BK Virus Infection and Its Management in Renal Transplantation: An Update
All India Institute of Medical Sciences (AIIMS) Jodhpur, India
Manipal Hospitals, Jaipur, India
Fortis Escorts Hospital, Jaipur, India
Academic Editor: Deborah B. Adey
Received: April 10, 2023 | Accepted: July 06, 2023 | Published: July 14, 2023
OBM Transplantation 2023, Volume 7, Issue 3, doi:10.21926/obm.transplant.2303192
Recommended citation: Chakrabarti U, Chaurvedy M, Bajpai NK, Goswami J, Garsa RK, Jhorawat R. BK Virus Infection and Its Management in Renal Transplantation: An Update. OBM Transplantation 2023; 7(3): 192; doi:10.21926/obm.transplant.2303192.
© 2023 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
BK virus (BKV) is a common opportunistic pathogen in kidney transplant recipients and one of the most challenging causes of allograft dysfunction and loss. This virus was named after a Sudanese kidney transplant recipient with ureteric stenosis who was the first patient to have BKV isolated from urine . BK virus is a small DNA virus that establishes lifelong infection in the renal tubular and uroepithelial cells of most of the world's population. Though quiescent and benign in the majority, immunocompromised BKV can reactivate, and in some, lead to BKV-associated nephropathy (BKVAN). BKV reactivation is common among kidney transplant recipients and is a risk factor for premature allograft loss. Therefore screening for reactivation is recommended for all kidney transplant recipients after transplantation. Reduction of immunosuppression is the cornerstone of management, and no specific antiviral or immunomodulatory therapy is sufficiently effective for routine use.
BKV is a ubiquitous virus with a worldwide seroprevalence of 80-90 percent. Primary infection is usually acquired in childhood, possibly via fecal-oral or respiratory transmission. The virus establishes lifelong infection in renal tubular and uroepithelial cells following primary infection. For most individuals, primary and persistent infections are clinically silent and not associated with known adverse effects .
Among kidney transplant recipients, reactivation of latent infection or transmission of new infection via the donor's kidney can lead to viruria (detection of intact virus or virus components in urine), viremia (detection of viral DNA in thae blood), or allograft nephropathy (demonstration of virus or virus components in allograft tissue) . Viral replication commonly occurs during the first year after transplant when cellular immunity is most suppressed. Viruria and viremia are detected in approximately 25-30 and 12 percent of kidney transplant recipients, respectively , and almost invariably precede the development of nephropathy in a stereotypical pattern of viruria, followed by viremia, followed by BKV-associated nephropathy (BKVAN). Approximately 1-10 percent of kidney transplant recipients will develop BKVAN . Though historically associated with more than 50%  graft loss rates, with the implementation of standardized screening protocols, rates of short-term graft loss have fallen substantially .
2.2 Risk Factors
The intensity of immunosuppression appears to be a dominant risk factor for BKV replication and disease. Replication rates are higher in the early posttransplant period and following treatment for allograft rejection when the intensity of immunosuppression is highest. Thymoglobulin, either as induction therapy or treatment of rejection, increases the risk for BKV infection whereas neither alemtuzumab nor interleukin 2 receptor antibody (i.e., basiliximab) use appears to increase the risk . The risk for BKV replication is increased with higher cumulative steroid dose , corticosteroid pulses as rejection treatment, and steroid maintenance compared with steroid withdrawal regimens .
No specific immunosuppressive drug or regimen has been definitively associated with clinically significant BKV infection . Several studies have suggested that certain drugs (particularly tacrolimus) may be associated with an increased relative risk . In contrast, others (e.g., mammalian [mechanistic] target of rapamycin [mTOR] inhibitors) may be associated with a lower relative risk . However, BKV replication and BKVAN have occurred in patients receiving nearly all immunosuppressive drugs and their combinations . High-risk serostatus (i.e., kidney transplant from a BKV-seropositive donor to a seronegative recipient) , impaired immune response to BKV , and donor BKV viruria prior to transplant  contribute to higher risk. Other risk factors with an increased risk of BKVAN include older age , ureteral stent placement , ABO incompatibility , rejection or ischemia of the transplanted kidney , delayed graft function , HLA mismatch , specific HLA-C alleles , BKV polymorphisms , and transplantation from an HCV-positive donor . Factors associated with decreased risk include recipient HLA-B51 positivity , and polycystic kidney disease .
