Starting at the Source: Donor Research, Done Right.

Abstract

Transplant research needs to start at the source. Optimizing graft function to ameliorate ischemia-reperfusion needs to occur before the injury occurs to protect organs and prevent graft failure. The aim of donor management is to optimize perfusion and oxygen delivery to the grafts by maintaining favorable hemodynamics, intravascular volume, and metabolic states while averting the pathophysiological derangements that occur with death by neurological criteria. Defining specific donor management goals a priori and implementing standardized interventions to meet these goals improve organ yield1 and are widely put in practice by organ procurement organizations. Achieving the hemodynamic goals (usually mean arterial pressure between 60 and 110 mm Hg) to maintain organ perfusion is considered particularly important; however, it is controversial what interventions are best suited to reach that goal. The study by van Bakel et al2 studied almost 200 organ donors who were randomized to receive either high-dose methylprednisolone, levothyroxine, both, or neither before organ procurement. Although the study was not powered to detect a difference in organ yield or quality, the authors found that methylprednisolone either alone or in combination with levothyroxine (but not levothyroxine alone) reduced vasopressor requirements. Administration of methylprednisolone further reduced a number of inflammatory markers, specifically of interleukin-6, interleukin-12p40, and tumor necrosis factor-alpha, potentially an indication that the reduction of vasopressors may actually improve organ perfusion. Vasopressors are a double-edged sword that may—in the vasodilated state—restore vascular tone and organ perfusion and can also decrease graft perfusion and cause ischemia. Nevertheless, use of high-dose vasopressors in donors has consistently been associated with worse outcome, and reduction of vasopressor requirements should probably be considered beneficial. A number of studies have demonstrated that bundles of hormone replacement (steroids, thyroid hormone, vasopressin) improve organ yield and function,3 but which component of the bundle is beneficial has been unknown. Based on the results of the present study, administration of steroids should be considered part of donor management protocols. Unfortunately, this study was not powered to actually detect the difference in outcomes and therefore does not provide the conclusive, strong evidence needed to unequivocally support wide spread use of steroids in all donors. There is scant evidence for any donor interventions before procurement to a large degree because of the logistical difficulties of organ donor research. A landmark study by Niemann et al4 demonstrated the benefit of mild donor hypothermia to prevent delayed graft function in kidney recipients. More importantly, this study provided a blueprint on how to conduct large, randomized studies of transplant donors. Ethical considerations are real: studying donors who are dead by neurological criteria is not human subject research. But any (randomized) intervention applied to the donor can affect up to 8 solid organ recipients. True equipoise is essential for donor research to avoid biases and potential harm to recipients. Some interventions that may be favorable for 1 organ may harm others, and coordination of organ donor intervention research may be needed. The National Academies of Sciences, Engineering, and Medicine recognized the need for more donor research and provided a broad framework in their 2017 consensus study report “Opportunities for Organ Donor Intervention Research: Saving Lives by Improving the Quality and Quantity of Organs for Transplantation.”5 This report delineates a process to address the ethical concerns of donor research and recommends the institution of a single institutional review board, a Donor Research Oversight Committee, to coordinate different projects and data and the institution of safety monitoring boards to oversee the conduct of these studies. This is a great step in the right direction to create a scaffolding to support studies that further our knowledge about donor management and may help us improve organ yield, graft function, and outcomes after transplantation.