Blog entry by Meguid El Nahas
Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation: Results of the randomized ELEVATE trial.
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 GFR from randomization to month 12, was similar for everolimus versus CNI: mean (SE) 0.3(1.5)mL/min/1.732 versus -1.5(1.5)mL/min/1.732 (p=0.116). At month 24, mean (SD) estimated GFR was 62.5(22.4)mL/min/1.73m2 with everolimus and 57.4 (19.9) mL/min/1.73m2 with CNI (p=0.005), and 59.7(20.5)mL/min/1.73m2 and 53.0(18.0)mL/min/1.73m2 , respectively, for the tacrolimus- and cyclosporine-treated CNI subgroups. BPAR at month 12 was more frequent under everolimus versus CNI overall (9.7% versus 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 post-transplant was associated with similar renal function to standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus thaneverolimus. This article is protected by copyright. All rights reserved.
From this and previous studies, I can see little advantage, and possible disadvantages from CNI to mTOR inhibitors (mTORi) conversion in renal transplantation.
Beside marginally better renal function, that can be ascribed to CNI withdrawal rather than mTORi substitution,https://www.ncbi.nlm.nih.gov/pubmed/25088685
it would seem that mTORi are associated with more biopsy proven acute rejections (BPAR) as also shown in the SOCRATES study: https://www.ncbi.nlm.nih.gov/pubmed/24279685
and possibly more AMR (antibody mediated rejection)... https://www.ncbi.nlm.nih.gov/pubmed/24684741
mTORi are generally poorly tolerated and associated with numerous and often significant side effects. https://www.ncbi.nlm.nih.gov/pubmed/25146383
In the absence of malignancy, I see no place for these agents in renal transplantation.
Prevention of progressive IFTA (Interstitial Fibrosis and Tubular Atrophy) could be managed by CNI dosage optimisation to avoid renal fibrosis whilst minimising AMR.
Combination therapy with mTORi and low dose CNI therapy has also been advocated rather than total discontinuation of CNI as in the ELEVATE study. This may attenuate the risk of DSA and associated chronic AMR: https://www.ncbi.nlm.nih.gov/pubmed/25040585
I invite comments and a discussion.