BK polyomavirus is a small (30 to 45 nm), icosahedral, nonenveloped, double-stranded, closed circular DNA virus . The 5 kb genome encodes six viral proteins-two "early" nonstructural or enzymatic proteins, an apoprotein, and three "late" proteins. The early proteins are the large tumor antigen or "T antigen," the small tumor antigen, or the "t antigen." The T antigen is responsible for cell immortalization and the establishment of latent infection. The agnoprotein helps in the assembly of viral particles. The three "late" viral capsid proteins, VP-1, VP-2, and VP-3, mediate cell entry and progeny virion assembly.
Mutations in noncoding control regions can be progressively acquired during an infection, leading to altered cell tropism, permissivity (i.e., cell types supporting viral replication), and replication rates . Virulence may also vary among serotypes, which differ genetically and in their cellular tropism. Serotype I is the most prevalent and is responsible for most human diseases. Neutralizing antibodies to one serotype does not appear to confer protection against others .
Insufficient cellular immune control is presumed to be an important part of BKVAN pathogenesis . After primary infection, which typically occurs in childhood, BKV maintains persistent infection in the renal and uroepithelium (transitional epithelium, renal tubular epithelium, and parietal epithelium of Bowman's capsule) of most individuals . Control of this persistent infection is dependent on CD4+ and CD8+ T cell immunity . When immune control is disrupted as with immunosuppressive drugs, BKV begins to actively replicate.
As viral replication persists, injury to the renal tubular epithelium results from direct viral replication and cell turnover. Subsequent inflammation and fibrosis lead to further injury and ultimately tubular atrophy, necrosis, and nephron loss . The inflammatory milieu may further promote viral replication and perpetuate injury . Transcriptional analysis of kidney allograft tissue in BKVAN has demonstrated the upregulation of multiple inflammatory pathways that overlap considerably with those seen in acute allograft rejection .
2.5 Clinical Manifestations
ssBKV replication typically develops in stages in kidney transplant recipients: viruria followed by viremia if viral replication persists, nephropathy.
2.6 Viruria and Viremia
Viruria is the earliest manifestation of BKV infection in kidney transplant recipients, affecting approximately one-quarter to one-third of patients during the first year of transplantation . Viruria is mostly asymptomatic, detected only by screening, and does not progress to viremia. Though viruria is a sensitive marker for progression to BKVAN, it is nonspecific . Shedding of BKV in the urine as detected by PCR methods is common among otherwise healthy older adult patients, pregnant women, and patients with suppressed cellular immunity. It is generally without any clinical consequence . Urine decoy cells (renal tubular or uroepithelial cells containing intranuclear viral inclusions), which typically represent higher-level viruria, may be present at this stage. However, they do not have a significant prognostic value for progression to viremia than detection of viruria by more sensitive methods such as PCR.
Viremia may follow viruria in a few weeks and occurs most frequently in those with high urine viral loads and sustained viruria. Viremia is detected in 10 to 30 percent of recipients in the first six months posttransplantation and 5 to 10 percent thereafter. Viremia is typically asymptomatic. However, viremia carries a greater predictive value than viruria for progression to BKVAN . Viremia is present in nearly all patients with BKVAN and has a positive predictive value of approximately 40 to 65 percent for the development of BKVAN. Since BKVAN can follow viremia (usually within one to two weeks) and the graft damage can be irreversible, viremia is generally accepted as an indication to reduce immunosuppression. Higher viral loads and sustained viremia have greater predictive value for concomitant or progression to biopsy-confirmed BKVAN .
2.7 BKV-Associated Nephropathy (BKVAN)
Asymptomatic viruria, viremia, and/or a slow progressive rise in serum creatinine are typically the only indicators of BKVAN. The incidence of BKVAN is highest in the first 6 months posttransplant. While most cases occur in the first posttransplant year, they can occur years after transplant. The incidence of late BKVAN appears to be highest in patients with multi-organ transplants and is possibly related to the more intensive immunosuppressive regimens .
