Removing the Chill From Organ Storage

Abstract

The majority of organs used for transplantation are stored by simple cold storage at approximately 4°C, and cold storage times are minimized to reduce the inevitable organ injury that occurs upon reperfusion after implantation. The availability of improved organ perfusion technology has led to a resurgence of interest in the use of hypothermic perfusion storage systems, but these do not overcome the basic energy and metabolic derangements that arise from hypothermic storage and result in reperfusion injury. An alternative and possibly more effective approach to organ storage is that of normothermic perfusion with oxygenated blood-based solutions. The potential advantages of normothermic perfusion are the possibility of avoiding a period of cold injury, permitting prolonged preservation, and avoiding accumulation of toxic metabolites that contribute to reperfusion injury. Normothermic perfusion has been applied clinically to all stages of the ischemic period. In circulatory arrest donors (donation after circulatory death), restoration of a normothermic circulation using an extracorporeal membrane oxygenator circuit has been used to resuscitate organs before removal and cold storage, with impressive results in terms of early graft function in kidneys and livers (1, 2). Normothermic perfusion has also been used for the total duration of the storage period, with current evaluation for the storage of hearts, lungs, and livers. This may permit prolonged storage and evaluation of function before transplantation, with the opportunity to resuscitate suboptimal organs. Impressively, ex vivo normothermic perfusion of the lung has been shown to improve organ quality and allow transplantation of lungs that would otherwise have been considered unsuitable (3). In this edition of Transplantation, Nicholson et al. (4) present their first clinical experience with the ex vivo normothermic perfusion of kidneys immediately before transplantation. Following standard cold preservation, they have employed a short period of normothermic perfusion using a pediatric extracorporeal membrane oxygenator circuit to facilitate recovery of a kidney from cold ischemia with a view to minimizing reperfusion injury. Although this is a single case report, it is underpinned by a considerable amount of experimental work in animals both by this group and others. This report suggests that normothermic perfusion can be applied safely to human donor kidneys, but caution is required before drawing conclusions about its efficacy. The use of leukocyte-depleted red cells seems to be an important element in permitting organ recovery without significant injury and was also a feature of Steen's technique for the lung. By using red cells suspended in an electrolyte solution, Nicholson et al. also removed the contribution of circulating mediators such as complement to the reperfusion injury, although local production of complement within the kidney may still occur. The perfusate also contained additives designed to minimize the inflammatory response (dexamethasone and prostacyclin) as well as mannitol, which may have a role as free-radical scavenger, removing the harmful metabolites produced during ischemia. The period of warm perfusion in the case described by Nicholson et al. was short, and further work is necessary to identify the optimal duration of normothermic resuscitation and also to define what other elements can usefully be added to the perfusate, or removed from it, for maximum benefit. In the ex vivo lung perfusion model of Steen et al., a switch from sanguineous perfusate to an acellular perfusate was associated with better results, oxygenation being maintained by continued ventilation of the lungs. Whether a totally acellular perfusate would be better for the kidney remains to be determined, although the challenge then would be to ensure adequate oxygen delivery. The brief period of preimplantation normothermic perfusion utilized by Nicholson et al. seems to be a promising approach for minimizing reperfusion injury. However, it is unclear what degree of ischemic damage such a strategy would be able to reverse. So, for example, would organs with longer cold ischemia times, or significant periods of warm ischemia, respond to this preimplantation conditioning as well as the case reported here, or would they exceed some ill-defined threshold beyond which irreversible damage was inevitable. In the short term, there is a need for additional studies to ensure that normothermic kidney perfusion is safe and to permit the many variables to be optimized. Ultimately, there will be a need to conduct properly powered randomized controlled clinical trials to determine benefits of this approach compared with the well-tried, safe, and cheaper alternative of cold storage. The future prospects for organ storage are very exciting, and warm perfusion offers additional opportunities for intervention using micro RNA, gene therapy, and stem-cell-based therapeutic manipulation to improve the quality of donor organs.