Sirolimus-related thrombotic microangiopathy in a renal transplant recipient: a case report

Introduction: Sirolimus is an immunosuppressive agent commonly administered to renal transplant recipients since it is associated with less long-term nephrotoxicity than calcineurin inhibitors (CNIs). Sirolimus, as well as other drugs in this class (e.g. everolimus, temsirolimus), is also used as treatment options for some malignancies. Observations : A 65-year-old Caucasian male, with a history of left kidney nephrectomy for renal cell carcinoma (1999), developed end-stage renal disease due to progressive hypertensive nephrosclerosis on residual kidney. The patient was maintained on hemodialysis for nearly 3 years prior to receiving a cadaveric renal transplant in June 2011. Immunosuppression therapy consisted of mycophenolate mofetil (MMF), tacrolimus and prednisone. In December 2011 tacrolimus treatment was switched to sirolimus to minimize nephrotoxicity related to CNIs and in consideration of patient’s history of malignant neoplasm. At the end of January 2012 patient reported pain, swelling, warmth and redness of the left leg. A deep venous thrombosis of soleal veins was diagnosed by color Doppler and so anticoagulant therapy was started. Two weeks later, in concomitance with routine examinations, a mild proteinuria was observed. Proteinuria progressively increased, reaching 5 g/24 h at the end of March, moreover serum creatinine gradually rose from 1.7 mg/dL to 3.4 mg/dL, so a renal allograft biopsy was performed. Based on histologic findings, negative C4 deposition and absence of circulating anti-HLA antibodies, the patient was diagnosed with acute thrombotic microangiopathy (TMA) not due to transplant rejection. In the same days the patient complained of hematochezia, a subsequent colonoscopy reveled a severe pancolitis most likely related to TMA. Since some previous reports have suggested a relationship between sirolimus and TMA, treatment with sirolimus was discontinued and replaced with belatacept. Prednisone and MMF were continued. This resulted in a rapid and sustained improvement of the clinical picture. Discussion : Although it is still unclear how sirolimus can trigger TMA, it is possible that the drug decrease VEGF podocyte production and induce endothelial damage leading to platelet aggregation, thrombosis and tissue ischemia. In summary, TMA may be an emerging complication of sirolimus as its therapeutic applications expand, therefore clinicians should be careful for this potentially life-threatening complication.