Progressive kidney allograft dysfunction and graft loss can ensue over months without resolution of infection . Early infection triggers interstitial inflammation within the allograft progressing to fibrosis and tubular injury. Urinalysis may reveal pyuria, hematuria, cellular casts of renal tubular cells and inflammatory cells, or may be normal. Reduction of immunosuppression is the primary means of restoring immunity and control of BKV replication. However, this also carries a risk of rejection, which can be difficult to distinguish clinically from progressive BKVAN .
2.8 Ureteral Stenosis
BKV infection has been implicated in late ureteral stenosis (>1 month posttransplantation). Ureteral infection is initially focal, followed by a destructive phase in which the uroepithelium and smooth muscle cells are affected. This phase is characterized by marked inflammation and ulcerations, ultimately leading to ureteral stenosis. Clinically it is characterized by asymptomatic hydronephrosis leading to a decline in GFR with the diagnosis confirmed by ultrasound. BKV replication should therefore be sought for in cases of late ureteral stenosis especially in mid ureteric strictures .
2.9 Other Manifestations
Case reports exist of BKV causing pneumonitis, retinitis, vasculopathy, meningoencephalitis, and Guillain-Barre syndrome, among other manifestations . Hemorrhagic cystitis is a rare manifestation of BKV infection in kidney transplant recipients and is mostly reported in hematopoietic cell transplant recipients . There is a putative link between BKV and the development of genitourinary cancers, largely based on animal models . However, a causal role for BKV and human malignancies has not been established.
2.10 Screening and Diagnosis
Patients should be screened with a quantitative plasma BKV PCR at the following time points:
- Monthly for the first six months following transplant, then every three months until two years posttransplant, and then annually until five years posttransplant .
- Whenever kidney allograft dysfunction occurs or when an allograft biopsy is performed for allograft dysfunction .
Generally, levels >1000 copies/mL are considered positive in most assays, and levels >10,000 copies/mL correlate with biopsy-confirmed BKVAN. For patients with viremia (e.g., viral loads >1000 copies/mL) and normal allograft function, the immunosuppression is reduced and viral load is monitored every 2-4 weeks to ensure it is downtrending. For patients with viremia and new-onset allograft dysfunction, the immunosuppression is reduced and viral loads are monitored every 2-4 weeks after that when the clinical picture points towards BKVAN. Allograft biopsy should be considered if the cause for allograft dysfunction is uncertain or if kidney dysfunction and/or viremia fail to resolve despite reducing immunosuppression .
3. Testing Methods
3.1 Plasma Quantitative PCR
Quantification of plasma BKV DNA by real-time polymerase chain reaction (PCR) is the preferred screening test for BKVAN . It is both sensitive (100%) and specific (88%) for the diagnosis of BKVAN and has a higher positive predictive value for BKVAN than the detection of viruria by urine quantitative PCR or urine cytology (50 to 60 percent versus 40 and 29 percent, respectively) .
Plasma PCR can monitor the patient's response to therapy since a decrease in BKV viremia usually occurs soon after a reduction in immunosuppression and precedes a decrease in viruria by weeks to months . Even in the absence of histologic evidence of BKVAN, persistent high-grade viremia is associated with worse allograft function and risk of allograft loss . Though no established threshold levels for BKV viremia predict BKVAN most centers agree that a BKviral load of ≥10,000 copies/mL, particularly when sustained for more than three weeks duration is highly suggestive of BKVAN .
3.2 Urine Quantitative PCR
Urine quantitative PCR for BKV DNA is not recommended though some centers prefer it given its high sensitivity and less invasive nature. Patients found to have viruria require confirmation with quantitative plasma PCR as around half of the patients with BK viruria will not develop viremia or BKVAN . Furthermore, urine PCR for BKV DNA is not as useful as plasma PCR for monitoring the response to therapy as changes in the urine viral load lag behind the plasma viral load upon lowering immunosuppression. However, some studies suggest that the detection of high-grade viruria might be helpful to predict clinically significant viremia .
