Title: Normothermic preservation and repair of transplant donor kidneys
Funder: Department of Health and Social Care

Abstract: Research Question Is prolonged normothermic ex-vivo preservation of donor kidneys safe and feasible? Does it improve organ assessment and reduce injury? Background The shortage of kidney donors and long waiting list has led to increasing use of more marginal donors, including those with comorbidities and greater risk of pre-existing renal damage. The most commonly used method for storing and transporting kidneys for transplantation currently is static cold storage (SCS) in an ice box. However, cellular metabolism continues at a reduced rate, resulting in depletion of ATP and reperfusion injury in the recipient. New methods for preserving and assessing kidneys for transplantation are needed. Previous studies have demonstrated that normothermic machine preservation (NMP) with blood at body temperature is safe for periods of up to one hour, and may allow repair, resuscitation and assessment of organ viability. We have previously demonstrated that much longer periods of NMP in the liver are feasible, improve early function and reduce the rate of organ discard. Experimental work with discarded human kidneys suggests that longer periods of NMP for the kidney are also feasible. This study aims to investigate this in the clinical setting. Aims and objectives To assess safety and feasibility of NMP in organs perfused for durations starting at 2 hours and incrementally increasing To investigate the use of biomarkers and other parameters during perfusion to predict the viability of donor kidneys To study the outcomes and function of transplanted kidneys preserved by NMP Methods We have developed a clinical-grade, stand-alone device for the normothermic preservation of kidneys. This Phase 1 clinical trial will test the use of this device in deceased donor kidneys. 36 patients will receive NMP-preserved kidneys, with incrementally increasing periods of NMP in three cohorts: (i) up to 6 hours (12 patients); (ii) up to 12 hours (12 patients); (iii) up to 24 hours (12 patients). Each recipient will be matched to two historical control patients from the same centre and with similar clinical characteristics to allow comparison of clinical outcomes. Primary outcome will be 30-day graft survival. Secondary clinical outcomes will include 12-month patient and graft survival, graft function, incidence of delayed graft and primary non-function and organ discard rates. Existing biobanking facilities will be used to collect samples for histology and biomarker analysis, looking for markers of cellular injury and inflammation. Timelines The total planned study duration is 36 months. Study design, Ethical approval, MHRA, Trust R&D approval: 6 months Recruitment (36 patients): 12 months Follow-up: 12 months Analysis and reporting: 6 months. Impact and Dissemination If successful, prolonged periods of NMP may reduce injury and facilitate assessment of kidneys for transplantation, ultimately increasing transplant rates and reducing organ discard. Clinical outcomes from this study will be used to power a phase III efficacy study to assess clinical and cost effectiveness. The results of this study will be disseminated to professionals though peer-reviewed journal articles, conference presentations, social media and websites, and to patient groups through patient organisations, newsletters, websites and social media.

Lay abstract: Kidney transplantation is the best treatment for most patients with chronic kidney failure: it doubles life expectancy, improves quality of life and is much more cost-effective compared to dialysis. Despite a 95% increase in organ donor numbers over 10 years, almost 5000 patients in the UK remain on the NHS waiting list for a kidney transplant because of a persistent shortage of suitable donor organs. Not all donors are suitable: many potential donor organs are at risk of failing after the transplant from a combination of pre-existing donor factors (older age, cardiovascular disease, diabetes), damage incurred at the time of death (cardiac arrest and oxygen deprivation), and damage caused by storage in an ice box after recovery from the donor. These factors limit the number of these higher-risk kidneys that can be transplanted: importantly, there is no reliable way to determine which organs would function if transplanted. For reasons of patients best interests, kidneys are declined if there is serious doubt about organ viability, and it is inevitable that viable organs are discarded as a result. Unlike the ice box, normothermic machine perfusion places the organ in an environment that closely resembles that of the body: blood, oxygen and nutrition are provided at normal body temperature (37oC), to allow the kidney to recover from the process of donation, avoiding the progressive injury that occurs if the organ is stored on ice. Also, because the kidney is functioning during preservation, it is possible to test its viability before the transplant. This would allow surgeons to accept a higher-risk organ provisionally, deferring the final surgical decision until it is clear that the kidney is suitably healthy. This ability not only to resuscitate, but also to test-drive the organ before transplantation would make a very large difference to the number, as well as to the success of these transplant operations. We have built a normothermic kidney perfusion machine and have tested this in kidneys that were not suitable for transplantation. We are now ready to test this new technology in a clinical trial. This will involve 36 patients undergoing kidney transplants at the Oxford Transplant Centre. Duration of machine perfusion will be gradually increased during the study ensuring safety at each stage. Patients will be fully informed about the trial and invited to take part: apart from the method of organ preservation, there will be no other difference in the way the transplants are conducted, or the patients treated. This trial is primarily designed to test the safety and feasibility of the new technology. It will also provide some evidence regarding effectiveness and, if successful, will be the precursor to a large randomised trial that will test efficacy formally.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RENAL AND UROGENITAL