Immunosuppressive therapy for renal transplantation in adults: a systematic review and network meta-analyses.


Background Renal transplantation accompanied with induction and maintenance immunosuppressive therapy is the preferred option in end stage kidney disease due to improved duration and quality of life when compared to dialysis. The National Institute for Health and Care Excellence conducted a technology appraisal to update a previous guidance for the NHS in England on the use of immunosuppressive agents in adult kidney transplantation (TA85). We present the results of the systematic review conducted as part of the appraisal. Methods The evidence for the clinical effectiveness of basiliximab (BAS) and rabbit anti-human thymocyte immunoglobulin (rATG) as induction therapy, and immediate-release tacrolimus (TAC), prolonged-release tacrolimus (TAC PR), belatacept (BEL), mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus (SRL), and everolimus (EVL) as maintenance therapy in adult renal transplantation was reviewed. Searches were conducted in Medline (OVID), Embase (OVID), CENTRAL (Wiley) and Web of Science (ISI), CDSR, DARE and HTA (The Cochrane Library via Wiley) and HMIC (OVID). Included studies were selected according to predefined methods and criteria. Outcomes evaluated were mortality, biopsy-proven acute rejection (BPAR), graft function and graft loss. Included studies were extracted and quality appraised. Data were tabulated, discussed narratively and, where appropriate, network meta-analyses (NMAs) were undertaken within a Bayesian framework. For NMAs assessing the effectiveness of induction therapy, the reference treatment was no induction/placebo. For NMAs evaluating the effectiveness of maintenance therapy, the reference treatment was ciclosporin (CSA) + azathioprine (AZA). Results Eighty-six RCTs of variable quality were included. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing BPAR, but the evidence does not suggest a statistically significant difference between the two treatments. None of the maintenance regimens performed consistently well on all outcomes. BEL+MMF appeared more effective than TAC+MMF and SRL+MMF at reducing mortality. MMF+CSA, TAC+MMF, SRL+TAC, TAC+AZA and EVL+CSA appeared more effective than CSA+AZA and EVL+MPS at reducing BPAR. SRL+AZA, TAC+AZA, TAC+MMF and BEL+MMF appeared more effective in improving graft function than CSA+AZA and MMF+CSA. Conclusions Despite the high number of included studies there is limited conclusive evidence on the clinical effectiveness of induction or maintenance therapies. Compared with placebo/no induction, we found evidence that rATG and BAS were more effective in reducing BPAR. With regard to maintenance therapy, the NMAs showed none of the maintenance regimens performed consistently well on all four outcomes and a great deal of heterogeneity was noted. High quality, better reported, longer-term RCTs sufficiently powered for subgroup analysis are needed. Acknowledgements This project was funded by the NIHR Health Technology Assessment Programme (project number 09/46/01). It will be published in full in Health Technology Assessment journal (in press). See the HTA Programme website ( ) for further project information. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health.