microscopy.
Therapeutic interventions include:
· Immunosuppression reduction
· Leflunomide
· Cidofovir and Brincidofovir (CMX001)
· intravenous immunoglobulin
· Fluoroquinolone
level of evidence: review article, level 5
I agree with your analysis, and the level of evidence this article provides.
Please summarize this article.
Introduction
Transmission
Risk factors:
Clinical picture:
Diagnosis:
Differential diagnosis:
Treatment:
Conclusion
-What is the level of evidence provided by this article?
I agree with your analysis, summary and level of evidence this article provides.
Introduction:
BK polyomavirus (BKV) is a common human polyomavirus, particularly in immunocompromised people. BKV may cause tubulointerstitial nephritis, ureteral stenosis, and hemorrhagic cystitis in renal and bone marrow transplant recipients.
Transmission mechanism:
Primary BKV infection develops around 4–5 years old. Possible routes:
(1) airborne transmission through air droplets;
(2) feco-oral transmission, as hospitalized children have fecally eliminated polyomaviruses;
(3) other mechanisms, such as urinary-oral route or seroconversion after solid-organ transplant (such as renal transplantation); and
(4) both blood transfusion and vertical transmission, as BKV DNA has been found in the placenta, brain, and renal tissue.
Risk factors and pathogenesis:
Clinical Picture of BK virus infection:
Range from Asymptomatic, slow-growing serum creatinine and BKVN on surveillance renal allograft biopsies are clinically symptomatic and may end with graft dysfunction and failure by causing tubulointerstitial nephritis and/or ureteral obstruction. BKV infection has no symptoms. BKV infection develops 10–13 months post-transplant.
BK virus nephropathy may emerge at week 1 or 5 years posttransplant.
Diagnosis of BK virus nephropathy:
The renal biopsy must show distinctive cytopathic alterations and positive immunohistochemistry (against BKV or SV40 big T antigens), which is 100% specific and pathognomonic for BKV infection. Because BKV has a localized tropism in the medulla rather than the cortex, a renal biopsy may miss BKVN in 30% of patients.
If there is prolonged (more than 2 weeks) urine viral shedding and considerable BKV replication (plasma DNA PCR load > 10,000 copies/mL), as measured by a particular test with or without kidney impairment, presumptive BKVN may be diagnosed.
Specific Histologic Findings of BK Virus Nephropathy:
Pattern A Cytopathic/cytolytic changes with absent or minimal inflammation
Pattern B Cytopathic/cytolytic changes associated with patchy or diffuse tubulointerstitial inflammation and atrophy
Pattern C Graft sclerosis
Laboratory Tests:
Therapeutic interventions:
1-immunosuppression reduction: Despite being the cornerstone of BKV infection management, immunosuppression decrease increases the chance of rejection, making this option difficult.
2-Cidofovir: Multiple single-center studies and case series have described the benefits of adding cidofovir with immunosuppression reduction. Nephrotoxicity makes using cidofovir improbable.
3-Brincidofovir: Brincidofovir reduces nephrotoxicity in clinical studies. Multiple case reports of brincidofovir-treated BKVN resulted in successful renal and hematopoietic transplants.
4-Leflunomide: Immunosuppressant leflunomide also inhibits BKV in vitro. It replaced mycophenolate in many case series. These studies have shown a substantial relationship between leflunomide and BKV viral load reduction, but they do not indicate the reason (i.e., immunosuppression reduction or leflunomide’s antiviral activities).
5-IVIG: treats BKVN because it includes BKV-neutralizing antibodies.
Multiple case reports and case series have described IVIG as a supplementary treatment for BKVN, but no controlled trials have been published.
6-fluoroquinolone: data suggest that fluoroquinolones do not currently have a clinically significant role in the management of BKV-related diseases.
7-cellular immunotherapy: This method involves transferring primed BKV-reactive T cells to manage BKV-associated illness.may carry potential hope for the treatment of BKV infection.
What is the level of evidence provided by this article?
Level 5, Narrative review
I agree with your analysis, summary and level of evidence this article provides.
