Organ Procurement and Perfusion before Transplantation

Organ transplantation is one of the great success stories of modern medicine. Living-donor kidney transplantations between identical twins during the early 1950s first demonstrated the overall feasibility of this procedure and ultimately paved the way to long-term success. Outcomes improved rapidly with a greater understanding of the immunobiology of graft rejection, with more refined surgical techniques, with scientific advancements in fields related to transplantation, and, most importantly, with the advent and continuous refinement of immunosuppressive agents.

Research in the area of organ procurement and preservation began even before the first successful clinical transplantations. Before World War II, in France Alex Carrel became interested in the cultivation and perfusion of organs with the support of small pumps, a technique that he refined in the 1930s in cooperation with the aviator Charles Lindbergh.

In the United States, Folkert Belzer and coworkers initiated detailed investigations into organ storage and introduced a clinically successful pulsatile pumping system (Figure 1Figure 1Pulsatile Perfusion in Organ Preservation.) in the early 1960s.1 These early perfusion devices filled the entire bed of a truck that the inventor had to rent when harvesting donated organs. Although more portable units were devised shortly thereafter, the use of pumping machines decreased with the introduction of more efficient perfusion solutions for static cold storage and the availability of potent immunosuppressant agents such as cyclosporine.

Currently, organ transplantation is considered the treatment of choice for people with end-stage organ disease, and patient and graft survival rates exceed 90% per year. However, the unsatisfactory long-term outcomes of transplantation and organ shortages are two pressing issues in the field. As a result, less-than-optimal donor organs are increasingly being used in an effort to reduce the growing number of people awaiting transplants. Expanded-criteria donor organs are defined by the advanced age of the donor or additional donor risk factors. The use of organs obtained from donors after cardiocirculatory death has also increased in some countries. Despite these changes, there has been a growing discrepancy between the demand for and the supply of organs; this discrepancy has led to greater interest in the pulsatile perfusion of harvested organs. In this issue of the Journal, Moers and coworkers2 present the results of a clinical trial comparing the effects of cold storage with pulsatile perfusion on the outcome of renal transplantation.

Numerous clinical studies have evaluated the effects of machine perfusion on rates of acute rejection and delayed graft function and on graft and patient outcomes.3,4 A meta-analysis5 showed a significant reduction in delayed graft function associated with pulsatile perfusion. In previous studies, kidneys from expanded-criteria donors that were preserved by cold storage had an overall increased risk of reduced graft viability. However, when they were perfused during preservation, they were associated with a reduced incidence of delayed graft function, an overall improved graft survival, and an increased rate of use.6-8 Conclusions have remained limited because of the heterogeneity of existing clinical studies and the lack of prospective clinical studies.

Moers et al. enrolled 336 consecutive deceased donors and randomly assigned one kidney to pulsatile perfusion and the contralateral kidney to cold-storage preservation. The recipients of these 672 kidneys were followed over a period of 1 year, with delayed graft function as the primary end point. Machine perfusion reduced the risk of delayed graft function and graft failure and improved graft survival in the first year after transplantation, thus confirming the beneficial effects of machine perfusion in a randomized, prospective trial.

A limitation of this study is that the definition of delayed graft function as the need for dialysis after transplantation involves a subjective decision process. However, it can be assumed that this effect was equally distributed between the groups. Of interest, and to some degree surprising, is the lack of an advantage of pulsatile perfusion in the subgroup analysis of expanded-criteria donation and donation of organs after cardiocirculatory death.

Concepts that provide support for the synergistic or additive effects of innate and adaptive immunity may have led to predictions of higher rates of acute rejection in association with increased frequencies of delayed graft function. The rate of acute rejection, although reported only for the very early period after transplantation, was not influenced by the perfusion technique in the study by Moers et al.

Most research in transplantation immunology to date has relied on aspects of adaptive immunity. Clearly, aspects of organ quality and additional nonspecific injuries appear to predict, at least in part, transplantation outcome. Basic principles connecting concepts of innate and adaptive immunity are receiving increased attention in clinical and experimental transplantation research.9-11 The consequences of ischemia and reperfusion contribute to both overall organ quality and immune activation, and they are still incompletely understood.

One hopes that the study by Moers et al. will fuel more research in the area of organ procurement. A more extensive analysis of organ quality, the potential benefits of pulsatile perfusion in nonrenal transplants, and studies on potential mechanisms may be areas of future interest.

Furthermore, this study suggests that other factors related to ischemia–reperfusion injury — in addition to hypoxia, a lack of nutrients, and the accumulation of toxic metabolic products — are detrimental to organs during cold storage. Indeed, protection of the vasculature, especially the vascular endothelium, may be critical in explaining the beneficial aspects documented by Moers and colleagues.

Key vasoprotective endothelial genes, which are strictly flow-dependent, have been described recently.12 The expression of one of these genes, Kruppel-like factor 2 (KLF2), a transcription factor, decays rapidly once pulsatile flow ceases.13 Endothelial expression of this transcriptional integrator is necessary for the inhibition of proinflammatory cytokines, adhesion molecules, and prothrombotic genes. KLF2 and other flow-dependent transcription factors also play a role in the up-regulation of genes critical for the production of nitric oxide and the resolution of inflammation.12 Thus, one might speculate that continuous pulsatile flow during the organ-procurement period will sustain endothelial homeostasis, allowing an earlier functional recovery of the organ and potentially ameliorating the immune response. Perhaps in the future additives to perfusion solutions will mimic the vasoprotective effects of pulsatile flow.

No potential conflict of interest relevant to this article was reported.
Source Information

From the Division of Transplant Surgery (S.G.T.) and the Department of Pathology (G.G.-C.), Brigham and Women's Hospital, and Harvard Medical School, Boston.

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