Efficacy on Renal Function of Early Conversion from Cyclosporine to Sirolimus 3 Months After Renal Transplantation: Concept Study

Abstract

Sirolimus (SRL) allows to minimize the use of cyclosporine (CsA), but de novo administration after transplantation is associated with various complications. We report a prospective, open-label, multicenter randomized study to evaluate conversion from a CsAbased regimen to a SRL-based regimen 3 months after transplantation. One hundred ninety-two of a total of 237 patients were eligible at 3 months to be converted to SRL (n = 95) or to continue CsA (n = 97). All patients were also given mycophenolate mofetil (MMF) and oral steroids, planned to be discontinued at month 8. The primary endpoint, the clearance estimated according to Cockcroft and Gault at week 52, was significantly better in the SRL group (68.9 vs. 64.4 mL/min, p = 0.017). Patient and graft survival were not statistically different. The incidence of acute rejection episodes, mainly occurring after withdrawal of steroids, was numerically but not statistically higher in the SRL group (17% vs. 8%, p = 0.071). Sixteen patients discontinued SRL, mainly for adverse events (n = 11), and seven patients discontinued CsA for renal failure or acute rejection. Significantly, more patients in the SRL group reported aphthous, diarrhea, acne and high triglyceride levels. Conversion CsA to SRL 3 months after transplantation combined with MMF is associated with improvement in renal function.

Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial

“…The adherence was somewhat worse than we had anticipated but nonetheless in keeping with previous studies 8, 25, 27, 28, 29, 30. The low adherence level in the 3C Study reduces the sensitivity of the trial to detect a true difference in transplant function but also, importantly, means that estimates of the hazards may be less than would be observed with full adherence.…”

“…In contrast, early (ie, within 6 months of transplantation) conversion to mTORi has been shown in some (but not all) trials to improve transplant function compared with remaining on cyclosporine‐based immunosuppression 8, 9, 10, 11, 12. Another potential benefit of conversion to mTORi is a reduction in the risk of malignancy posttransplantation (especially skin cancer) 13, 14, 15.…”

Effects of sirolimus alone or in combination with cyclosporine A on renal ischemia/reperfusion injury

“…We believe that the preserved GFR in the I + SRL + CsA group was probably due to the SRL-induced increase in capillary filtration coefficient, since glomerular filtration was restored despite RBF reduction. Our findings agree with other studies, which have reported that the combination of CsA and SRL may have a beneficial, synergistic immunosuppressive effect (without additional nephrotoxic effects), which might result in improved post-transplant renal function (9,10,26,33). The protection provided by SRL against CsA nephrotoxicity in ischemia/reperfusion injury cannot be attributed to reduced blood concentrations of CsA since blood levels of CsA were comparable between groups I + CsA and I + SRL + CsA.…”

“…The use of SRL allows early CsA discontinuation or dose reduction, decreasing nephrotoxicity without increasing the risk of graft loss or acute rejection (6). However, other studies of kidney transplantation have shown that SRL may have long-term adverse subclinical effects or enhance the nephrotoxicity of full doses of CsA (7)(8)(9)(10). In addition to drug-induced nephrotoxicity, kidney transplant recipients are at risk of developing ischemia/reperfusion injury, which can influence the clinical outcome and graft survival negatively.…”

Five-Year Outcomes in Kidney Transplant Patients Converted From Cyclosporine to Everolimus: The Randomized ZEUS Study

“…Results have demonstrated that immunosuppressive efficacy is maintained, but although an improvement in graft function has been observed (13) a significant difference may not be sustained (17). Evidence from a series of randomized studies indicates that longer-term renal benefit may be achieved if an mTOR inhibitor is introduced and CNI therapy is withdrawn during the first 6 months after kidney transplantation (18)(19)(20)(21), before extensive, irreversible CNI-related nephrotoxicity develops (2).…”