Mycophenalate mofetil in renal transplant recipients: predisposition to gastrointestinal intolerance

Chen, Min-Shien
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Objective Renal transplantation is the ideal therapeutic option for patients that reach end-stage renal failure. However, patients require long term immunosuppression following surgical transplantation to prevent graft rejection [1,2,4]. Mycophenolate mofetil (MMF) had proven to be an effective immunosuppressant in transplant patients[8,9,10], although it is associated with an increase in gastrointestinal adverse effects, which may result in dose adjustment or termination of use [22]. There is a paucity of data regarding gastrointestinal side effects of MMF in South Africa. This study attempts to describe the incidence of gastrointestinal complications, incidence of dose adjustment and discontinuation of MMF due to side effects, to compare the incidence of GI complications between those that had prior gastrointestinal ailments and those that had no prior gastrointestinal ailments and finally to determine possible risk factors (age, gender, ethnicity, donor type, pre-transplant GI diagnosis, pre-transplant diabetes and combination of MMF with tacrolimus) of gastrointestinal adverse effects. Method Data was collected retrospectively from the file records of the renal transplant unit at CMJAH (Charlotte Maxeke Johannesburg Academic Hospital) on adult patients who had received kidney transplants between 1998 and 2010 and who had received MMF as part of the immunosuppressive regimen for at least the one year post-transplant. Relevant data was captured in an anonymous fashion on a collection sheet. Descriptive analysis of the data was carried out. Time-to-event data were analysed by Kaplan-Meier survival analysis. The assessment of the effect of prior gastrointestinal ailments, as well as risk factors, was carried out by Cox Proportional Hazards regression to estimate the Hazard Ratios. Results A total of 188 patients were included in the study group, which comprised 65.4% males and 32.4% females (2.1% missing data). The mean age at transplant was 38.1 years. The patients were predominantly black (69.1%). Donors were predominantly deceased donors. Of the 24.5% of donors who were living donors, 76.1% were related living donors, while the rest were non-related living donors. The majority of patients (82%) were induced with MMF dose of 2 grams per day. After 5 years, 13.8% of patients discontinued MMF while 86.2% of the patients were still on MMF. 48.1% had a dose adjustment due to gastrointestinal side effects. 61% of patients had had a diarrhoeal adverse event by 5 years. 21.8% of the patients had gastrointestinal side effects other than diarrhoea by 5 years. The combination of tacrolimus and MMF was found to be a significant risk factor for diarrhoeal adverse events (Hazard Ratio 1.82; 95% CI 1.21-2.73). Having a living donor graft reduced the chance of non-diarrhoeal gastrointestinal adverse event (Hazard Ratio 0.33; 95% CI 0.13-0.84, p<0.02). A trend towards significance was seen in living donors having less diarrhoeal events although it did not reach statistical significance (Hazard Ratio 1.32; 95% CI 0.87-2.00, p=0.20). Conclusion As far as the authors are aware, this is the first local study on MMF and GIT adverse effect. We found the combination of MMF and tacrolimus is associated with increased risk of having diarrhoeal adverse events, which is consistent with international data[34,35]. Living donor graft is associated with a lower risk of developing non-diarrhoeal gastrointestinal events. Although non-significant, data suggest the same trend favoring living donor graft with regards to diarrhoeal events.
Division of Nephrology Department of Internal Medicine School of Clinical Medicine Faculty of Health Sciences University of Witwatersrand 7th June, 2017