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MacAllister R, Clayton T, Knight R, et al. REmote preconditioning for Protection Against Ischaemia–Reperfusion in renal transplantation (REPAIR): a multicentre, multinational, double-blind, factorial designed randomised controlled trial. Southampton (UK): NIHR Journals Library; 2015 May. (Efficacy and Mechanism Evaluation, No. 2.3.)

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

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

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Chapter 4Discussion

The REPAIR trial is the largest clinical trial of IPC to measure the effect of this procedure on a clinically relevant (real) end point. The REPAIR trial examined the early and delayed effects of RIPC on kidney function after transplantation. Although an effect of early RIPC on iohexol clearance (primary end point) did not reach conventional statistical significance, we observed a beneficial effect of early preconditioning on eGFR (secondary end point) 3 months and 1 year after living-donor transplantation, which was mirrored by an increase in GFR measured by iohexol clearance. There was little evidence of an effect of delayed preconditioning on kidney function. RIPC was tolerated by > 90% of patients, had minimal morbidity, had a very low cost and caused minimal inconvenience to patients. Regardless of the uncertainty that arises from interpreting a single Phase III clinical trial, and the larger than expected variability in the iohexol measurements, the benefit–risk ratio of RIPC is sufficiently large to recommend it for living-donor kidney transplantation.

Design of the REPAIR trial

Remote ischaemic preconditioning is a whole-body systemic reflex activated by localised transient ischaemia that is itself non-injurious. The discovery that limb ischaemia could activate this reflex, and limit tissue injury to vital organs in animals and humans, has stimulated a large number of clinical trials to detect protective effects in patients. Most of these have been too small to measure real clinical end points and the small sample sizes have doubtless contributed to heterogeneity and uncertainty in the trial findings. We chose living-donor kidney transplantation as a model for testing whether RIPC had more than a biological effect in patients. Kidney transplantation in this setting is carefully scheduled to facilitate the application of a preconditioning stimulus before surgery. It was possible to arrange for a preconditioning stimulus to be applied to the donor and recipient 24 hours before surgery and immediately before surgery to test for early and late effects of preconditioning. Lastly, the careful planning of surgery meant that kidney ischaemia times would be expected to be consistent, reducing the variability in ischaemia times, kidney injury and kidney function after surgery.

The RIPC stimulus that was used was based on that which had induced cardioprotection in a number of previous clinical trials, namely 5-minute cycles of arm ischaemia and reperfusion. Our previous work had indicated that at least three cycles were needed to induce systemic protection and, to build in a safety margin to ensure that the stimulus was sufficient, we designed the REPAIR trial to use a four-cycle preconditioning stimulus. Approximately 10% of patients did not receive the full preconditioning stimulus as planned, most commonly because arm ischaemia was poorly tolerated by a small number of donors or recipients. We planned a PP analysis of the effect of RIPC in those undergoing the full intervention cycle because it seemed unlikely that an inability to tolerate arm ischaemia would significantly bias the outcome of the trial.

We designed the REPAIR trial to have a large enough sample size to enable us to measure kidney function 12 months after transplantation. The usual measure of kidney function is the eGFR, calculated from the serum creatinine level, taking into account certain phenotypic features of the patient. In the REPAIR trial we elected to measure GFR directly from the rate of excretion of iohexol, taking the view that the increased precision of this assessment over the eGFR would be an advantage. We were mindful of the theoretical disadvantages of iohexol GFR, including its greater complexity requiring an additional outpatient visit and the greater potential for human error in administering the correct dose and in the timing of blood sampling. By setting iohexol GFR as our primary end point we attempted to optimise the possibility of capturing data on renal function using this direct measure.

The factorial design of the REPAIR trial was chosen to allow separate assessments of the immediate and delayed protection that RIPC might stimulate. In the early phase a window of protection of about 4 hours is provided immediately on completing a threshold preconditioning stimulus. Approximately 24 hours after preconditioning, a second more prolonged phase of protection is provided, mediated by a complex of anti-inflammatory mediators. The factorial design allowed us to investigate these two phases separately and, uniquely for a preconditioning study, to examine whether additional protection was provided by a combination of early and delayed protection stimulated by sequential application of preconditioning stimuli. To maximise the chances of inducing tissue protection during ischaemia and reperfusion, donors and recipients underwent the same preconditioning protocol. In this way the donor kidney underwent preconditioning in advance of its ischaemic insult, and reperfusion injury in the recipient might also be modulated by preconditioning.

