0041-1337/00/6911-2405/0 TRANSPLANTATION Vol. 69, 2405–2409, No. 11, June 15, 2000 Copyright © 2000 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. MYCOPHENOLATE MOFETIL REDUCES LATE RENAL ALLOGRAFT LOSS INDEPENDENT OF ACUTE REJECTION AKINLOLU O. OJO, 1 HERWIG-ULF MEIER-KRIESCHE, 1 JULIE A. HANSON, 1 ALAN B. LEICHTMAN, 1 DIANE CIBRIK, 1 JOHN C. MAGEE, 2 ROBERT A. WOLFE, 3 LAWRENCE Y. AGODOA, 4 AND BRUCE KAPLAN 1,5 Departments of Medicine, Surgery, and Biostatistics, The University of Michigan, Ann Arbor, Michigan 48109; and The United States Renal Data System, Division of Kidney, Urologic, and Hematologic Diseases, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-6600 Background. Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejec- tion episodes in renal transplant recipients during the 1st year. A beneficial effect of MMF on long-term graft sur- vival has been more difficult to demonstrate. This benefi- cial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft nephropathy independent of that of rejection. Methods. Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. Patients who received a solitary renal trans- plant between October 1, 1988 and June 30, 1997 were studied. The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival. Results. MMF decreased the relative risk for devel- opment of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P<0.001). This effect was independent of its outcome on acute rejection. Censored graft sur- vival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.6% v. 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR1.9, 1988 –91; RR2.9, 1992–94; RR3.7, 1995– 97). Conclusion. MMF therapy decreases the risk of de- veloping CAF. This improvement is only partly caused by the decrease in the incidence of acute rejection observed with MMF; but, is also caused by an effect independent of acute rejection. Chronic allograft nephropathy (CAN) is a major impedi- ment to long-term renal graft survival (1–4). Although my- cophenolate mofetil (MMF) substantially reduces the occur- rence of acute rejection, it has been difficult to discern a significant impact on long term graft survival (5–9). Several clinical trials of new agents such as tacrolimus, rapamycin, and the interleukin-2 receptor blockers have been shown to significantly decrease acute rejection in renal allograft recip- ients (10 –18). However, to this date, none of these studies have been able to demonstrate a statistically significant im- pact on long term results. It is likely that this failure to detect a benefit is in part caused by the relatively small numbers of patients studied and, thus, the inadequate power to detect small but important differences. In addition to its demonstrated positive impact on acute rejection, experimental and clinical studies suggest that MMF may have additional effects that could potentially at- tenuate the development of chronic allograft failure (8,19 – 25). Prospective follow-up analysis of the European clinical trial of MMF to prevent acute rejection demonstrated a sta- tistically insignificant trend toward a small improvement in 3-year graft survival in recipients treated with 2–3 g/day of MMF (81.2 and 084.8%) compared with the placebo group (78.0%, P=0.12) (8). The 3-year graft loss rates (excluding death as a cause of graft loss) in the follow-up analysis demonstrated a favorable effect of MMF (15.2% for MMF 2 g/day vs. 22.0% for the placebo, P=0.03). However, reports from the Tricontinental and U.S. mycophenolate mofetil study groups did not show a significant improvement in 3-year graft survival between the MMF and control groups (6, 9). The three large multicenter trials (European trial and 2 other multicenter trials) enrolled 300 –500 patients each and were not statistically powered to detect the effect of MMF therapy on late graft loss. A definitive answer regard- ing the effect of MMF on late graft loss may not be obtainable from a meta-analysis of these three multicenter trials be- cause of the heterogeneity of study participants and major differences in the immunosuppressive regimen prescribed to the control groups in these trials. Since 1992, the U.S. Scientific Transplant Registry has collected data on over 10,000 adult kidney transplant recip- ients who received MMF as part of their maintenance immu- nosuppressive regimen. This extensive follow-up permits a cohort evaluation of the effect of MMF on late renal allograft survival. In the current study, we performed a multivariate analysis of risk factors for chronic allograft failure in approx- imately 8,500 renal transplant recipients treated with MMF between 1992 and 1997 in comparison with a cohort of recip- ients treated with azathioprine (AZA) to determine whether MMF confers protection against graft loss beyond 6 months after transplantation. The large number of patients allowed us to analyze whether that effect was caused simply by reduction of acute rejection or in addition was caused by an effect independent of acute rejection. METHODS This study was based on data collected by the U.S. Renal Trans- plant Scientific Registry and supplemented with end-stage renal 1 Departments of Medicine. 2 Department of Surgery. 3 Department of Biostatistics. 4 The United States Renal Data System. 5 Address correspondence to: Bruce Kaplan, M.D., The University of Michigan Medical Center, Department of Internal Medicine, 3914 Taubman Center, Box 0364, Ann Arbor, MI 48109-0364. E-mail address: brkaplan@umich.edu. 2405