MYCOPHENOLATE INTOLERANCE INCREASES THE RISK OF REJECTION IN KIDNEY TRANSPLANT PATIENTS ON CYCLOSPORINE BUT NOT ON TACROLIMUS TRIPLE THERAPY

Abstract

O289 Aims: We analysed mycophenolate mofetil (MMF) safety profile and the effect of MMF dosing changes on early results of kidney transplantation. Methods: Between September 1, 1992 and October 1, 2003, 407 cadaveric kidney transplantations were performed using triple immunosuppression with cyclosporine (CyA, N=264) or tacrolimus (Tac, N=143) and MMF plus steroids. The initial dosage of MMF was usually 1000 mg b.i.d. in CyA-patients and 500 mg b.i.d. in Tac-patients. We evaluated the safety profile and efficacy of these regimens. Original patient documents were examined and adverse events (AE), MMF dose changes and rejections during the first 100 posttransplant days were recorded. For this analysis, laboratory limits for AEs were set as follows: platelet count <100 x 109, WBC count <3,0 x 109, and liver toxicity was defined as alanine aminotransferase (ALAT) >60 U/l. Results: Liver toxicity was found in 49.6% of patients, thrombocytopenia in 9.1%, leukopenia in 6.4%, diarrhoea in 20.9%, other gastrointestinal (GI) AEs in 23.1% and infections in 25.8%. CyA patients had significantly more liver toxicity (55.3 % vs. 39.2 %, p<0.005) and thrombocytopenia (11.4 % vs. 4.9 %, p< 0.05), whereas Tac patients had more diarrhoea (32.9 % vs. 14.4 %, p<0.001) and other GI AEs (30.8 % vs. 18.9 %, p<0.01). Patients with delayed graft function had significantly more diarrhoea (29.6% vs 16.3%, p<0.005), other GI symptoms (31.9% vs 17.5%, p<0.005), and thrombocytopenia (15.6% vs 6.1%, p<0.005). MMF dose reductions or discontinuations had been done according to clinical judgement in 136/407 cases (33.4%), and 77% of them had been done before day 21 post TX. The indications were liver toxicity in 90 (22.1% of all patients), thrombocytopenia in 8 (2.0%), leukopenia in 15 (3.7%), anaemia in 4 (1.0%), diarrhoea in 7 (1.7%), other GI AEs in 8 (2.0%) and infection in 4 patients (1.0%). Dose reductions had been done in 39.8% of all CyA patients and in 24.5% of all Tac patients (p=0.001). The overall rejection rate was 11.5% (CyA 11.4%, Tac 11.9%). With full MMF throughout, the rejection rate was 8.3% compared to 17.6% with MMF dose reductions (p=0.005). In CyA patients, reduction of MMF within the first three weeks increased the rejection rate during the subsequent three-week period, from 0.6% to 10 % (Chi-square: p<0.001). In Tac patients no increase could be seen. Conclusions: MMF intolerance, especially liver toxicity, occurred in a high proportion of our patients, more often in CyA patients with the higher MMF dosage. In one third of all patients, MMF reduction was deemed necessary. These results demonstrate that if an adequate MMF dose can not be maintained, patients on CyA-MMF-steroid immunosuppression carry a highly increased risk of rejection during a vulnerable post transplant time period.