Abstract: We included 23 studies (94 reports) that involved 3301 participants. All studies tested mycophenolate mofetil (MMF), an MPA, and 22 studies reported at least one outcome relevant for this review. Assessment of methodological quality indicated that important information on factors used to judge susceptibility for bias was infrequently and inconsistently reported. MMF treatment reduced the risk for graft loss including death (RR 0.82, 95% CI 0.67 to 1.0) and for death-censored graft loss (RR 0.78, 95% CI 0.62 to 0.99, P < 0.05). No statistically significant difference for MMF versus AZA treatment was found for all-cause mortality (16 studies, 2987 participants: RR 0.95, 95% CI 0.70 to 1.29). The risk for any acute rejection (22 studies, 3301 participants: RR 0.65, 95% CI 0.57 to 0.73, P < 0.01), biopsy-proven acute rejection (12 studies, 2696 participants: RR 0.59, 95% CI 0.52 to 0.68) and antibody-treated acute rejection (15 studies, 2914 participants: RR 0.48, 95% CI 0.36 to 0.65, P < 0.01) were reduced in MMF treated patients. Meta-regression analyses suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rate (relative risk reduction (RRR) 0.34, 95% CI 0.10 to 1.09, P = 0.08), AZA dose (RRR 1.01, 95% CI 1.00 to 1.01, P = 0.10) and the use of cyclosporin A micro-emulsion (RRR 1.27, 95% CI 0.98 to 1.65, P = 0.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures. Data on malignancies and infections were sparse, except for cytomegalovirus (CMV) infections. The risk for CMV viraemia/syndrome (13 studies, 2880 participants: RR 1.06, 95% CI 0.85 to 1.32) was not statistically significantly different between MMF and AZA treated patients, whereas the likelihood of tissue-invasive CMV disease was greater with MMF therapy (7 studies, 1510 participants: RR 1.70, 95% CI 1.10 to 2.61). Adverse event profiles varied: gastrointestinal symptoms were more likely in MMF treated patients and thrombocytopenia and elevated liver enzymes were more common in AZA treatment. MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation. These benefits must be weighed against potential harms such as tissue-invasive CMV disease. However, assessment of the evidence on safety outcomes was limited due to rare events in the observation periods of the studies (e.g. malignancies) and inconsistent reporting and definitions (e.g. infections, adverse events). Thus, balancing benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent the individual patient should be started on.

Plain-language summary: Searches to 21 September 2015 identified 23 studies in which 3301 patients were treated with MPA (all studies used MMF) or AZA. Methodological quality of the studies was limited, e.g. only in two RCTs was the study medication administered in a blinded fashion. MMF was more effective than AZA for reducing the risk of graft loss (by approximately 20%) and acute rejection (by approximately 30%). No difference in mortality was observed. Moreover, graft function appeared to be similar in both treatments. When drugs are given to suppress the immune system, this can result in serious side effects such as infections and malignancies. The data on adverse events was limited by relatively short follow up in the studies as some of these side effects occur after several years of treatment. Furthermore, the studies did not focus on these harms and did not use harmonised diagnostic criteria. The incidence of cytomegalovirus infections did not differ between MMF and AZA, but there was a 1.7-fold increased risk for the more severe, tissue-invasive cytomegalovirus disease in MMF-treated patients. Information on malignancies was reported only in five studies; therefore no robust conclusions can be drawn. Gastrointestinal side effects (e.g. nausea, diarrhoea) were more common with MMF-treatment, whereas bone marrow suppression (e.g. thrombocytopenia) and elevated liver enzymes were observed more frequently in AZA treated patients. In general, evidence for efficacy outcomes is of high quality and can be seen as considerably robust, but there is less certainty on aspects of safety. Therefore, caregivers should balance potential benefits and harms of MMF and AZA according to individual patient's risks and preferences. Physicians need to individualise the decision between these agents as components of the immunosuppressive regimen.