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Calcineurin Inhibitor–Free Mycophenolate Mofetil/Sirolimus Maintenance in Liver Transplantation: The Randomized Spare-the-Nephron Trial

Authors


  • Lewis Teperman, M.D., Dilip Moonka, M.D., Anthony Sebastian, M.D., Linda Sher, M.D., Paul Marotta, M.D., Christopher Marsh, M.D., Baburao Koneru, M.D., John Goss, M.D., and John P. Roberts, M.D., received funding from Roche (Nutley, NJ) for the conduct of this study. Sher and Roberts currently are receiving research funding from Novartis. Dennis Preston, Pharm.D., currently is an employee of Genentech, which was acquired by Roche after the study was completed.

  • The study sponsor, Roche, provided financial support for this research and contributed to the study design, analysis, and interpretation; and the development of the article.

  • The members of the Spare-the-Nephron Trial Liver Transplantation Study Group are listed in the Supporting Information.

Address reprint requests to Lewis Teperman, M.D., Mary Lea Johnson Richards Organ Transplant Center, New York University School of Medicine, 403 East 34th Street, 3rd Floor, New York, NY 10016. Telephone: 212-263-8134; Fax: 212-263-8157; E-mail: lewis.teperman@med.nyu.edu

Abstract

Mycophenolate mofetil (MMF) and sirolimus (SRL) have been used for calcineurin inhibitor (CNI) minimization to reduce nephrotoxicity following liver transplantation. In this prospective, open-label, multicenter study, patients undergoing transplantation from July 2005 to June 2007 who were maintained on MMF/CNI were randomized 4 to 12 weeks after transplantation to receive MMF/SRL (n = 148) or continue MMF/CNI (n = 145) and included in the intent-to-treat population. The primary efficacy endpoints were the mean percentage change in the calculated glomerular filtration rate (GFR) and a composite of biopsy-proven acute rejection (BPAR), graft lost, death, and lost to follow-up 12 months after transplantation. Patients were followed for a median of 519 days after randomization. MMF/SRL was associated with a significantly greater renal function improvement from baseline with a mean percentage change in GFR of 19.7 ± 40.6 (versus 1.2 ± 39.9 for MMF/CNI, P = 0.0012). The composite endpoint demonstrated the noninferiority of MMF/SRL versus MMF/CNI (16.4% versus 15.4%, 90% confidence interval = −7.1% to 9.0%). The incidence of BPAR was significantly greater with MMF/SRL (12.2%) versus MMF/CNI (4.1%, P = 0.02). Graft loss (including death) occurred in 3.4% of the MMF/SRL-treated patients and in 8.3% of the MMF/CNI-treated patients (P = 0.04). Malignancy-related deaths were less frequent with MMF/SRL. Adverse events caused withdrawal for 34.2% of the MMF/SRL-treated patients and for 24.1% of the MMF/CNI-treated patients (P = 0.06). The use of MMF/SRL is an option for liver transplant recipients who can benefit from improved renal function but is associated with an increased risk of rejection (but not graft loss). Liver Transpl 19:675–689, 2013.. © 2013 AASLD.

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