3.3 Urine Cytology
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 BKV infection, urine cytology is less sensitive and specific for the diagnosis of BKVAN compared with plasma quantitative PCR. The diagnostic utility is further limited by interobserver variability and this test’s qualitative, rather than quantitative, nature .
3.4 Donor-Derived Cell-Free DNA (dd-cfDNA)
The association of dd-cfDNA with plasma BK viral loads and biopsy findings was evaluated in a study to determine whether dd-cfDNA can distinguish asymptomatic BKV from BKVAN . It demonstrated that higher dd-cfDNA levels were associated with higher BK viral loads, biopsy-diagnosed BVAN, and histologic changes meeting Banff criteria for T-cell-mediated rejection. These preliminary findings show that dd-cfDNA may be a useful noninvasive test to assess for progression of BKV to BKVAN .
3.5 Kidney Allograft Biopsy
Kidney allograft biopsy is the gold standard for diagnosing BKVAN, assessing its severity, and evaluating concomitant processes. However, since biopsy is invasive and associated with sampling, a presumptive diagnosis is often made based on significant viremia (plasma BK viral load ≥10,000 copies/mL).
A definitive diagnosis of BKVAN requires the following findings on kidney biopsy :
- Characteristic cytopathic changes plus.
- Positive immunohistochemistry tests using antibodies directed specifically against BKV or against the cross-reacting SV40 large T antigen. Positive SV40 staining is associated with a specificity of almost 100% for polyomavirus nephropathy, although it does not distinguish between BKV and JC virus-associated cases.
Because of the focal nature of early BKVAN, the diagnosis may be missed in one-third of biopsies. As a result, at least two biopsy cores, preferably including the medulla, should be examined as BKV is more likely to be present in the medulla. A repeat biopsy should be considered if the initial biopsy does not confirm BKVAN .
3.6 Histologic Findings
BKVAN is associated with characteristic histologic findings on kidney biopsy:
- Intranuclear basophilic viral inclusions without a surrounding halo.
- Anisonucleosis, hyperchromasia, and chromatin clumping of infected cells.
- Interstitial mononuclear or polymorphonuclear cell infiltrates the areas of tubular damage.
- Tubular injury, is characterized by tubular cell apoptosis, cell dropout, desquamation, and flattened epithelial lining.
- Tubulitis, which is manifested by lymphocyte permeation of the tubular basement membrane. When extensive, it is difficult to differentiate BKVAN from allograft rejection .
With electron microscopy, intranuclear viral inclusions (with a diameter size of 30 to 50 nm) and tubular damage characterized by tubular cell necrosis, lysosomal inclusions, and luminal protein and cellular casts are seen.
The Banff Working Group on Polyomavirus Nephropathy 2017 established a classification system that defined three histologic classes of definitive (biopsy-proven) BKVAN based on two morphologic variables: intrarenal polyomavirus replication/load levels (pvl) and Banff interstitial fibrosis (ci) score . The pvl score is based on the extent of virally induced tubular changes. A tubule with intranuclear viral inclusion bodies (type 1 or 2) and/or a positive immunohistochemical reaction for SV40 large T antigen in one or more cells per tubular cross-section is considered "a positive tubule." The overall percentage of positive tubular cross-sections is estimated in the entire biopsy sample (i.e., all available cores and all tubules/ducts in the cortex and medulla) and three levels of pvl are defined: pvl 1 ≤ 1 percent, pvl 2 = 1 to 10 percent, pvl 3 ≥ 10 percent positive tubules/ducts. The three histologic classes of PVN are as follows :
- PVN class 1 – pvl 1, ci ≤ 1
- PVN class 2 – pvl 1, ci ≥ 2 or pvl 2, any ci score or pvl 3, ci ≤ 1
- PVN class 3 – pvl 3, ci ≥ 2
Though found to correlate with clinical outcomes  in a retrospective analysis of 178 patients, the same correlation was not documented across all studies . SV40 T antigen stain may be falsely negative due to sampling error and/or limited staining sensitivity. Persistent high-level viremia is the most significant risk factor for allograft loss. However, no single clinical or pathologic feature could predict the clinical course of BKVAN in an individual patient. A high proportion of cases eventually evolve into interstitial fibrosis and tubular atrophy despite the treatment of BKVAN which highlights the importance of prevention over treatment strategies .
