A BLINDED, RANDOMIZED CLINICAL-TRIAL OF MYCOPHENOLATE MOFETIL FOR THEPREVENTION OF ACUTE REJECTION IN CADAVERIC RENAL-TRANSPLANTATION

Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhib its the proliferation of T and B lymphocytes by blocking the enzyme in osine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double- blind, multicenter trial to compare the efficacy and safety of MMF and azathioprine within a standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 pat ients were randomized to groups receiving MMF 3 g (n = 164), MMF 2 g ( n = 173), or azathioprine (AZA) 100-150 mg (n = 166) daily. All were t reated simultaneously with equivalent doses of cyclosporine and oral c orticosteroids and followed for 12 months. The primary endpoint was tr eatment failure, defined as the occurrence of biopsy-proven graft reje ction, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure oc curred in 50.0% of patients in the AZA group by 6 months after transpl antation, compared with 34.8% in the MMF 3 g group (P = 0.0045) and 38 .2% in the MMF 2 g group (P = 0.0287). Biopsy-proven rejection occurre d in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF 2 g g roup, compared with 35.5% in the AZA group. Rejection of histologic se verity grade II or more developed in 6.1%, 10.4%, and 19.9% of patient s in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients rece iving MMF required less frequent and less intensive treatment for acut e rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tr eated for acute rejection, compared with 47.5% on AZA. Only 4.9% on MM F 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treat ment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year afte transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, alth ough this difference was not statistically significant. Gastrointestin al toxicity and tissue-invasive cytomegalovirus infection were more co mmon in the MMF 3 g group. Noncutaneous malignancies occurred in six p atients on MMF 3 g, three patients on MMF 2 g, and four patients on AZ A. Lymphoproliferative disorders occurred in two patients per MMF grou p, compared with one patient receiving AZA. MMF appears to be an impor tant advance in prophylaxis following renal transplantation. It is ass ociated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and pro duces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist through out the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalo virus infection, and malignancies were slightly more common at that do se. The appropriate dose may lie between 2 g and 3 g per day and may r equire individualization depending on clinical course or other factors .