The Treatment of Antibody-Mediated Rejection in Kidney Transplantation: An Updated Systematic Review and Meta-Analysis

ABSTRACTBackgroundCurrent treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B-cells, plasma-cells and the complement system have featured in recent studies of AMR.MethodsWe conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE and CENTRAL from inception to February 2017.ResultsOf 14,380 citations we identified 21 studies, including 10 randomized controlled trials, involving 751 participants. Since the last systematic review conducted in 2011, we found 9 additional studies evaluating: plasmapheresis + intravenous immunoglobulin (IVIG) (2), rituximab (2), bortezomib (2), C1-inhibitor (2), and eculizumab (1). Risk of bias was serious or unclear overall and evidence quality was low for the majority of treatment strategies. Sufficient RCTs for pooled analysis were available only for antibody removal, and here there was no significant difference between groups for graft survival (HR 0.76; 95% CI 0.35–1.63; P=0.475). Studies showed important heterogeneity in treatments, definition of AMR, quality and follow-up. Plasmapheresis and IVIG were used as standard-of-care in recent studies, and to this combination, rituximab appeared to add little or no benefit. Insufficient data are available to assess the efficacy of bortezomib and complement inhibitors.ConclusionNewer studies evaluating Rituximab showed little or no difference to early graft survival, and the efficacy of bortezomib and complement inhibitors for the treatment of AMR remains unclear. Despite the evidence uncertainty, plasmapheresis and IVIG have become standard-of-care for the treatment of acute AMR. Background Current treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B-cells, plasma-cells and the complement system have featured in recent studies of AMR. Methods We conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE and CENTRAL from inception to February 2017. Results Of 14,380 citations we identified 21 studies, including 10 randomized controlled trials, involving 751 participants. Since the last systematic review conducted in 2011, we found 9 additional studies evaluating: plasmapheresis + intravenous immunoglobulin (IVIG) (2), rituximab (2), bortezomib (2), C1-inhibitor (2), and eculizumab (1). Risk of bias was serious or unclear overall and evidence quality was low for the majority of treatment strategies. Sufficient RCTs for pooled analysis were available only for antibody removal, and here there was no significant difference between groups for graft survival (HR 0.76; 95% CI 0.35–1.63; P=0.475). Studies showed important heterogeneity in treatments, definition of AMR, quality and follow-up. Plasmapheresis and IVIG were used as standard-of-care in recent studies, and to this combination, rituximab appeared to add little or no benefit. Insufficient data are available to assess the efficacy of bortezomib and complement inhibitors. Conclusion Newer studies evaluating Rituximab showed little or no difference to early graft survival, and the efficacy of bortezomib and complement inhibitors for the treatment of AMR remains unclear. Despite the evidence uncertainty, plasmapheresis and IVIG have become standard-of-care for the treatment of acute AMR. Received 10 July 2017. Revision received 29 October 2017. Accepted 1 November 2017. CORRESPONDANCE: Professor Steve Chadban, Department of Renal Medicine, Royal Prince Alfred Hospital, Missenden Rd, Camperdown NSW 2050, Australia. E: Steve.Chadban@health.nsw.gov.au AUTHORSHIP - Susan Wan – Research design, study protocol preparation, performed search and study selection, data synthesis and manuscript preparation - Tracey Ying – Research design, study protocol preparation, performed search and study selection, data synthesis and manuscript preparation - Kate Wyburn – Research design, data review and manuscript preparation - Darren Roberts – Research design and manuscript preparation - Melanie Wyld – Research design and manuscript preparation - Steve Chadban – Research design, data review and manuscript preparation All authors approved the final manuscript DISCLOSURE The authors declare no conflicts of interest FUNDING SW is funded by the Royal Australasian College of Physicians (RACP) Jacquot Research Entry Scholarship for her postdoctoral studies TY is funded by the Australian Postgraduate Award for her postdoctoral studies Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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