We are currently witnessing a remarkable technological revolution which brings a variety of options to the way organs are preserved, assessed, and even improved before transplantation. After decades in which “cold ischemia” was an accepted fact of transplantation, many are challenging the notion that any amount of ischemia is necessary at all. This sea change in the way we preserve organs between their recovery and their transplantation has been largely driven by the development of systems designed to maintain organs at physiologic temperature while providing oxygen for aerobic metabolism. In parallel with these technological developments, the field has been driven by a need to better utilize organs from older donors, as well as those recovered after circulatory death.
Among the first such systems have been several designed for normothermic lung preservation. These have capitalized on the ability to oxygenate lung tissue directly via endotracheal intubation. Clinical experience with these devices has illustrated the potential not only to maintain organs for extended periods of time, but to use this interval to assess quality, and potentially deliver therapeutics that will diminish reperfusion injury or promote tolerance.1
Analogous devices for other organs are in various stages of development, have seen limited deployment, and reflect a dimension common to all nonpulmonary grafts: the complexity of meeting temperature-based metabolic demand with oxygen delivery. In general, normothermic machine preservation (NMP) in the maintenance of organs usually requires blood-based oxygenation, as well as attention to nutrient supply, acid-base balance, and disposition of products of metabolism. This entails greater complexity of systems and greater cost. In addition, in the event of mechanical failure, the organ is at risk of loss. These drawbacks must therefore be weighed against the potential advantages of such an approach. At the opposite end of the scale, hypothermic machine preservation (HMP) provides a low-risk avenue for organ maintenance, albeit with less potential gain: functional evaluation and therapeutic intervention strategies are limited, and benefits, although certainly tangible, have been less than dramatic.2 HMP systems have become widely deployed, particularly for kidney grafts.
Between these extremes, several new concepts are emerging. Hypothermic or subnormothermic oxygenated perfusion (HOPE) systems allow for oxygen delivery at rates not requiring blood-based carriers, commensurate with the reduced metabolic rate at these temperatures. Their potential advantage is in reduced device complexity, and in the case of hypothermic systems, greater safety margin.3 Less well developed, but similarly promising, subnormothermic machine perfusion and controlled-rewarming systems aim to minimize the transition between cold preservation and warm reperfusion, for which some evidence points to a deleterious role.4
In liver transplantation, preliminary clinical trials of NMP and HOPE have shown their safety, their ability to maintain livers for extended periods, and the potential to minimize cellular injury.5 Some evidence also exists to suggest the potential for reduction in ischemic cholangiopathy may be realized.6 More ambitious goals, such as treating steatosis, remain in the experimental realm.
Ex vivo mechanical preservation systems for kidney transplants have begun to evolve from the widespread HMP, to HOPE and NMP, with potential for significant improvements in organ quality and utilization. Trials of such systems are currently under way with preliminary results suggesting a dramatic improvement in delayed graft function, particularly with the use of NMP.7 Hypothermic or subnormothermic oxygenated perfusion and NMP concepts are also being applied to pancreas,8 islet,9 and heart transplantation.10 In these organs, transplantation rates have remained low due to risks of inflammation and complications in the former, and graft dysfunction in the latter. It remains to be seen if such systems will have a positive impact on organ utilization, particularly in donors after circulatory death, or those where prolonged arrest, hypotension or graft injury are feared.
In this issue, Patel et al11 illustrate the potential benefits of HOPE in an experimental kidney context. This middle road toward ex vivo preservation could be an important answer to modulating the effects of lengthy cold ischemia while allowing for prevention of the worst effects of anaerobic conditions in organ preservation. It is an avenue certainly worthy of deeper exploration.
1. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med
2. Moers C, Pirenne J, Paul A, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med
3. Hamar M, Selzner M. Ex-vivo machine perfusion for kidney preservation. Curr Opin Organ Transplant
4. Jochmans I, Akhtar MZ, Nasralla D, et al. Past, present, and future of dynamic kidney and liver preservation and resuscitation. Am J Transplant
5. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature
6. Dutkowski P, Polak WG, Muiesan P, et al. First comparison of hypothermic oxygenated PErfusion versus static cold storage of human donation after cardiac death liver transplants: an international-matched case analysis. Ann Surg
. 2015;262:764–770; discussion 770–1.
7. Hosgood SA, Saeb-Parsy K, Wilson C, et al. Protocol of a randomised controlled, open-label trial of ex vivo normothermic perfusion versus static cold storage in donation after circulatory death renal transplantation. BMJ Open
8. Barlow AD, Hamed MO, Mallon DH, et al. Use of ex vivo Normothermic perfusion for quality assessment of discarded human donor pancreases. Am J Transplant
9. Kelly AC, Smith KE, Purvis WG, et al. Oxygen perfusion (persufflation) of human pancreata enhances insulin secretion and attenuates islet proinflammatory signaling. Transplantation
10. Fujita B, Sievert A, Sunavsky J, et al. Heart transplantation using the normothermic ex-vivo perfusion device organ care system for donor heart preservation—long-term outcomes. J Heart Lung Transplant
11. Patel K, Smith T, Neil D, et al. The effects of oxygenation on ex vivo kidneys undergoing hypothermic machine perfusion. Transplantation