EXPERIMENTAL AND CLINICAL TRANSPLANTATION

BK polyomavirus remains an important cause of allograft dysfunction and graft loss in kidney transplant recipients. Current consensus emphasizes early detection of viremia and timely immunosuppression reduction as the cornerstone of management. Novel diagnostic adjuncts, including donor-derived cell-free DNA, urinary biomarkers, and risk prediction models, are under investigation for more precise stratification of patients at risk for BK polyomavirus-associated nephropathy. Conventional antivirals have shown inconsistent efficacy; however, recent interest has focused on adoptive virus-specific T-cell therapy and neutralizing antibodies for refractory cases. This review reports the current understanding of BK polyomavirus epidemiology, diagnostics, management strategies, and emerging therapies, with emphasis on practical application of guidelines and identification of future research directions.

Key words : Donor-derived cell-free DNA, Immunosuppression reduction, Virus-specific T cells

BK polyomavirus (BKPyV) was first isolated from the urine of a renal transplant recipient in 1971 and named with the patient's initials.¹ BK polyomavirus is a double-stranded DNA virus² and remains an important cause of allograft dysfunction and graft loss in kidney transplant recipients.³ Current consensus emphasizes early detection of viremia and timely reduction of immunosuppression as the cornerstone of management.⁴ Novel diagnostic adjuncts, including donor-derived cell-free DNA (dd-cfDNA), urinary biomarkers, and risk prediction models, are under investigation for more precise stratification of patients at risk for BKPyV-associated nephropathy (BKPyVAN).⁵ Conventional antivirals have shown inconsistent efficacy; however, recent interest has focused on adoptive virus-specific T-cell therapy and neutralizing antibodies for refractory cases.⁶ In this review, we provide updates on current understanding of BKPyV epidemiology, diagnostics, management strategies, and emerging therapies, with emphasis on practical application of guidelines and identification of future research directions.

Definitions
Definitions were adopted from the updated "The Transplantation Society" guidelines.⁷ Possible BKPyVAN was defined as high-level urine BKPyV loads (defined as BKPyV-DNAuria >10 million copies/mL or equivalent or decoy cells or polyomavirus virions by electron microscopy) but undetectable plasma BKPyV-DNAemia. Probable BKPyVAN was defined as plasma BKPyV-DNAemia >1000 copies/mL (or equivalent) sustained for >2 weeks. Presumptive BKPyVAN was defined as plasma BKPyV-DNAemia >10 000 copies/mL (or equivalent). Biopsy-proven BKPyVAN was defined as detection of compatible cytopathic effects plus immunohistochemistry and a specific diagnostic test identifying BKPyV as opposed to JC polyomavirus.

Epidemiology and Risk Factors
BK polyomavirus infection is generally acquired during childhood through person-to-person contact through respiratory secretions.^8,9 The virus remains dormant in the urinary tract (tubular epithelial cells) and circulating leukocytes and becomes reactivated during immunosuppression.¹⁰ The absence of a quantitative relationship between BK viremia and viruria may reflect independent BKPyV reactivation in different tissues during immunosuppression.¹⁰ The incidence of BKPyV replication varies by immunosuppressive regimen and patient characteristics. Established risk factors include transplant from BKPyV-seropositive donor to a BKPyV-seronegative recipient,¹¹ HLA mismatch,¹² history of rejection episodes, male sex, old age, and ischemia-reperfusion injury.¹³ Treatment with lymphocyte-depleting agents, especially thymoglobulin, has a higher risk compared with no induction or induction with interleukin 2 receptor antagonists,^14,15 whereas induction with alemtuzumab does not significantly affect the incidence of BKPyVAN.¹⁶ Treatment with tacrolimus combined with mycophenolate mofetil is associated with increased risk, whereas treatment with cyclosporine or mammalian target of rapamycin inhibitors and everolimus or sirolimus is associated with reduced risk.^14,15,17-19

Diagnostics and Surveillance

Urine testing
Detection of replicating BKPyV in urine (intact virions, polyomavirus Haufen, or decoy cells) or detection of viral components in urine (mRNA, DNA, or potentially BKPyV antigens) by quantitative polymerase chain reaction (qPCR) is a frequently used screening test but has limited utility in guiding treatment recommendations.^20-22

