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Summary

This study aims to demonstrate the safety and feasibility of using a novel device for preserving kidneys prior to transplantation. The current standard of care is for kidneys to be transported from the donor hospital to the recipient on ice (Static Cold Storage, SCS). Whilst cooling the organ slows the rate of metabolism and deterioration, it precludes assessment of the kidney in a functioning state and does not prevent deterioration.

SCS affects kidneys from elderly donors and those with co-morbidities such as high blood pressure most severely, and these donors are accounting for an increasing number of transplants. The median waiting time for a kidney transplant in the UK is 829 days, with around 250 patients dying on the waiting list each year. An improved method of preservation would increase the proportion of available organs that could successfully be transplanted, decreasing waiting time and the number of deaths on the waiting list.

We have developed a device that perfuses kidneys with oxygenated perfusate at normal body temperature (normothermic perfusion, NMP). We have demonstrated that kidneys that have been rejected for transplantation can be preserved in this manner for up to 24 hours. This study would bring this technology into clinical practice, starting with short duration perfusions of two hours and increasing up to 24 hours. Kidneys that are deemed suitable for transplantation will be transported to the Oxford Transplant Centre in the usual manner (SCS). Those that are appropriate for our study will be perfused for increasing lengths of time, then transplanted. We will assess the safety and feasibility of this technique, and simultaneously study the clinical outcomes and function of NMP-preserved kidneys; compare this to historical matched controls; examine the effects of NMP on the kidney; identify markers during preservation that may predict future kidney function; and characterise the perfusion system.

Background 

Much progress has been made in the UK to increase the number of organ donors. The annual number of deceased donors has increased from 809 (2007-8) to 1575 (2017-8), an increase of 95%. The rate of increase in transplant numbers, although substantial, does not reflect the same degree of change: this is because many of the additional donors are less suited to the needs of patients. Nonetheless, to maximise the number of transplants, the transplant community has increasingly turned to the use of older and higher risk donor organs, those which would not have been considered acceptable for transplant previously.

Higher risk kidneys include those from donors declared dead by cardiovascular criteria (donation after circulatory death, DCD) rather than neurological criteria (donation after brain death, DBD), as well as donors with additional comorbidities, including older age, cardiovascular disease and diabetes (extended criteria donors, ECD). High risk donor organs of this sort are much more likely to be declined for clinical transplantation, sometimes because of clear evidence of non-viability (e.g. obvious vascular and/or parenchymal disease), but much more commonly due to uncertainty as to whether the organ will provide adequate function after the transplant.

Many such kidneys are either not accepted for transplantation at the time of donor offering (and not retrieved) or retrieved and then declined after inspection. In the UK in 2016-17, 2822 kidneys were offered, of which only 2390 (85%) were transplanted. If even half of these discarded kidneys were transplanted, these would represent an additional 216 transplants per year. Finding ways to transplant a higher proportion of available organs without compromising the outcome is one of the major challenges facing organ transplant clinicians. Even a modest increase in organ utilisation would bring vital benefit to patients on transplant waiting lists.

The reasons for this low level of organ utilisation are two-fold: (i) organs suffer damage during the transplant process of brain death, organ retrieval, preservation and reperfusion; (ii) the criteria whereby organ viability is assessed are inadequate: there is a lack of objective and reliably predictive metrics. It is very likely that many of the organs currently discarded could be transplanted successfully if: (i) improved methods were available to reduce the damage caused by the transplant process, and (ii) more reliable methods were available to assess organ viability.

For many years, standard practice has been to cool kidneys after removal from the donor for storage and transport on ice (static cold storage; SCS). This involves flushing the organ with a specialist solution designed primarily to prevent cell swelling as cell membrane functions cease with decreasing temperature. More recently, there has been a resurgence of interest in hypothermic machine perfusion (HMP), pumping cold preservation solution through the circulation of the organ throughout preservation. There is evidence that this form of preservation is superior to SCS, especially in the context of extended criteria donor organs.

However, neither SCS nor HMP achieve physiological conditions which would allow: (i) the organ to remain in a functioning state; (ii) injury sustained before/during retrieval (e.g. hypoxia) to be reversed; (iii) direct measurement of the function of the organ to assess its potential to function after transplantation. In particular, cooling and hypoxia are known to be most damaging to ECD and DCD organs, the categories most affected by poor utilisation.

We are proposing to test a novel approach to the practice of kidney transplantation, normothermic machine perfusion, which maintains the organ in a physiological, functioning state during preservation. This potentially fulfils the three criteria defined in the previous paragraph and would, if successful, unlock the potential of many donors/donor organs that are currently not used. Our group has previously developed comparable technology for the liver and recently published a Phase 3 trial showing clear evidence that NMP greatly reduces preservation-related damage, reduces the rate of discard of retrieved organs (by 50%) and allows (54%) longer preservation times. NMP may, therefore, benefit not only transplant outcome and organ utilisation, but also allocation of organs, operating theatre logistics and cost.

Aims and objectives

Primary objective:

To assess the safety and feasibility of a normothermic perfusion device for the prolonged ex-vivo perfusion of deceased donor kidneys prior to transplantation

Primary outcome measure/endpoint:

The primary outcome is 30-day graft survival. This is defined as a functioning transplant in a patient who does not require chronic dialysis. This is primarily a safety endpoint, representing organs that have been safely and successfully preserved and transplanted.

Secondary objectives:

To study the clinical outcomes and function of kidneys preserved by prolonged ex-vivo normothermic perfusion

To study the effects of prolonged ex-vivo normothermic preservation on post-transplant reperfusion injury

To identify biomarkers and machine perfusion parameters during NMP that are predictive of clinical outcome following transplantation

To characterise the machine perfusion system during perfusion of human kidneys for transplantation

Study design 

This is a prospective, 3-stage cohort study investigating gradually increasing durations of NMP prior to transplantation of up to 24 hours.

A historical control cohort will comprise deceased donor kidney transplant recipients from the Oxford Transplant Centre transplanted in the previous 3 years.  Control patients will be matched 2:1 to study participants based upon donor type, preservation time, and donor risk index