Low-dose sirolimus in combination with mycophenolate mofetil improves kidney graft function late after renal transplantation and suggests pharmacokinetic interaction of both immunosuppressive drugs

Aims: Chronic allograft nephropathy and/or calcineurin inhibitor toxicity are common problems after organ transplantation. The aim of this study was to examine the safety and efficacy of switching from a calcineurin inhibitor-based to a calcineurin inhibitor-free immunosuppressive regimen consisting of sirolimus and mycophenolate mofetil (MMF) late after renal transplantation. Methods: Kidney biopsies were performed in renal-transplanted patients with increasing serum creatinine levels at least 6 months after transplantation ( mean time +/- SD after renal transplantation: 76.4 +/- 50.4 months). Patients with no signs of acute rejection were switched to MMF ( 500 - 2,000 mg/ day) in combination with a low dose of sirolimus ( 1 mg/ day). Renal function, serum chemistry, blood trough levels of sirolimus and MMF, and blood pressure were monitored. Results: 13 patients were investigated. During our observation period ( mean observation time +/- SD: 11.2 +/- 5.9 months), an improvement in renal function was observed in 10/13 patients. In 3/13 patients, renal function deteriorated further and hemodialysis was initiated in 2 patients within the next 6 months. However, a serum creatinine concentration above 3.5 mg/dl was measured in 2 of those 3 patients prior to the switch of the immunosuppressive protocol. Administration of a low dosis of sirolimus ( 1 mg/day) led to relevant sirolimus (4.16 +/- 1.85 ng/ml) and MMF blood trough levels ( month 1: 6.8 +/- 3.46; month 3: 4.67 +/- 1.78 mg/l). The following adverse events were observed: borderline acute rejection (1/11 patients), anemia responding to higher dosage of erythropoietin (3/11), hyperlipidemia (1/11), and urinary tract infections (4/11). Conclusions: Low-dose sirolimus therapy in combination with concentration-adjusted MMF therapy leads to improvement of organ function late after renal transplantation. The follow-up of those patients should include assessments of blood cell counts, serum lipids and urinalysis to recognize the possible side effects. Copyright (C) 2004 S. Karger AG, Basel.