Quantitative polymerase chain reaction
Plasma BK viral load by qPCR is the gold standard for detecting viral replication and guiding management.²³ The American Society of Transplantation recommends monthly screening until month 9 and then every 3 months until 2 years posttransplant.²⁴ Intervention is considered when BKPyV-DNAemia exceeds 1000 copies/mL on repeated testing or when levels rise progressively. Higher viral loads (>10 000 copies/mL) are strongly associated with progression to BKPyVAN and demand urgent management.^4,5,19,25

Histopathology
Biopsy remains the diagnostic gold standard for BKPyVAN, but false negatives up to 30% are common because of the focal nature of the disease and preferential involvement of medulla. A minimum of 2 cores should be obtained; the sample should contain a minimum of 10 glomeruli and 2 arteries and should have medulla in the specimen, and immunohistochemical staining for SV40 large T antigen or in situ hybridization staining should be performed.^22,24 A classification schema for grading polyomavirus nephropathy was proposed at the 2009 Banff meeting. The schema included 3 stages of polyomavirus nephropathy: early (stage A), florid (stage B), and late sclerosing (stage C) to allow for comparative analyses.²⁶ In an effort to standardize morphologic assessment and reporting, the Banff working group on polyomavirus nephropathy in 2018 published a morphologic classification of definitive BKPyVAN into 3 groups: class 1, 2, and 3 based on polyomavirus load (pvl) and Banff ci (interstitial fibrosis) score. Polyomavirus nephropathy class 1 had pvl 1, ci ≤1; polyomavirus nephropathy class 2 had pvl 1, ci ≥2 or pvl 2, any ci score or pvl 3, ci ≤1; and polyomavirus nephropathy class 3 had pvl 3, ci ≥2.²⁷

Emerging Biomarkers

Donor-derived cell-free DNA
Elevated plasma dd-cfDNA correlates with viral replication and histopathological injury, offering a noninvasive marker for graft injury. Combined urinary and plasma cfDNA testing may further improve diagnostic accuracy, although routine use awaits further validation. Integration of dd-cfDNA with other molecular rejection biomarkers, such as gene expression profiling, is under investigation to provide a comprehensive picture of graft injury and viral activity.⁵ Because BKPyV is associated with the development of de novo donor-specific antibodies, elevated dd-cfDNA levels in this infection could represent alloantibody-mediated microcirculation injury.^28,29 Other work found no relationship between dd-cfDNA levels and the extent of tubulointerstitial infiltrates, BKPyVAN class, and BK viremia/viruria.³⁰

Urinary chemokines
Elevated levels of CXCL9 and CXCL10 have been reported with BKPyVAN with high sensitivity but lower specificity since these are markers of inflammation.³¹ Weseslindtner and colleagues found increasing urine CXCL10 levels in parallel with disease progression, from BKPyV DNAuria to DNAemia and histological evidence of BKPyVAN. This increase correlated with heightened viral replication, excretion of decoy cells, and decline in kidney function. In addition, blood levels of CXCL10 and also CCL8 were notably higher in patients with elevated levels of viral replication.^5,32

Immune surveillance
BKPyV-specific cellular immunity directed to 5 BKPyV proteins was shown to correspond with resolution of active BKPyV infection.^33,34 Assays such as enzyme-linked immunosorbent spot and flow cytometry for BKPyV-specific CD8+ T cells are useful tools and could support clinicians in guiding immunosuppressive therapy in patients with BKPyVAN.^5,35 Batal and colleagues showed that the Cylex ImmuKnow test, which measures immune cell function and is based on the amount of adenosine triphosphate released when T cells are stimulated by phytohemagglutinin, can be used to stratify kidney transplant recipients according to the risk of developing BKPyV infection. A decreased immune cell function test result correlated with active viral replication in kidney transplant recipients.³⁶ These functional measures of immunity could allow pre-emptive adjustment of immunosuppression before clinically significant viremia develops.

