Polyomavirus BK Replication in De Novo Kidney Transplant Patients Receiving Tacrolimus or Cyclosporine: A Prospective, Randomized, Multicenter Study

Abstract

Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log10 copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36–0.99) and month 12 (OR 0.33; 95% CI 0.16–0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant.

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12

“…This condition has been associated with a variety of risk factors (e.g. male recipient, older recipient age, higher number of HLA mismatches, acute rejection episodes, higher steroid exposure, ureteric stents, as well as transplanting organs from donors with high BKPyV antibody titers into recipients with low or undetectable antibody titers) 5, 9, 13, 17, 18, 19, 20, 21, 22, 23, 24, 25.…”

Persistent BK Viremia Does Not Increase Intermediate-Term Graft Loss but Is Associated with De Novo Donor-Specific Antibodies

“…[3][4][5] The best elucidated risk factor for BK virus infection in kidney recipients is the overall degree of immunosuppression, with lymphodepleting antibody induction as well as tacrolimus-and mycophenolic acid (MPA)-based regimens considered by some to be especially permissive. [6][7][8] If untreated, BKviremia can progress to BK nephropathy, impaired allograft function, and graft loss. 9 There is currently no effective antiviral prophylaxis or therapy for BK virus.…”

Immunosuppression and risk of polyomavirus BK replication

“…3 However, similar doses of this drug cannot be equated with comparable drug exposures. Mycophenolic acid has high interindividual pharmacokinetic variabil ity, which might lead to a poor correla tion between dose and plasma concen tration of the drug.…”

“…Some but not all studies have reported a higher risk of BKV viruria, viraemia and/or nephropathy in patients treated with tacrolimus than in those who received ciclosporin A. [3][4][5][6] However, whether a particu lar immunosuppressive agent, a combination of agents or the overall degree of immunosuppression has a major effect on the risk of BKV viruria after transplantatio n remains unclear. Hirsch and colleagues recently investi gated the incidence of BKV replication in more than 600 de novo kidney transplant recipients who were randomly assigned to receive either tacrolimus or ciclosporin A as part of the Diabetes Incidence after Renal Transplantation (DIRECT) study.…”

“…Hirsch and colleagues recently investi gated the incidence of BKV replication in more than 600 de novo kidney transplant recipients who were randomly assigned to receive either tacrolimus or ciclosporin A as part of the Diabetes Incidence after Renal Transplantation (DIRECT) study. 3 All patients received basiliximab induc tion therapy as well as mycophenolic acid (either mycophenolate mofetil or enteric coated mycophenolate sodium) and predni sone. Risk factors for BKV repli cation were analysed in patients who had at least two BKV positive plasma or urine samples obtained on different occasions during the first 12 months after transplantation.…”