Investigating the role of pharmacological preconditioning of organs from brain dead donors to improve the outcomes of kidney transplantation

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Medical context of proposed research and its importance: Organ transplantation saves the lives of thousands of patients every year. Most types of organ transplantation including liver, kidney, pancreas, heart, lung and even bowel transplants are now recognised as definitive treatments for patients with end stage organ failure. Despite the increasing awareness of transplantation both amongst medical professionals and members of the general public, a significant gulf still exists between organ availability and need. This is predicted to worsen over the course of the next decade making this disparity one of the biggest challenges facing the transplant community today. In an attempt to reconcile this difference researchers have been exploring how the "donor pool" can be expanded and how organs previously considered unsuitable for transplantation can be repaired or resuscitated.Kidneys donated from brain dead donors have poorer short and long-term outcomes when compared to living donors, even when immunological factors and storage times are taken into consideration. Part of the reason for the poorer function of these organs is because of a reduction in the blood, oxygen and nutrient supply during the brain death process itself. This leads to toxic metabolite production which, when the blood supply is restored, results in dramatic tissue injury. In addition, the immune system appears to be overactive. I speculate that interventions made in the brain dead donor can help protect organs against damage. In doing so, I propose that interventions will make previously unusable organs transplantable, and also reduce the incidence of acute and chronic organ failure. It is recognised that a short period of deprivation of blood supply (ischaemia) to an organ can prevent against future damage from prolonged ischaemic periods. The mechanism for this protection has not been fully delineated, however, Hypoxia Inducible Factor (HIF) and the genes that it regulates have been suggested as being responsible for some of the conferred protection. The HIF pathway is part of the cellular response mechanism to oxygen deprivation. HIF can be pharmacologically induced by administering dimethyloxaylglycine (DMOG). To date no published scientific research has investigated the role of the HIF pathway in preventing kidney injury following brain death and improving the outcomes of transplantation. Goals of project and methods:I propose to carry out experiments to explore the role of the HIF pathway in protecting against kidney injury following brain death. I will use a rat model I have developed during my Academic Clinical Fellowship. I will activate and sustain the HIF pathway using DMOG. I will be assessing the kidneys procured from brain dead rats treated with this agent using techniques including a rat model of renal transplantation. By conducting this research I aim to establish the ability of DMOG to abrogate the kidney injury caused by brain death, and improve our understanding of the mechanisms of brain death induced kidney injury. In doing so, I aim to protect kidneys from brain dead organ donors, improving the quality of kidneys procured, but also salvaging previously unusable kidneys and thereby making the untransplantable transplantable.