3.7 Distinguishing BKVAN from Rejection
Allograft rejection may closely resemble BKVAN on kidney biopsy . Distinguishing BKVAN from allograft rejection is important since treatment for presumed rejection with increased immunosuppression may result in allograft loss if BKVAN is present. BKVAN is distinguished by the presence of BKV inclusions and immunohistologic or in situ hybridization evidence of virally infected cells, usually tubular epithelial cells, rather than podocytes or endothelial cells . It is important to correlate the histologic findings with PCR evidence of viremia.
Diagnosing concomitant T cell-mediated rejection and BKVAN is difficult because of similar histologic features . Extensive tubulitis in areas remote from the viral cytopathic changes suggests that acute rejection BKVAN are present. The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of concurrent rejection. However, some patients with BKVAN without concurrent rejection may have C4d deposits in the tubular basement membrane . In some patients, distinguishing BKV infection from rejection may be possible by empirically altering the immunosuppressive regimen and observing the clinical response.
3.8 Other Diagnostic Methods
Negative-staining electron microscopy of the urine of patients with BKVAN often reveals cast-like, three-dimensional polyomavirus aggregates, termed Haufen. Haufen form in injured tubules with BKV replication and a high intratubular uromodulin concentration and are excreted like 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 BKVAN of greater than 95 percent , suggesting that this might be a noninvasive way to diagnose BKVAN. However the limiting factor lies in the usage of electron microscopy for diagnosis. Therefore it is not a widely used screening test, however may be used in certain scenarios, such as in pediatric patients or when a kidney allograft biopsy cannot be safely performed.
With no specific antiviral therapies, the cornerstone of BKVAN management is reduced immunosuppression. This approach applies to both the prevention of BKVAN in detected BKV viremia and the treatment of established BKVAN. Protocols, however, vary among centers and are often individualized.
3.10 Reduction of Immunosuppression
Approaches to reducing immunosuppression vary among centers, and no randomized controlled trials directly compare different protocols. A plasma BKV quantitative PCR is obtained prior to the reduction of immunosuppression. It is monitored every 1-2 weeks until BKV DNA is undetectable for two consecutive tests obtained at least one week apart. The serum creatinine level is monitored weekly. If it increases by ≥25 percent from baseline at any time during reduction of immunosuppression, evaluation should be done for a possible acute rejection.
For patients not having concurrent acute rejection and on triple immunosuppression (calcineurin inhibitor, antimetabolite, steroid), the antimetabolite is reduced by 50 percent. The antimetabolite is completely discontinued if the BKV viral load does not decrease within 2-4 weeks. If there is still no decrease in viral load after another two weeks, the CNI dosage is reduced by 25-50 percent, targeting a whole blood tacrolimus trough level of 4 to 6 ng/mL or a whole blood cyclosporine trough level of 60 to 100 ng/mL. An alternative approach is to first decrease the CNI dosage by 25 to 50 percent, then reduce the antimetabolite by 50 percent, and discontinue the antimetabolite .
A similar approach can be followed for patients on steroid-free regimens as for patients on triple immunosuppression. Alternatively, both the CNI and antimetabolite dosage can be reduced concomitantly, allowing targeting of two pathways and lowering the total immunosuppression. In one meta-analysis of observational data from 40 studies, graft loss rates were similar when comparing the reduction in immunosuppression alone versus the reduction of immunosuppression plus either cidofovir or leflunomide . Similar findings have been reported in subsequent cohort studies .
3.11 Role of Adjunctive Therapies
The initial approach of decreasing immunosuppressives is effective in most patients. For those with progressive allograft dysfunction despite a maximal decrease in immunosuppressive therapy for a period of several weeks to months and who also have severe hypogammaglobulinemia (IgG <400 mg/dl), IVIg can be attempted though the efficacy is unproven. Suppose administered is usually given at a dose of 300 mg/kg every 3 weeks along with a reduction of immunosuppression with a repeat IgG trough level after 3 months of therapy with a goal of IgG >400 mg/dl [53,54,55,56].
There is no role of leflunomide, cidofovir, or quinolone antibiotics .
