Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation

Results of the Randomized ELEVATE Trial

J. W. de Fijter; H. Holdaas; O. Øyen; J.-S. Sanders; S. Sundar; F. J. Bemelman; C. Sommerer; J. Pascual; Y. Avihingsanon; C. Pongskul; F. Oppenheimer; L. Toselli; G. Russ; Z. Wang; P. Lopez; J. Kochuparampil; J. M. Cruzado; M. van der Giet

Disclosures

American Journal of Transplantation. 2017;17(7):1853-1867. 

In This Article

Abstract and Introduction

Abstract

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10–14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus −1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10–14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Introduction

As the risk of kidney allograft loss due to acute rejection has declined, the goal of management has switched to long-term preservation of kidney function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective.[1] One significant development has been the introduction of mammalian target of rapamycin (mTOR) inhibitors which, in addition to their immunomodulatory effect, inhibit tumor growth and posttransplant malignancies,[2,3] and are associated with a lower frequency of cytomegalovirus (CMV) infections than conventional CNI-based regimens.[4] Moreover, there is growing evidence that inhibition of mTOR signaling may offer cardioprotective benefits, including an anti-atherogenic effect[5] and reduction of cardiac hypertrophy[6–10] and fibrosis,[11] and possibly attenuation of arterial stiffness.[12,13]

In a series of randomized trials, kidney transplant patients were converted pre-emptively from CNI therapy to an mTOR inhibitor agent between day 30 and month 6 posttransplant.[14–18] Results showed a benefit in renal function compared to conventional CNI therapy, although higher rates of mild acute rejection were observed after switch in some studies.[14–17] All but one trial[18] included only cyclosporine (CsA) in the CNI comparator arm, whereas tacrolimus is now used by a majority of centers in the de novo setting.

The ELEVATE study was an international 2-year study in which over 700 de novo kidney transplant patients were randomized to convert to everolimus at 10–14 weeks posttransplant or to remain on their CNI therapy.[19] The primary objective was to assess the renal effect of early conversion from CNI therapy to everolimus, but also included novel secondary endpoints including left ventricular mass index (LVMi) and prevalence of antibodies against HLA donor-specific antigens in addition to efficacy variables.

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