Combination of Leflunomide and Everolimus for treatment of BK virus nephropathy

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The natural history and virology of BK virus has been recently described by Jamboti.1 BK virus infection in renal transplant recipients may be linked to the use of newer and more potent immunosuppressive agents. Detection of BK viremia within the first year following transplantation has reached an equivalent rate to that of acute rejection while on newer immunosuppressive therapy.2 Hirsch reported an occurrence of BK viremia in 13% of transplant recipients with nephropathy in 8%.5 Despite the lack of a randomized controlled trial, treatment has been directed towards reduction of immunosuppressive medication to prevent graft loss. This needs to be balanced with the risk of rejection. In some cases, despite reduction of immunosuppression, infection with polyomavirus can persist and leads to graft loss.
Recent in vitro experiments have shown a reduction in BK viral proliferation with the combination of Leflunomide and Sirolimus, an inhibitor of mammalian target of rapamycin (mTORi).6 Liacini et al. proposed the hypothesis of intracellular protein kinase pathways inhibition activated by BK virus as a potential effective therapeutic target rather than reduction of immunosuppression. They observed that infected renal epithelial cells lines and human primary tubular epithelial cells expressed an increased phosphorylation of 3′‐phosphoinositide‐dependent kinase‐1 (PDK‐1), the protein kinase Akt (Akt), mammalian target of rapamycin and 70 kDa ribosomal protein S6 kinase (p70S6K). Sirolimus targets p70S6K phosphorylation and was able to reduce BK virus large T antigen expression in a dose‐dependent manner, while Leflunomide, a tyrosine kinase inhibitor decreased PDK‐1 and Akt phosphorylation and inhibited BK virus genome replication and early gene expression. The resultant outcome is inhibition of viral replication, large T antigen expression, PDK‐1, Akt, mammalian target of rapamycin and p70S6K phosphorylation. This is summarized in Figure 1.
Based on this observation, we described our experience in treating three renal allograft patients who failed to respond to standard immunosuppression reduction for treatment of BK nephropathy (BKN). The current local protocol for immunosuppression reduction was initially 25–50% reduction in dose of mycophenalate mofetil, followed by lowering Tacrolimus dose to target level of four to six. Leflunomide was substituted for mycophenolate mofetil if the prior reductions in immunosuppression failed to lower BK viral load. In the patients who did not have an improvement in renal function and a fall in BK viral load over the following month/s, Everolimus was substituted for Tacrolimus.
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