Effects of remote ischaemic preconditioning on glomerular filtration rate

The major finding from the REPAIR trial was the effect of early RIPC on GFR. When measured by iohexol clearance the group randomised to early RIPC had a higher GFR at 12 months, although the evidence for an effect was weak. When measured by eGFR at 3 and 12 months, the evidence for a beneficial effect was stronger, with an increased eGFR in the early RIPC group, amounting to an approximate 5 ml/minute/1.73 m2 difference at 12 months. When missing values of iohexol GFR were imputed using the eGFR, the strength of evidence for an effect of RIPC also increased. These conclusions were supported by PP analyses, which increased the size of the effect of early RIPC and increased confidence in the findings. Given a mean annual rate of decline of eGFR after living-donor transplantation of 1.5 ml/minute/1.73 m2, a patient starting out after transplantation with a 5 ml/minute/1.73 m2 advantage might reasonably expect a 2- to 3-year extension to the lifespan of the transplant. In contrast to these findings were the largely null effects of delayed preconditioning. In a pilot trial in paediatric transplantation, we had observed a protective effect of late RIPC on eGFR, but this was not apparent in the REPAIR trial. Indeed, using the iohexol GFR, eGFR at 3 and 12 months and iohexol GFR with imputed values for eGFR, and in the PP analyses, there was no evidence of a clinical effect of delayed preconditioning. The most likely explanation for the difference in the strength of evidence between the primary and secondary GFR end points is the greater variability in the more complex and less standardised measure of GFR and the attrition of data for this measure. This conclusion is supported by the consistency between the effects of early and delayed RIPC when assessed by either estimate of GFR.

Effects of remote ischaemic preconditioning on short-term secondary end points

There was no evidence of an effect of RIPC on the short-term secondary end points. The time taken for creatinine to fall by 50% following transplantation was similar between early RIPC and the control (p = 0.75) and between late RIPC and the control (p = 0.64), with a median time of 48 hours in all treatment groups. However, it is possible that there were insufficient sample analyses for creatinine in the first 24 hours after transplantation to detect very early effects of RIPC or to assess accurately the time taken for creatinine to fall by 50%. There was little evidence of a difference in the rate of acute rejection between early RIPC and the control (p = 0.86) or between late RIPC and the control (p = 0.17); however, only 10% of participants experienced acute rejection during the trial. There was little evidence that the incidence of delayed graft function differed between the early RIPC group and the control group (p = 0.61) but the incidence was lower among the late RIPC group than among the control group (1.0% vs. 5.3%, p = 0.031). However, only 12 patients experienced delayed graft function and so substantial uncertainty remains with regard to the effects of early and late RIPC on this outcome. The median length of hospital stay was 6 days in all groups. Nine recipients experienced graft loss and only two recipients died during the initial 12 months following transplantation. There was little evidence of any differences between those receiving RIPC and those in the control group. The results of the PP analysis for the main secondary outcomes were similar to those of the ITT analysis.

Remote ischaemic preconditioning had no effect on the systemic inflammatory response to surgery in the donor or the recipient, with similar profiles of TNF-α, IL-1β, INF-γ and IL-6. The lack of any anti-inflammatory effect of RIPC is consistent with the null effects of delayed RIPC. Other mechanistic analyses are ongoing.

Safety of remote ischaemic preconditioning

There were no major safety concerns around RIPC. As expected, RIPC caused some discomfort to approximately 40% of donors and recipients alike. However, RIPC was discontinued in only nine pairs because they were unable to tolerate the intervention. Direct pressure effects of the cuff used to occlude blood flow in the arm resulted in a small proportion experiencing asymptomatic petechiae. However, during follow-up there were no differences between the groups in the adverse events recorded, the majority of which were unscheduled hospital admissions unrelated to preconditioning.

Limitations of the REPAIR trial

The length of follow-up in the REPAIR trial was set at 12 months. Longer-term follow-up is needed to determine whether differences in GFR are maintained in subsequent years, to such an extent that one can have greater confidence that RIPC will alter the lifespan of the transplant. As only about one-third of screened patients were recruited, the generalisability of our findings can be legitimately questioned. RIPC might have exerted its action by inducing ischaemic protection in the donor or limiting reperfusion injury in the recipient; as the donor and the recipient underwent RIPC, our data do not inform on the phase of IR injury influenced by RIPC. The lack of any effect of late RIPC on kidney function contrasts with that seen in our pilot data in children. Possible explanations for this include small study bias, differences in preconditioning pathways between children and adults and loss of the precision of the intervention when moving from a single-centre to a multicentre study.

Research recommendations

Further studies will, of course, help define the role of RIPC in renal transplantation, as one trial rarely changes practice and it would be necessary to confirm the effects of early RIPC on kidney function after living-donor transplantation. The REPAIR trial also refines the optimal design for a trial of RIPC in deceased-donor transplantation, which should test the effects of early RIPC, applied to the recipient only, on eGFR.

Copyright © 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.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK294378


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