Everolimus with Very Low-Exposure Cyclosporine A in De Novo Kidney Transplantation: A Multicenter, Randomized, Controlled Trial
Salvadori M, Scolari MP, Bertoni E, Citterio F, Rigotti P, Cossu M, Dal Canton A, Tisone G, Albertazzi A, Pisani F, Gubbiotti G, Piredda G, Busnach G, Sparacino V, Goepel V, Messa P, Berloco P, Montanaro D, Veroux P, Federico S, Bartezaghi M, Corbetta G, Ponticelli C. Transplantation. 2009 Nov 27;88(10):1194-202
Like sirolimus, everolimus is an inhibitor of mTOR. Previous studies have shown that the combination of a calcineurin inhibitor at full-dose with an mTOR inhibitor is associated with increased nephrotoxicity. This RCT compared standard-dose everolimus and low-dose cyclosporine to high-dose everolimus and very-low dose cyclosporine (measured by C2 levels, which are more accurate). There was no difference in renal function or rejection between groups, but there were more graft losses in the low-dose cyclosporine arm. This trial does not include a comparison with a cyclosporine and mycophenolic acid-containing regimen.
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- Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation
Abstract:
BACKGROUND: In combination with everolimus (EVL), cyclosporine A (CsA) may be used at low exposure, so reducing the risk of renal dysfunction in renal transplant recipients (RTR). We evaluated whether higher exposure of EVL could allow a further reduction of CsA. METHODS: De novo RTR were randomized to standard exposure EVL (C0 3-8 ng/mL) with low-concentration CsA (C2 maintenance levels 350-500 ng/mL, group A) or higher EVL exposure (C0 8-12 ng/mL) with very low-concentration CsA (C2 maintenance levels 150-300 ng/mL, group B). The primary endpoints were 6-month creatinine clearance (CrCl) and biopsy-proven acute rejection (BPAR) rate. After 6 months, patients were followed up (observational extension) to 12 months. RESULTS: Two hundred eighty-five RTR (97% from deceased donors) were enrolled. Two patients per group died (1.4%). The 6-month death-censored graft survival was 90.2% in group A and 97.9% in group B and was unchanged at 12 months (P=0.007). There was no significant difference between groups at 6 months in CrCl (59.9 vs. 57.8 mL/min) and BPAR rates (14.7% vs. 11.9%) and also at 12 months (CrCl 62.5+/-20.7 vs. 61.3+/-22.0 mL/min, BPAR 14.7% vs. 14.1%). No significant differences were seen in treated acute rejections, steroid-resistant acute rejections, treatment failures, or delayed graft function, although there was a trend to better results in group B. CONCLUSIONS: EVL given at higher exposure for 6 months plus very low CsA concentration may obtain low acute rejection rate and good graft survival in De novo renal transplantation. However, there was no difference between groups in CrCl.
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