[en] In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.
Disciplines :
Surgery Gastroenterology & hepatology
Author, co-author :
Saliba, F; Hepatobiliary Center, AP-HP Hôpital Paul Brousse, Université Paris-Sud,
Tedesco Silva H Jr., Cibrik D, Johnston T, et al. Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant 2010; 10: 1401-1413.
Flechner SM, Kobashigawa J, Klintmalm G., Calcineurin inhibitor-sparing regimens in solid organ transplantation: Focus on improving renal function and nephrotoxicity. Clin Transplant 2008; 22: 1-15.
De Simone P, Metselaar HJ, Fischer L, et al. Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: A prospective, randomized, multicenter trial. Liver Transpl 2009; 15: 1262-1269.
Saliba F, Dharancy S, Lorho R, et al. Conversion to everolimus in maintenance liver transplant patients: A multicenter, retrospective analysis. Liver Transpl 2011; 17: 905-913.
Masetti M, Montalti R, Rompianesi G, et al. Early withdrawal of calcineurin inhibitors and everolimus monotherapy in de novo liver transplant recipients preserves renal function. Am J Transplant 2010; 10: 2252-2262.
Fischer L, Klempnauer J, Beckebaum S, et al. A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation-PROTECT. Am J Transplant 2012; 12: 1855-1865.
De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: A randomized controlled trial. Am J Transplant 2012; 12: 3008-3020.
Poggio ED, Wang X, Weinstein DM, et al. Assessing glomerular filtration rate by estimation equations in kidney transplant recipients. Am J Transplant 2006; 6: 100-108.
Banff schema for grading liver allograft rejection: An international consensus document. Hepatology 1997; 25: 658-663.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604-612.
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693-699.
Shetty K, Timmins K, Brensinger C, et al. Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 2004; 10: 911-918.
Burra P, Senzolo M, Masier A, et al. Factors influencing renal function after liver transplantation. Results from the MOST, an international observational study. Dig Liver Dis 2009; 41: 350-356.
Herlenius G, Fistouris J, Olausson M, Felldin M, Bäckman L, Friman S., Early renal function post-liver transplantation is predictive of progressive chronic kidney disease. Scand J Gastroenterol 2008; 43: 344-349.
O'Riordan A, Wong V, McCormick PA, Hegarty JE, Watson AJ., Chronic kidney disease post-liver transplantation. Nephrol Dial Transplant 2006; 21: 2630-2636.
Albano L, Berthoux F, Moal MC, et al. Incidence of delayed graft function and wound healing complications after deceased-donor kidney transplantation is not affected by de novo everolimus. Transplantation 2009; 88: 69-76.
Wadei HM, Zaky ZS, Keaveny AP, et al. Proteinuria following sirolimus conversion is associated with deterioration of kidney function in liver transplant recipients. Transplantation 2012; 93: 1006-1012.
Lebranchu Y, Thierry A, Thervet E, et al. Efficacy and safety of early cyclosporine conversion to sirolimus with continued MMF-four-year results of the Postconcept study. Am J Transplant 2011; 11: 1665-1675.
Sánchez-Fructuoso AI, Ruiz JC, Calvo N, et al. Everolimus as primary immunosuppression in kidney transplantation: Experience in conversion from calcineurin inhibitors. Transplantation 2012; 93: 398-405.
Lee JP, Heo NJ, Joo KW, et al. Risk factors for consequent kidney impairment and differential impact of liver transplantation on renal function. Nephrol Dial Transplant 2010; 25: 2772-2785.
Fabrizi F, Dixit V, Martin P, Messa P., Chronic kidney disease after liver transplantation: Recent evidence. Int J Artif Organs 2010; 33: 803-811.
Gonwa TA, Jennings L, Mai ML, Stark PC, Levey AS, Klintmalm GB., Estimation of glomerular filtration rates before and after orthotopic liver transplantation: Evaluation of current equations. Liver Transpl 2004; 10: 301-309.
Cantarovich M, Yoshida EM, Peltekian KM, et al. Poor prediction of the glomerular filtration rate using current formulas in de novo liver transplant patients. Transplantation 2006; 82: 433-436.