Polyoma viruses are DNA virus.
It is characterised genetically into 4 groups.
BK virus is a polyoma virus affecting humans.
o Transmission
Primary BKV infection occurs in the first decade of life.
Routes –
Airborne
feco – oral
Urinary -oral route
Seroconversion often SOT
Blood transfusion
Vertical transmission
o Risk factor and pathogenesis
Degree of immunosuppression
DM
DGF
Ureteral trauma
treated episode of acute rejection
use of anti-lymphocyte antibody
coinfection with CMV
older age
maintenance steroid immunosuppression
older age
white race/ ethnicity
specific HLA – C loci
presence of BKV Titre in donor
H LAI and ABO i transplant
o Clinical Picture
asymptomatic
slow and progressive increase in Serum creatinine
progressive renal damage BKVN on surveillance renal allograft biopsy.
BKV infection occurs from 10th to 13th month post transplant
BKVN can our from 1 week post transplant to as late as 5years post transplant.
o Laboratory
Increased Serum creatinine
Urine shows pyuria, hematuria
BKV causes interstitial nephritis and/ or Urethral obstruction
o Diagnosis
Tissue biopsy, however involvement may be patchy.
BKV tropism in for medulla.
Quantitative PCR of body fluid
BKV infection mimics tubulointerstitial nephritis.
If decoy cells present in urine then QPCR to be done of blood rather than urine.
o Definitive diagnosis of BKVN
Requires characteristic cytopathic changes on renal biopsy
Plus
Positive immunohistochemistry against BKV or against SV40 large T antigens – specificity of 100%.
BY Can be missed on renal biopsy in 30%.
2 core biopsies are needed which include the media.
o Specific histologic findings
Pattern A – Cytopathic changes with no /or minimal in flammation.
Pattern B – Cytopathic changes with tubulointerstitial inflammation and atrophy.
Pattern C- graft sclerosis.
o Presumptive diagnosis
>2 week duration urinary viral shedding and plasma DNA PCR load > 10000 copies /mI.
With or without Kidney dysfunction.
o Banff grading for BKVN
Grade 1 – Minimal viral replication in<1% of biopsy with< 25% fibrosis
Grade 2- Any between grade 1 and 3
grade 3- Marked virus replication in >10% of cores with > 25% fibrosis.
o BKVN light microscopy
Basophilic intranuclear viral inclusion with surrounding halo.
anisonucleosis, hyperchromasia, and chromatin cIumping in cells.
interstitial infiltration with tubular damage
tubular cell apoptosis,desquannation and flattened epithelial lining.
tubulitis with lymphocyte invasion.
o BKVN EM
30 to 50nm sized viral inclusions
tubular cell necrosis, prominent lysosomal inclusions, luminal protein and cellular casts.
o D/D
CMV
H SV
adenovirus
So a blood QPCR showing > 60 to 100 BKV copies plus characteristic pathologic morphology is needed.
o Urine Cytology
Decoy cells- cell with enlarged nucleus with a single large basophilic intranuclear inclusion.
Urine Q PCR
decoy cells are Sensitive not specific
Decoy cells also seen in –
CMV
adenovirus
o QPCR
Sensitivity is 100% and specificity is 88%.
Viriuria precede viraemia by 4 weeks and nephropathy by 12 weeks.
Decision to be made on trends than single value.
Active screening every 3 months post renal transplant.
o Serology
Not useful
o Viral culture
Not clinically applicable
o Urine EM
Haufen bodies
Can act as an non-invasive method Dr BkvAN diagnosis.
o Therapeutic intervention.
Immunosuppression reduction
Cidofovir
nephrotoxicity
Brincidofovir
lower nephrotoxicity
Leflunomide
SIE
TMA
hepatitis
bone marrow suppression
Iv Ig
In patients with hypogammaglobulinemia may be beneficial.
also guards against rejection.
Fluoroquinolone
Currently no significant role
Cellular immunotherapy
Transfer of primed BKV reactive Tcells is being studied.
level 5 evidence