Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients

After kidney transplantation, patients receive a combination of immunosuppressive medications to prevent rejection of the transplanted kidney. These regimens usually contain a calcineurin-inhibitor (tacrolimus or cyclosporin A), corticosteroids and an antiproliferative agent (mycophenolic acid (MPA), e.g. mycophenolate mofetil (MMF), or azathioprine (AZA)). MPA is considered to be of stronger immunosuppressive potency than AZA, but the benefits on survival of the graft and its safe use over a long period of time are insufficiently understood.

In this systematic review, we compared the efficacy and safety of MPA versus AZA in randomised controlled trials (RCTs) when given as part of the immunosuppressive regimen immediately after kidney transplantation.

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.

Authors' conclusions: 

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.

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Background: 

Modern immunosuppressive regimens after kidney transplantation usually use a combination of two or three agents of different classes to prevent rejection and maintain graft function. Most frequently, calcineurin-inhibitors (CNI) are combined with corticosteroids and a proliferation-inhibitor, either azathioprine (AZA) or mycophenolic acid (MPA). MPA has largely replaced AZA as a first line agent in primary immunosuppression, as MPA is believed to be of stronger immunosuppressive potency than AZA. However, treatment with MPA is more costly, which calls for a comprehensive assessment of the comparative effects of the two drugs.

Objectives: 

This review of randomised controlled trials (RCTs) aimed to look at the benefits and harms of MPA versus AZA in primary immunosuppressive regimens after kidney transplantation. Both agents were compared regarding their efficacy for maintaining graft and patient survival, prevention of acute rejection, maintaining graft function, and their safety, including infections, malignancies and other adverse events. Furthermore, we investigated potential effect modifiers, such as transplantation era and the concomitant immunosuppressive regimen in detail.

Search strategy: 

We searched Cochrane Kidney and Transplant's Specialised Register (to 21 September 2015) through contact with the Trials' Search Co-ordinator using search terms relevant to this review.

Selection criteria: 

All RCTs about MPA versus AZA in primary immunosuppression after kidney transplantation were included, without restriction on language or publication type.

Data collection and analysis: 

Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI).

Main results: 

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.

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