Leflunomide therapy in kidney transplantation: ready for prime time?

B K polyomavirus has become a scourge in kidney transplantation, mediating graft loss with progressive tubular cell death and interstitial inflammation and fibrosis (1). In the setting of immunosuppression, the virus reactivates, replicating along the tubular epithelium, spreading to other uninfected tubules, entering the tubular lumen after cell lysis, and eventually entering the bloodstream through destruction of peritubular capillaries (2). Whereas viruria is common, viremia occurs in only 13% of recipients, and nephropathy in 8% (3). Once a diagnosis is established by transplant biopsy and viral load measurements, the primary treatment strategy is immunousuppressive withdrawal (4). Disease that is more fully progressed may be unresponsive to any manipulation. Adjuvant therapies have included intravenous immune globulin, quinolones, and cidofovir, all with varying results (5). Centerspecific experiences have been reported, but there are no definitive treatments. Leflunomide is an immunosuppressive agent approved for use in rheumatoid arthritis. Metabolized by the liver, the active metabolite A77 1726 blocks tyrosine kinase activity as well as pyrimidine synthesis. Leflunomide also has antiviral activity against cytomegalovirus replication in vitro and in rodent models. Although limited, initial experience in kidney transplant recipients demonstrated significant interpatient variability in drug levels and anemia while facilitating calcineurin inhibitor withdrawal (6). Based on this immunosuppressive profile and the potential to halt BK activity, leflunomide has entered into practice for BK nephropathy. The initial report in 17 kidney transplant recipients in place of mycophenolate mofetil demonstrated a drop in viral loads by 2 to 3 logs when A77 1726 levels were more than 40 g/ml (7). Graft loss or bone marrow suppression was not reported. Treatment of an additional 13 patients at this center with targeted levels at 50 to 100 g/ml or used in combination with cidofovir resulted in consistent reduction in viral loads when levels were greater than 35 g/ml (8). Graft loss was 15%, lower than seen in other reports, with 2 patient deaths due to cardiovascular complications. However, levels of A77 1726 varied considerably among recipients on 20 to 60 mg daily, doses often in excess of those recommended for rheumatoid arthritis. Less optimistic results were recently reported in a small, prospective open label study in which viral clearance was only 42% with significant toxicity to discontinue the drug in 17% of recipients (9). Is leflunomide ready for prime time in the treatment of BK polyomavirus nephropathy? In this issue of CJASN, Leca et al. (10) retrospectively review leflunomide usage in recipients with BK nephropathy as well as TA/IF. Patients received doses averaging from 33 mg/d (“low level” 40 g/ml; n 12) to 48 mg/d (“high level” 40 g/ml; n 9), based on levels monitored monthly. In both groups, the rate and timing of viral clearance and the rate of graft loss were similar. Serum creatinine was indeed lower in the high level group, despite more frequent rejection episodes. Moreover, adverse events in all patients were common. In particular, hemolytic anemia occurred in 29% of all patients, particularly in high-level recipients. Thrombotic microangiopathy was seen in two recipients, one of whom eventually lost her graft. Potential contributing factors, such as donor alloantibody, infection, or tacrolimus, were not apparent, leaving the association with leflunomide. Speculated potential mechanisms include direct endothelial cell effects or via inhibition of tyrosine kinases. Alternatively, vascular endothelium damaged directly by the virus (11) and perhaps in combination with the drug could have led to endothelial cell activation. Transplantation has always contained special challenges, with the recognition that risk is acceptable if the overall outcome is improved. Presently, there is no effective antiviral agent for BK infection. The acceptance of leflunomide therapy as effective antiviral and anti-inflammatory has been based on limited published clinical experience and limited unpublished experience. As frustrating a disease as BK nephropathy is, we must recognize that current strategies reported in the literature have ill defined efficacy and safety in larger transplant populations under varying conditions. Clearly, there are several concerns with the use of leflunomide in kidney transplant subjects. Studies in individuals with renal failure, the population often targeted for therapy, are incomplete (6). There is wide interpatient variation in pharmacokinetics making predictable dosing difficult (6,8). Moreover, the antiviral activity measurements are limited and not optimally assayed. Using Published online ahead of print. Publication date available at www.cjasn.org.