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REmote preconditioning for Protection Against Ischaemia–Reperfusion in renal transplantation (REPAIR): a multicentre, multinational, double-blind, factorial designed randomised controlled trial Raymond MacAllister,1* Tim Clayton,2 Rosemary Knight,2 Steven Robertson,2 Jennifer Nicholas,2 Madhur Motwani1 and Kristin Veighey3 1Division of Medicine, University College London, London, UK 2Clinical Trials Unit, London School of Hygiene and Tropical Medicine, London, UK 3Portsmouth Hospitals NHS Trust, Portsmouth, UK *Corresponding author r.macallister@ucl.ac.uk Background: Long-term kidney allograft survival has remained unchanged in recent years despite immunosuppressive and surgical advances. Ischaemia–reperfusion (IR) injury sustained at transplantation contributes to kidney damage that limits allograft lifespan. Interventions to reduce IR injury may prolong graft life, delaying the need for a return to dialysis. Remote ischaemic preconditioning (RIPC), in which brief episodes of non-lethal ischaemia applied to the limb activate a systemic protective reflex against subsequent damaging IR injury, has been reported to cause cardiac, renal and neurological protection in small-scale trials. Objectives: The REmote preconditioning for Protection Against Ischaemia–Reperfusion in renal transplantation (REPAIR) trial investigated whether RIPC improves kidney function and other outcomes following living-donor renal transplantation. Design: Multicentre, multinational, double-blind, 2 × 2 factorial designed randomised controlled trial. Setting: Thirteen tertiary care hospitals in the UK, the Netherlands, Belgium and France. Participants: The REPAIR trial recruited 406 live donor–recipient pairs aged ≥ 18 years. Patients on adenosine triphosphate (ATP)-sensitive potassium channel opening or blocking drugs, on ciclosporin, with a known iodine sensitivity or with ABO incompatibility or those requiring human leucocyte antigen (HLA) antibody removal therapy were excluded. Interventions: Each pair was randomised using a factorial design to one of four groups: sham RIPC, early RIPC (immediately before surgery), late RIPC (24 hours before surgery) and dual RIPC (early and late RIPC). The donor and recipient received the same intervention (active RIPC or sham RIPC) at the two time points. Main outcome measures: The primary outcome was glomerular filtration rate (GFR) 12 months after transplantation measured by iohexol clearance. Important secondary outcomes were estimated GFR (eGFR) (using routine clinical assessment), safety, inflammatory cytokine profile and biological mechanisms. DOI: 10.3310/eme02030 EFFICACY AND MECHANISM EVALUATION 2015 VOL. 2 NO. 3 © Queen’s Printer and Controller of HMSO 2015. This work was produced by MacAllister et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. v Results: In total, 406 donor–recipient pairs were randomised: 99 to sham RIPC, 102 to early RIPC, 103 to late RIPC and 102 to dual RIPC. Early RIPC resulted in a small but clinically important increase in iohexol GFR (ml/minute/1.73m2) at 12 months, although the evidence is weak [58.3 vs. 55.9; adjusted difference 3.08, 95% confidence interval (CI) –0.89 to 7.04; p=0.13], likely because of the higher than expected variability in the iohexol measurements. There was stronger evidence for a treatment effect when eGFR was used and missing values imputed (adjusted difference 3.41, 95% CI –0.21 to 7.04; p=0.065) and when eGFR was used to assess kidney function (adjusted difference 4.98, 95% CI 1.13 to 8.29; p=0.011). Late RIPC had no effect on renal outcomes, there was no benefit of combining early and late RIPC and RIPC had no effect on the inflammatory response to surgery. RIPC was safe and well tolerated by recipients and donors. Conclusions: RIPC is a safe intervention in living-donor transplantation. The evidence for an effect of RIPC on GFR (primary outcome) was weak, but other measures of GFR (in our secondary analysis) provided persuasive evidence of a clinically meaningful improvement in kidney function after transplantation. Future work should investigate the role of RIPC in deceased-donor kidney transplantation. Trial registration: Current Controlled Trials ISRCTN30083294. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership. ABSTRACT NIHR Journals Library www.journalslibrary.nihr.ac.uk vi

efficacy and mechanism evaluation

REmote preconditioning for Protection Against Ischaemia–Reperfusion in renal transplantation (REPAIR): a multicentre, multinational, double-blind, factorial designed randomised controlled trial