Mycophenolate Mofetil in the Treatment of Chronic Rejection in Renal Transplantation: 3-Year Follow-Up I.L. Noronha, A.C. Oliveira, H. Abensur, J.E. Roma ˜ o Jr, M.R.T. Arau ´ jo, and R. Zatz C HRONIC REJECTION (CR) is the main cause of late renal allograft dysfunction. Although risk factors of both immunologic and nonimmunologic origin have been implicated, the pathogenesis of CR remains poorly under- stood. Once established, CR progresses inexorably to end- stage renal disease. Conventional triple therapy (TT) with azathioprine (AZA), cyclosporine (CsA), and prednisone (Pred) only partly attenuates the renal injury associated with CR. In recent years, mycophenolate mofetil (MMF) has been shown to effectively prevent acute rejection in renal allo- graft recipients. Given its antiproliferative effects on lym- phocytes and vascular smooth muscle cells, 1 MMF might be expected to attenuate CR as well. However, the effective- ness of MMF in the treatment of CR is still uncertain. In this prospective single-center study we compared two groups of patients with biopsy-proven CR. One of them received conventional TT, whereas the other received a TT scheme in which AZA was replaced by MMF without changing the CsA dose. In this manner, we were able to evaluate whether MMF can specifically delay the progres- sion of CR. MATERIALS AND METHODS Twenty renal transplant patients with clinical and histopathologic diagnosis of CR were included in this study. Renal histologic changes included vascular intimal proliferation, interstitial fibrosis, tubular atrophy, and transplant glomerulopathy, without evidence of acute rejection. CsA nephrotoxicity was excluded. At the time CR was diagnosed, patients were receiving conventional triple therapy consisting of CsA Neoral, azathioprine, and prednisone. Patients were subdivided into two groups: control group, patients remained on conventional TT, consisting of AZA (1.5 to 2 mg/kg per day), CsA Neoral (to maintain through blood levels around 200 ng/mL), and Pred (0.15 mg/kg per day); MMF group, patients received MMF orally (1 g BID) in place of azathioprine with the doses of CsA and Pred equal to those in the control group. Antihypertensive therapy was used to keep blood pressure 140/90 mm Hg. No angiotensin I– converting enzyme inhibitors or angio- tensin II receptor blockers were used. Serum creatinine concentration (S creat ) was monitored every 2 weeks during the first 3 months after beginning the protocol, and monthly thereafter to 36 months. The endpoints of the study were: (1) doubling of serum creatinine compared with baseline; (2) death; and (3) requirement for dialytic therapy due to end-stage renal disease. Survival curves showing the percentage of patients not reaching any of the endpoints were obtained according to the Kaplan–Meier method. The log-rank test was used to evaluate differences between survival curves. RESULTS Baseline clinical data are given in Table 1. Twenty patients were enrolled in this study: 10 in the MMF group and 10 in the control group (Table 1). No significant differences between MMF and control were observed regarding age (36  5 vs 34  5 years), cause of chronic renal failure, type of donor (living vs cadaver), number of retransplants, number of acute rejection episodes (2.9  0.6 vs 2.8  0.7), From the Renal Transplantation Unit, Hospital Benefice ˆ ncia Portuguesa Sa ˜ o Paulo, Sa ˜ o Paulo, SP, Brazil; and Renal Divi- sion, Department of Clinical Medicine, School of Medicine, University of Sa ˜ o Paulo, Sa ˜ o Paulo, SP, Brazil. Supported by a grant (01/01452-5) from the Sa ˜ o Paulo Foun- dation for Research Support (FAPESP), and a research award (301032/95-5) from the Brazilian Council of Scientific and Tech- nologic Development (CNPq). Address reprint requests Dr Irene L. Noronha, Laborato ´ rio de Fisiopatologia Renal, Avenida Dr Arnaldo, 455, Third Floor S-3342, Sa ˜o Paulo, SP 01246-903, Brazil. E-mail: irenenor@usp.br Table 1. Patient Characteristics and Clinical and Laboratory Parameters in the Two Study Groups MMF Group Control Group n 10 10 Gender (M:F) 5:5 7:3 Age (y) 36.4  4.8 33.7  5.2 Cadaver donor 4 (40%) 3 (33%) Second renal transplant 2 (20%) 1 (10%) Number of previous acute rejection episodes 2.9  0.6 2.8  0.7 Number of steroid-resistant rejections 2 (20%) 2 (20%) Time post-Tx of CR diagnosis (mo) 21.1  2.7 15.5  3.1 Serum creatinine before protocol (mg/dL) 2.25  0.23 2.31  0.17 CsA dose (mg/kg per day) before protocol 4.3  0.4 4.1  0.7 Follow-up (mo) 35.1  0.9 31.3  2.6 © 2002 by Elsevier Science Inc. 0041-1345/0-2000/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0041-1345(02)02605-2 Transplantation Proceedings, 34, 491–493 (2002) 491