19. Integration of time-honored principles of hypothermic cellular protection with modern day modalities of organ preservation

In recent years the role of hypothermia as the bedrock upon which techniques of organ preservation are based, has received renewed attention due to its importance in the procurement, storage and resuscitation of less-than-optimal donor organs. Clinical kidney and liver transplantation has evolved from an experimental procedure 50 years ago to the current treatment of choice for patients with end-stage organ disease where patient and graft survival rates exceed 90% per year. However, an ever increasing shortage of donor organs means that there is an increasing number of patients on the waiting lists for transplants such that future advances in this field are constrained by both the numbers of available organs and their quality. As a consequence, less-than-optimal donor organs are increasingly being used in an attempt to close the widening gap between supply and demand. The ex vivo perfusion of organs by hypothermic perfusion preservation (HPP) on a machine prior to transplant, as opposed to static cold storage (SCS) on ice, offers the prospect of making available more and better organs for transplantation. Studies have shown that expanded criteria donor (ECD) kidneys preserved by SCS had an overall increased risk of reduced graft viability. However, HPP was clearly associated with a reduced incidence of delayed graft function (DGF), an overall improved graft survival, and an increased rate of clinical use. Moers et al. reported the results of a controlled, prospective randomized study involving 336 consecutive deceased donors from whom one kidney was randomly assigned to pulsatile perfusion and the contralateral kidney to SCS (N Engl J Med 2009;360(1):7–19 and 2012;366:770–1). 1–3 year follow-up showed that HMP reduced the risk of DGF (43% less risk; p = 0.01) and graft failure ( p = 0.04) and improved graft survival ( p = 0.02). HPP significantly reduces the risk of DGF in ECD ( p = 0.047) and kidneys donated after cardiac death (DCD; p = 0.025), by 54% and 57% respectively. Very recently, the same HPP-approach has been reported for the first time for clinical liver transplantation and research continues to focus on other organs such as the pancreas. This presentation will re-visit the fundamental principles upon which hypothermia has proven to be a robust protective modality against ischemia and hypoxia. These basic principles will be considered in relation to the time-honoured interventional strategies that have been adopted for clinical organ preservation. In particular, the fundamentals of preservation solution design, to control the environment of cells to combat the deleterious events of ischemia and reperfusion injury, will be outlined. Integration of key modalities and technologies for hypothermic preservation will be further illustrated by recently reported extrapolation of clinical success in kidney transplantation to clinical liver preservation. Guarrera’s group undertook an analysis of molecular stress markers using liver biopsies from the same groups of patients as the Phase I clinical study (Am J Transpl 2010;10:372–81) and reported that expression of all mRNA markers examined, including inflammatory cytokines, was elevated in reperfusion biopsies from the SCS group compared with HPP. Upregulation of stress markers was significantly attenuated in livers preserved by HPP.