Conversion From Cyclosporine to Everolimus at 4.5 Months Posttransplant: 3-Year Results From the Randomized ZEUS Study

Abstract

†Members listed in the Appendix.The long-term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12-month, open-label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m 2 , 95%CI 4.3, 11.0 mL/min/ 1.73 m 2 ; p < 0.001) and month 36 (7.5 mL/min/1.73 m 2 , 95%CI 3.6, 11.4 mL/min/1.73 m 2 ; p < 0.001). The incidence of biopsy-proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

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

“…was maintained with mTOR inhibitor therapy at 3 years posttransplant (32), similar to the findings of our study (22). Together, these represent a convincing body of evidence that switching to an mTOR inhibitor early posttransplant leads to a sustained improvement in renal function compared to a standard CNI-based regimen.…”

“…After completion of the 12-month study (18), patients underwent annual follow-up assessments for 5 years posttransplant. Results at 3 years have been published previously (22). Exploratory analyses of predefined end points at the final 5-year follow-up visit are presented here, with a focus on the evolution of renal function over time.…”

Multinational Evaluation of Mycophenolic Acid, Tacrolimus, Cyclosporin, Sirolimus, and Everolimus Utilization

“…As tacrolimus can cause nephrotoxicity and subsequent rejection, everolimus substitution has shown promise as an alternative for the long-term management of rejection combined with mycophenolic acid [36]. Everolimus substitution is considered most clinically appropriate between 12 and 72 months post-transplant [37][38][39][40]. This evidence aligns well with the observed results and provides insight into the evolving practice of prescribers being shaped by the current literature.…”

m-TOR Inhibitors in Kidney Transplantation: A Comprehensive Review

“…Their complex with calcineurin binds to rapamycin target and inhibit signal 3 of T-cell activation, through inhibition of cytokines activating T-cell cycle [19].Again they have a lot of drug interactions as they are metabolized by p450, and interact with CNIs [4]. 61,62,65,66]. Data from the OPTN/SRTR showed that their use in kidney transplantation has largely reduced in the recent years see Figure 6 [2].…”