0041-1337/04/7702-215/0 TRANSPLANTATION Vol. 77, 215–220, No. 2, January 27, 2004 Copyright © 2004 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. MYCOPHENOLATE MOFETIL REDUCES DETERIORATION OF RENAL FUNCTION IN PATIENTS WITH CHRONIC ALLOGRAFT NEPHROPATHY AFOLLOW-UP STUDY BY THE SPANISH COOPERATIVE STUDY GROUP OF CHRONIC ALLOGRAFT NEPHROPATHY 1,2 MIGUEL GONZALEZ MOLINA, 3,9 DANIEL SERON, 4 RAIMUNDO GARCIA DEL MORAL, 5 MARTA CARRERA, 4 EUGENIA SOLA, 3 MARIA JESUS ALFEREZ, 3 PABLO GOMEZ ULLATE, 6 LUIS CAPDEVILA, 7 AND MIGUEL A. GENTIL 8 Background. Although studies have shown that my- cophenolate mofetil (MMF) with cyclosporine (CsA) and prednisone can reduce the incidence of acute re- jection and increase the half-life of the graft, the ef- fects of MMF on established chronic allograft ne- phropathy (CAN) are controversial. Methods. We studied 121 patients with biopsy- proven CAN, 59 treated with CsA and prednisone and 62 treated with triple-drug therapy with azathioprine. At inclusion, each group received 2 g per day of MMF and azathioprine was stopped. Renal function was measured by the glomerular filtration rate (GFR) ob- tained by creatinine clearance (Cockcroft-Gault) and monitored by the slope of the GFR, adjusted using linear regression. Results. The median follow-up, after incorporation of MMF, was 36 (13–36) months, with 103 (85.1%) hav- ing a full 3-year follow-up. Before the introduction of MMF, there was progressive deterioration in renal function (GFR: 54.820.9 vs. 39.714.0 mL/min, P<0.001). After introduction of MMF, renal function remained stable (GFR: 39.714.0 vs. 41.310.8 mL/min, PNS), with a significant change in the slope of the GFR (0.0144 vs. 0.00045, P<0.001). In 65 patients in whom CsA blood levels remained unchanged during follow-up (148.065.6 vs. 154.158.2, PNS), the slope of the GFR showed a reduction in loss of renal func- tion (0.0147 vs. 0.0001, P<0.001). Conclusions. Treatment with MMF reduced the pro- gressive deterioration of renal function in patients with CAN, independently of the blood levels of CsA. The most common cause of renal allograft failure after the first year is a clinicopathologic entity known as chronic allo- graft nephropathy (CAN), characterized by progressive dete- rioration of renal function produced by pathologic changes affecting blood vessels, glomeruli, the interstitium, and tu- bules (1). CAN is more common in patients with acute rejec- tion (AR) (2), those with greater HLA incompatibility (3), those with cytomegalovirus infection (4), and those receiving inadequate dosages of cyclosporine (CsA) after the first year (5). These data suggested that immunologic factors are the main cause of CAN. Various European (6), tricontinental (7), and U.S. (8) stud- ies of mycophenolate mofetil (MMF) have shown that MMF associated with CsA and prednisone (P) significantly reduces the number of episodes of AR and the incidence of corticoste- roid-resistant AR, but they have not conclusively shown a medium-term improvement in graft survival. This is impor- tant if we consider that AR is an independent risk factor for graft loss from CAN (9). Logically, a reduction in the number of episodes of AR, with its associated severity, would be expected to be accompanied by a general improvement in graft survival. Experimental studies have also shown a protective effect of MMF for the mechanical vascular damage induced by insuf- flation of the angioplasty catheter balloon. The lesion pro- duced by this technique is similar to the vasculopathy of CAN and is characterized by the proliferation of smooth muscle cells within hours and their migration to the intima, where they proliferate again and secrete collagen matrix. Rapamy- cin and MMF, although probably through different mecha- nisms, are the only immunosuppressive agents able to pre- vent this lesion (10). In a rat model of CAN, the combination of both drugs led to a significant reduction in vascular fibrous intimal thickening, glomerulopathy, and interstitial fibrosis (11). A retrospective study (12) of 66,774 renal transplant (RT) patients showed that MMF reduces the relative risk of chronic renal failure by 27%, independently of its effect on AR. Preliminary data from the Spanish Cooperative Study Group of CAN showed a protective effect of MMF on renal function in established CAN (13). These data support the concept that MMF can modify the course of CAN. 1 This work was supported by a Grant from Roche Farma, Madrid, Spain. 2 Presented in part at the ERA-EDTA Congress (Vienna, Austria, June 24 –27, 2001), the ESOT Congress (Lisbon, Portugal, October 6 –11, 2001), and The 2nd International Congress on Immunosup- pression (San Diego, CA, December 6 – 8, 2001). 3 Division of Nephrology, Hospital Universitario Carlos Haya, Malaga, Spain. 4 Division of Nephrology and Pathology, Hospital de Bellvitge, Barcelona, Spain. 5 Division of Pathology, Hospital Clinico Universitario, Granada, Spain. 6 Division of Nephrology, Hospital de Cruces, Bilbao, Spain. 7 Division of Nephrology, Hospital Vall d’ Hebron, Barcelona, Spain. 8 Division of Nephrology, Hospital Universitario Virgen del Rocio, Sevilla, Spain. 9 Address correspondence to: Miguel Gonzalez Molina, M.D., Di- vision of Nephrology, Hospital Universitario Carlos Haya, Plaza Dr. J.L. Gutierrez Calzada S/N, 29010 Malaga, Spain. E-mail: cotraspa.hch.sspa@juntadeandalucia.es. Received 11 February 2003. Revision Requested 2 April 2003. Accepted 18 June 2003. 215 DOI: 10.1097/01.TP.0000100684.59784.FF