Interventions for BK virus infection in kidney transplant recipients

Abstract

Background: BK virus-associated nephropathy (BKVAN), caused by infection with or reactivation of BK virus, remains a challenge in kidney transplantation. Screening is recommended for all kidney transplant recipients. For those with clinically significant infection, reduction of immunosuppression is the cornerstone of management. There is no specific antiviral or immunomodulatory therapy sufficiently effective for routine use.

Objectives: This review aimed to examine the benefits and harms of interventions for BK virus infection in kidney transplant recipients.

Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 5 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria: All randomised controlled trials (RCTs) and cohort studies investigating any intervention for the treatment or prevention of BKVAN for kidney transplant recipients.

Data collection and analysis: Two authors independently assessed the study quality and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: Twelve RCTs (2669 randomised participants) were included. Six studies were undertaken in single centres, and six were multicentre studies; two of these were international studies. The ages of those participating ranged from 44 to 57 years. The length of follow-up ranged from three months to five years. All studies included people with a kidney transplant, and three studies included people with signs of BK viraemia. Studies were heterogeneous in terms of the type of interventions and outcomes assessed. The overall risk of bias was low or unclear. Intensive screening for the early detection of BK viraemia or BK viruria prevents graft loss (1 study, 908 participants: RR 0.00, 95% CI 0.00 to 0.05) and decreases the presence of decoy cells and viraemia at 12 months (1 study, 908 participants: RR 0.06, 95% CI 0.03 to 0.11) compared to routine care (high certainty evidence). No other outcomes were reported. Compared to placebo, fluoroquinolones may slightly reduce the risk of graft loss (3 studies, 393 participants: RR 0.37, CI 0.09 to 1.57; I² = 0%; low certainty evidence), probably makes little or no difference to donor-specific antibodies (DSA), may make little or no difference to BK viraemia and death, had uncertain effects on BKVAN and malignancy, but may increase the risk of tendonitis (2 studies, 193 participants: RR 5.66, CI 1.02 to 31.32; I² = 0%; low certainty evidence). Compared to tacrolimus (TAC), cyclosporin (CSA) probably makes little or no difference to graft loss and death, may make little or no difference to BKVAN and malignancy, but probably decreases BK viraemia (2 studies, 263 participants: RR 0.61, 95% CI 0.26 to 1.41; I² = 38%) and probably reduces the risk of new-onset diabetes after transplantation (1 study, 200 participants: RR 0.41, 95% CI 0.12 to 1.35) (both moderate certainty evidence). Compared to azathioprine, mycophenolate mofetil (MMF) probably makes little or no difference to graft loss and BK viraemia but probably reduces the risk of death (1 study, 133 participants: RR 0.43, 95% CI 0.16 to 1.16) and malignancy (1 study, 199 participants: RR 0.43, 95% CI 0.16 to 1.16) (both moderate certainty evidence). Compared to mycophenolate sodium (MPS), CSA has uncertain effects on graft loss and death, may make little or no difference to BK viraemia, but may reduce BKVAN (1 study, 224 participants: RR 0.06, 95% CI 0.00 to 1.20; low certainty evidence). Compared to immunosuppression dose reduction, MMF or TAC conversion to everolimus or sirolimus may make little or no difference to graft loss, BK viraemia or BKVAN (low certainty evidence). TAC conversion to sirolimus probably results in more people having a reduced BK viral load (< 600 copies/mL) than immunosuppression reduction (1 study, 30 participants: RR 1.31, 95% CI 0.90 to 1.89; moderate certainty evidence). Compared to MPS, everolimus had uncertain effects on graft loss and BK viraemia, may reduce BKVAN (1 study, 135 participants: 0.06, 95% CI 0.00 to 1.11) and may increase the risk of death (1 study, 135 participants: RR 3.71, 95% CI 0.20 to 67.35) (both low certainty evidence). Compared to CSA, everolimus may make little or no difference to BK viraemia, has uncertain effects on graft loss and BKVAN, but may increase the risk of death (1 study, 185 participants: RR 3.71, 95% CI 0.42 to 32.55; low certainty evidence). Compared to immunosuppression reduction, the leflunomide derivative FK778 may make little or no difference to graft loss, probably results in a greater reduction in plasma BK viral load (1 study, 44 participants: -0.60 copies/µL, 95% CI -1.22 to 0.02; moderate certainty evidence), but had uncertain effects on BKVAN and malignancy. Aggravated hypertension may be increased with KF778 (1 study, 46 participants: RR 8.23, 95% CI 0.50 to 135.40; low certainty evidence). There were no deaths in either group.

Authors' conclusions: Intense monitoring early after transplantation for BK viruria and BK viraemia is effective in improving BK virus infection outcomes as it helps with early detection of the infection and allows for a timely reduction in immunosuppression reduction. There is insufficient evidence to support any other intervention for BK virus infection in kidney transplant recipients.

Trial registration: ClinicalTrials.gov NCT00104338 NCT01353339 NCT01034176 NCT01789203 NCT01624948 NCT00724022 NCT01860183 NCT01377467 NCT00251004 NCT04605484 NCT02495077 NCT04294472 NCT05385432 NCT05511779 NCT06059664 NCT06114953.