The Second International Consensus Guidelines on the Management of BK Polyomavirus in Kidney Transplantation

Abstract

BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.

Trial registration: ClinicalTrials.gov NCT05224583.

FIGURE 1.

Flowchart integrating screening, diagnosis, and management of BKPyV replication in kidney transplant recipients. For details, see consensus statements and recommendations, including Tables 6 and 7, which describe the principal approaches to reducing immunosuppression. AST, American Society of Transplantation; BK polyomavirus nephropathy; BKPyV, BK polyomavirus; BKPyVAN, PyVL, polyomavirus-tissue load.

FIGURE 2.

Timelines of BKPyV replication and related laboratory and clinical events after kidney transplantation. Urinary cytology data mostly describe the onset of decoy cell shedding. Low-level BKPyV-DNAuria in native urine is detected in <10% before transplantation and increases to high-level BKPyV-viruria defined by decoy cells or BKPyV-DNAuria of >10 million copies/mL of urine. BKPyV-DNAemia loads are identified in plasma by QNAT approximately 2 to 6 wk after high-level BKPyV-DNAuria. BKPyV-specific antibody levels increase before immunosuppression is reduced. As the net state of immunosuppression decreases, rising BKPyV-specific T cell activity is detectable. The colored dashed lines attempt to capture different scenarios of marker and disease evolution. Serum creatinine concentration may increase when allograft BKPyV loads and the associated interstitial inflammation become more extensive. Reducing immunosuppression facilitates antiviral immunity (immune reconstitution), clearance of intragraft replication foci, and clearance of BKPyV-DNAemia loads below the limit of detection while increasing the risk of antidonor immunity and allograft rejection. Increase in serum creatinine may arise because of antiviral immune reconstitution or acute rejection, whereby the former may be transient, unlike the latter. The shaded green area marks the window of opportunity for reincreasing maintenance immunosuppression to prevent acute T cell–mediated rejection. Potentially accelerated generation of donor-specific antibodies and antibody-mediated rejection are not depicted. BKPyV, BK polyomavirus; c/mL, copies/mL; hpf, high-power field; QNAT, quantitative nucleic acid testing.

FIGURE 3.

One-way sensitivity analyses: tornado diagram showing the influential variables on the incremental cost-effectiveness ratio in the base case model. The tornado diagram indicates the extent of the variability associated with these important variables on the incremental health benefits and costs. For example, if the age of transplantation is decreased from 70 y (shades of black) to 18 y (shades of gray), the incremental benefits of screening would increase from 0.20 to 0.24 QALYs. However, the total savings will be reduced from $7884 to $6844, as younger recipients would incur greater resources used over their lifetime compared with their older counterparts because of their longer expected posttransplant survival. EV, expected value; HD, hemodialysis; ICER, incremental cost-effectiveness ratio; PyVAN, polyomavirus-associated nephropathy; QALY, quality-adjusted life year. Adapted from Wong et al.