Prospective, Pilot, Open-Label, Short-Term Study of Conversion to Leflunomide Reverses Chronic Renal Allograft Dysfunction

Renal allograft recipients with thrombophilia (a hypercoagulable state) are at higher risk for early allograft loss. Following an episode of allograft renal vein thrombosis in a patient subsequently diagnosed with protein C deficiency, we adopted universal screening for hypercoagulable risk factors. Patients with a history of a thromboembolic event underwent laboratory screening for thrombophilia. Eight patients with a defined hypercoagulable disorder or a strong clinical history of thrombosis even in the absence of hematologic abnormalities were treated with anticoagulation following renal transplantation. We reviewed the outcomes of these eight patients and all renal transplant recipients at our center who developed thrombotic complications after renal transplantation. Leflunomide (LEF) is a synthetic isoxazole derivative with anti‐inflammatory and antiviral properties, which has been reported to prevent acute rejection and delay progression of chronic allograft nephropathy (CAN) in animal models. We performed a pilot, crossover trial in 22 renal transplant recipients who were converted from azathioprine (AZA) or mycophenolate mofetil (MMF) to LEF in an effort to slow progression of renal dysfunction [deteriorating renal function (n = 5), cyclosporine (CyA) nephrotoxicity (n = 4) or biopsy‐proven CAN (n = 13)]. Baseline maintenance immunosuppression consisted of CyA, AZA or MMF and prednisone. Six‐month postconversion patient and graft survival was 100% and 91%, respectively. Mean serum creatinine 6 months preconversion was 2.2 ± 0.6 mg/dL, at initiation was 3.0 ± 1.1 mg/dL, and 6 months postconversion was 2.8 ± 1.3 mg/dL. The rate of change in serum creatinine was 35 ± 39%/6 months preconversion and − 5 ± 21%/6 months postconversion to LEF (p = 0.003). Two patients discontinued LEF for diarrhea and myalgia. No readmissions, increase in liver function tests, infections or acute rejection episodes occurred. Mean CyA levels did not change, 146 ± 72 ng/mL pre‐LEF vs. 132 ± 51 ng/mL post‐LEF, p=NS. Conversion to LEF reversed progression of chronic renal allograft dysfunction with minimal toxicity.