Leflunomide is a prodrug with its active metabolite having both immunosuppressive and antiviral activity . However, the routine use of leflunomide is avoided in view of its uncertain efficacy, long half-life, potential for hematologic toxicity and hepatotoxicity, wide interpatient variability in metabolism, and the inability to easily monitor the active metabolite level. Studies on the efficacy of leflunomide have yielded mixed results. Though an initial case series showed an improvement of BKVAN with a reduction of tacrolimus trough level to 4-6 ng/ml and prednisolone 5-10 mg with mycophenolate mofetil being replaced by leflunomide, these results were not reciprocated in other studies [57,58,59]. In the phase II randomized trial, an investigational agent derived from an active metabolite of leflunomide (FK778) also provided no clinically significant benefit compared with the reduction of immunosuppressive agents .
Cidofovir, a nucleotide analog of cytosine has demonstrated modest in vitro activity against polyomaviruses with its use demonstrated in a few uncontrolled studies [63,64]. However, given its potential nephrotoxicity the use should only be restricted to cases where other interventions have failed.
3.12 Experimental Therapies
Based upon the important role of cellular and humoral immune mechanisms in control of BKV infection and the absence of other proven treatments, immune-based therapies in the form of Virus-specific T cells (ClinicalTrials.gov identifier: NCT04605484) and BKV-specific monoclonal antibodies (ClinicalTrials.gov identifier: NCT04294472) are being actively assessed for safety, tolerability, and antiviral effect in human clinical trials .
Following BKVAN, many patients experience allograft dysfunction and loss , with a 3-year allograft survival of 79% compared to 90% in patients without BKVAN . BKVAN has also been associated with developing class II de novo donor-specific antibodies, a risk factor for allograft failure . It remains unclear whether immunosuppression can be safely increased after the resolution of BKV infection. An individualized approach is advised considering the immunological risk of the patient and close monitoring of GFR, BK viremia, and donor-specific antibodies.
3.14 Concurrent BKVAN and Acute Rejection
There are no data to guide the optimal management. Some would advocate treating the acute rejection first (e.g., with pulse glucocorticoids) followed by a reduction of immunosuppression once the patient has a clinical response to antirejection treatment (i.e., a decrease in serum creatinine level) . However, more frequent monitoring of BK viremia may be warranted if immunosuppression is augmented. Others would avoid augmented immunosuppression and favor a reduction in maintenance immunosuppression alone .
3.15 Acute Rejection after Reduction of Immunosuppression
Acute rejection can occur in 8-12% of kidney transplant recipients with BK viremia or established BKVAN following a reduction in immunosuppression . Acute rejection should be suspected when serum creatinine increases after the decrement of immunosuppression. An allograft biopsy is helpful in such settings to establish the same. The optimal management of such patients varies among centers. Generally augmentation of immunosuppression is avoided if patients have biopsy-proven BKVAN and are maintained at the same reduced level when the patient developed rejection.
3.16 Kidney Retransplantation
Retransplantation in patients with graft failure due to BKVAN is a reasonable option and has been successfully performed . BKV replication’s absence should be confirmed before retransplantation , although successful pre-emptive, living, related kidney transplants have been reported during active BKVAN with viremia . Close screening is mandated following retransplantation with BKVAN. Some centers would recommend avoiding intense immunosuppression. There is no high-quality data for nephrectomy of the failed allograft or of the native kidneys, which may serve as a reservoir and a source of reinfection. Available data suggest that retransplantation is associated with good graft outcomes in those who have lost their first allograft due to BKVAN .
BK virus is a common opportunistic pathogen in kidney transplant recipients which can lead to allograft dysfunction and loss. Over-immunosuppression is the primary risk factor for BKV infection after transplantation. Routine screening post-renal transplant is important for early detection and immediate action to prevent graft loss. Reduction of immunosuppression remains the mainstay of BKV nephropathy treatment at present.
Dr Uttayan- Preparation, editing and Review of literature; Dr Rajesh Jhorawat- Review of literature, editing and Preparation of manuscript; Rest author help in Review of literature and editing of the manuscript.
The authors have declared that no competing interests exist.
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