To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)-free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus- and CsA-treated patients (60 ±27 vs. 57 ±21 mL/min). At 12 months, patient and graft survival, incidence of biopsy-proven rejection and rates of steroid withdrawal were not statistically different (97% vs. 97%; 90% vs. 93%; 14.3% vs. 8.6% and 82.8% vs. 84.1%, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6% vs. 12.3% and 11.4% vs. 13.7%, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 ±19 vs. 60 ±14 mL/min, p = 0.01). Overall study drug discontinuation rates were 28.2% with sirolimus and 14.9% with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g/24h (38.8% vs. 5.6%, p < 0.001) were significantly more frequent in sirolimus-treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6% vs. 23%, p <0.01). A CNI-free regimen using sirolimus-MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.
Although the use of calcineurin inhibitors (CNI) in transplantation, cyclosporine (CsA) from the eighties and tacrolimus from the nineties, improved short-term results, the nephrotoxicity of these drugs affects the long-term outcome of graft survival. In a retrospective analysis of 69 321 nonrenal organ transplant recipients' chronic renal failure occurred at 36 months in 16.5%. Furthermore, the chronic CNI nephrotoxicity can contribute to the morphologic changes of chronic allograft nephropathy, with the paradox that the same drugs can protect grafts from acute rejection during the first year following transplantation and enhance graft loss after the first year.
Sirolimus is a macrocyclic lactone antibiotic which binds to the same intracellular immunophilin FK-BP12 as tacrolimus but, instead of inhibiting calcineurin, binds to the mammalian target of rapamycin (m-TOR) and inhibits progression from the G1 to the S phase of the cell cycle. The absence of nephrotoxic effects and the patent immuno-suppressive efficacy in animal models has led to its use in protocols that spare or avoid CNI. Initial reports have been encouraging, with equivalent 1 year transplant outcome and acute rejection rates, better renal function and differences in side effect profiles. As the level of serum creatinine 1 year posttransplantation may predict long-term renal allograft survival, this may indicate a better long-term outcome in sirolimus-treated patients. Thus, total CNI avoidance with sirolimus substitution appears to be promising in renal transplantation.
Furthermore, avoidance or withdrawal of corticosteroids after renal transplantation is now a challenge as numerous side effects of corticosteroids have been identified. It has been shown that the steroid withdrawal is possible without high risk of acute rejection in patients receiving a CNI-based immunosuppressive regimen following induction therapy with antilymphocyte antibodies.
We therefore performed a prospective randomized study to compare the safety and efficacy of a sirolimus-mcophenolate mofetil (MMF)-based regimen with a CsA-MMF-based regimen after induction therapy with polyclonal antilymphocyte antibodies, with withdrawal of steroids 6 months' posttransplantation.