Sirolimus Versus Cyclosporine in Kidney Recipients Receiving Thymoglobulin®, Mycophenolate Mofetil and a 6‐Month Course of Steroids

Abstract

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.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

“…The method of random allocation, 71,86,128 including the method of sequence generation, was clearly stated and adequate in only two induction studies 71,128 and 18 maintenance studies, 86,103,110,112,119,122,124,126,127,[129][130][131][132][133][134][135][136]150 whereas 65 studies (nine induction studies [72][73][74]87,95,98,137 and 54 maintenance studies 51,58,59,75-85,88,89,91-94,99-102, 104-109,111,113-118,120,121,125,138-147,152-155 ) and both of the studies of induction and maintenance treatment 123,148 did not clearly specify the method used. The remaining maintenance study 149 used a minimisation technique that included a random element.…”

“…Fifty-four trials 51,[72][73][74][76][77][78][79][81][82][83][84][85][87][88][89][91][92][93]95,96,[98][99][100][102][103][104][105][106][108][109][110][111][112][113][115][116][117][118][119][120]124,127,131,134,135,139,141,[143][144][145][153][154][155] did not report any information on allocation concealment, whereas 20 trials 71,…”

Conversion of Calcineurin Inhibitors With Mammalian Target of Rapamycin Inhibitors After Kidney Transplant

“…Cyclosporine avoidance at different posttransplant times ranging from 10 to 24 days in the SMART study, 3 to 3 months in the CONCEPT study, 26 to 6 months in the SPIESSER trial, 27 and to 8 years 28 showed similar patient survival, graft survival, and biopsy-proven AR rates in both cyclosporine-and sirolimus-treated patients. However, all these studies showed significantly better renal function in mean serum Cr levels and/or glomerular filtration rate at month six, 1 the first year, 1,3,16,28,29 the second year, 23,30,31 the third year, 31 the fourth year, 32 and the fifth year 27,33 after transplant in sirolimus-treated patients compared to cyclosporine-treated patients.…”

“…This is because they have different liver metabolism and intestinal absorption in different people. 10 But because some mTORs lead to adverse effects (eg, wound healing delay and increased rate of biopsy-proven AR), 3,4,16 the immediate posttransplant replacement of CNIs with mTORs would be unpleasant; such replacement is better if it is used after 3 to 6 months. 3,4,7,17 Firstly, such strategy prevents CNI-induced nephrotoxicity and CAN in different organ transplants 9,18 ; secondly, it allows CNIs primary protection from AR 4,5 ; third, it prevents the adverse effects of mTOR inhibitors (eg, wound healing delay 4,5 ); and finally, it increases the number and effects of T-regulatory cells in prevention of the AR processes.…”

“…4,9,10,12,13 Compared with CNIs, mTORs cause better renal function and lower tissue chronicity in kidneys and other organ transplants. 3,7,11,14,15,16 The significance of such replacement is important when considering the fact that blood levels of CNIs cannot predict their own nephrotoxic effects. This is because they have different liver metabolism and intestinal absorption in different people.…”