Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: A multicentre, randomized trial

Abstract

Background. Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-Term kidney graft function, but the optimal strategy for CNI minimization remains uncertain. Methods. In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: ClinicalTrials.gov-NCT00514514). Results. The primary endpoint, change in estimated glomerular filtration rate (EGFR) (Nankivell) from randomization toMonth 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m2 [95% confidence interval (CI) 2.8-8.3mL/min/1.73 m2, P<0.001]. The improvement in EGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5mL/min/1.73 m2, 95% CI 2.8-8.2mL/min/1.73 m2, P<0.001), while results were similar in the low-CNI and standard CNI arms. The postrandomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P=0.27; low-CNI versus standard CNI, P=1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively. Conclusions. Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12months, with a similar rate of acute rejection.