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

Abstract

BackgroundLong-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.ObjectivesThe 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.DesignMulticentre, multinational, double-blind, 2 × 2 factorial designed randomised controlled trial.SettingThirteen tertiary care hospitals in the UK, the Netherlands, Belgium and France.ParticipantsThe 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.InterventionsEach 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 measuresThe 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.ResultsIn 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/1.73 m2) 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.ConclusionsRIPC 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 registrationCurrent Controlled Trials ISRCTN30083294.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

Is Remote Ischemic Conditioning of Benefit to Patients Undergoing Kidney Transplantation?

“…6 It is possible that elevated TNF-α in the setting of RIPC has a regenerative role rather than inflammatory, since IL-6 level, another cytokine in the acute phase response, was significantly lower in RIPC group at 30 days post kidney transplantation, despite the persistent elevation of TNF-α. The modulation of cytokine effects after RIPC was not observed in a previous clinical trial of RIPC in living donor kidney transplantation by MacAllister et al 7 Conversely, they demonstrated comparable serum levels of TNF-α and IL-6 in both Remote Ischemic Conditioning in Kidney Transplantation 3 RIPC and control groups. Moreover, published clinical trials have emphasized the clinical safety of RIPC in kidney transplantation and demonstrated potential beneficial effects (Table 1).…”

Remote ischaemic pre‐conditioning for the prevention of acute kidney injury

“…In the context of living‐donor kidney transplant, a recently published large‐scale, multi‐centre, multinational phase III RCT (REPAIR trial) reported promising results . The REPAIR trial studied the effect of rIPC on improving kidney function in living‐donor kidney transplant and also whether timing of rIPC stimulus application would affect outcome.…”

“…However, the study found a higher level of renoprotection as assessed by sCr, blood urea nitrogen and renal histology when rIPC was applied >24 h before ischaemic insult (late window of protection) versus that applied shortly before the index ischaemia (early window of protection). Data in humans has been lacking until recently, one phase III trial (REPAIR trial) was designed to explore the optimal window of protection in human transplant recipients . However, the study found no significant effect on renal outcomes by early, delayed rIPC or combining the two.…”

“…In the context of living-donor kidney transplant, a recently published large-scale, multi-centre, multinational phase III RCT (REPAIR trial) reported promising results. 68 The REPAIR trial studied the effect of rIPC on improving kidney function in living-donor kidney transplant and also whether timing of rIPC stimulus application would affect outcome. The study involved 406 live donor-recipient pairs ≥18 years old from 13 centres in the UK and Europe, and were randomized in 1:1:1:1 ratio to four groups: early rIPC (immediately before surgery), late rIPC (24 h before surgery), dual rIPC (early and late rIPC) and sham rIPC.…”

Remote Ischemic Preconditioning: Would You Give Your Right Arm to Protect Your Kidneys?

“…Results of the RIPHeart (Remote Ischaemic Preconditioning for Heart Surgery) trial, in which AKI was a component of the primary end point, are eagerly awaited. 18 Interestingly, RIPC has been reported to confer renoprotection in several other clinical settings, including major vascular surgery, 19,20 elective percutaneous coronary intervention for stable coronary artery disease, 21,22 primary percutaneous coronary intervention for patients with ST-segment elevation myocardial infarction, 23,24 and kidney transplantation, 25 although again, not all studies have been positive. 26,27 WHAT SHOULD CLINICIANS AND RESEARCHERS DO?…”