Gene expression
Intragraft gene expression using a polyomavirus 5-gene set (VP1, VP2, VP3, Agnoprotein, and LTAg) has been shown to reliably distinguish BKPyVAN from T-cell-mediated rejection.³⁷ The VP1 mRNA copy number in urine has been shown to discriminate patients with BKPyVAN from patients without T-cell-mediated rejection or BKPyVAN, with BKPyVAN diagnosed with a sensitivity of 86% and a specificity of 100%.³⁸ These novel diagnostics need further validation.

Reduction of immunosuppression
Stepwise reduction of immunosuppression is the cornerstone of management. Typically, the antimetabolite is reduced first, followed by lowering the trough levels of calcineurin inhibitors. The guideline from the American Society of Transplantation recommends a tacrolimus trough level of <6 ng/mL and cyclosporine trough level of <150 ng/mL when managing BKPyV infection. During dose adjustment, the patient's viral load and renal function should be monitored every 1 to 2 weeks. The antimetabolite dose is first reduced by 50%, and further reduction of immunosuppression is warranted in the form of antimetabolite discontinuation if BKPyV-DNAemia does not decrease by 10-fold at week 4 or does not clear below the lower limit of detection. Conversion to a mammalian target of rapamycin inhibitor (everolimus or sirolimus) may be considered, although evidence is mixed. The process must be carefully balanced to avoid acute rejection, especially in patients with high immunological risk.^7,24,39
The evidence supporting the use of adjunctive pharmacotherapy, including leflunomide, fluoroquinolones, and cidofovir, is limited, and these agents are not recommended, and data supporting the use of intravenous immunoglobulin as an adjunct to expedite viral clearance in patients with sustained BKPyV DNAemia is weak.⁷ Belatacept can be used as a rescue therapy in patients with high immunological risk with refractory BKPyV DNAemia.⁴⁰

Investigational Therapies

Virus-specific T-cell therapy
Virus-specific T-cell therapy represents a novel immunotherapeutic approach for patients with refractory BKPyV infection, particularly in patients who are unresponsive to immunosuppression reduction and adjunctive antivirals. Virus-specific T-cell therapies are generated by isolating and expanding BKPyV-specific T cells from the original donor or third-party partially HLA-matched healthy donors. Infusion of these cells aims to restore antiviral immune surveillance, with reported outcomes showing reductions in viral load, clearance of persistent viremia, and stabilization of allograft function. In published cohorts, virus-specific T-cell therapy has yielded complete or partial responses in most treated patients, although logistical barriers (manufacturing complexity, cell availability), risk of alloreactivity, and immune exhaustion remain challenges. The current evidence is derived from small case series and observational studies, with ongoing clinical trials evaluating optimal cell types, dosing, and infusion frequency (very low certainty evidence, investigational).^6,41,42

Neutralizing antibodies and vaccination
Low recipient neutralizing antibody titers against donor BKPyV serotype are associated with post-transplant replication. Monoclonal neutralizing antibodies may have therapeutic potential and are under investigation.⁴³ Vaccination of potential transplant recipients with BKPyV antigens in conjunction with an adjuvant that preferentially induces cell-mediated immune response is a potential area for future research. Recent studies highlight the complexity of serotype-specific immunity and the challenges of cross-reactivity, which must be addressed for vaccines or antibody therapies to be effective.^9,44,45

Posoleucel
Posoleucel is an off-the-shelf, allogeneic, multivirus-specific T-cell investigational therapy targeting BKPyV. Posoleucel aims to address the underlying T-cell deficit associated with BK viremia in kidney transplant recipients by providing patients with ex vivo, activated, polyclonal, and polyfunctional BKPyV-specific T cells to control BKPyV infection.⁴⁶

BK polyomavirus remains a major challenge in kidney transplantation. Early detection of DNAemia and prompt reduction of immunosuppression are the foundations of management, with adjunctive biomarkers providing added precision. No antiviral has supplanted immunosuppression reduction, but cellular immunotherapies and neutralizing antibodies represent promising avenues for refractory cases. Continued research into risk stratification, biomarkers, and therapeutic innovation will be critical to improving graft outcomes.

Volume: 24 Issue: 4 April 2026

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