Ischemic reperfusion injury in Liver transplantation

About 119,592 patients are currently on the organ transplant waiting list in the US, with the number increasing by 5% every year. In 2017, 11,640 candidates were added to the liver transplant waiting list. While the increase in the number of liver transplants is encouraging, the organ shortage remains critically high. During 2015, 1673 patients died without undergoing transplant and another 1227 were removed from the waiting list due to being too sick to undergo transplant. The major untapped pool of donor organs that could be used to alleviate this crisis in organ transplantation are steatotic livers and livers from Donors after Cardiac Death (DCD). Steatotic liver grafts are associated with an early allograft dysfunction rate of 60%-80% compared with less than 5% for nonsteatotic grafts. This is due to their poor tolerance to ischemic reperfusion injury. On the other hand, only 27% (518/1884) of the DCD livers were transplanted in 2017. The single major reason for this is the severe ischemia reperfusion injury in these livers. The severity of ischemic reperfusion injury is an important determinant of allograft function post-transplant. However, the mechanisms that contribute to increased susceptibility of steatotic and DCD grafts to ischemic reperfusion injury remains poorly defined. In solid organ transplantation, graft damage subsequent to ischemic reperfusion injury may result in delayed graft function. In the worst case, this complication can lead to primary graft non- function resulting in an urgent need of re-transplantation. Ischemic reperfusion injury is the consequence of temporary interruption of blood flow to the liver. Warm ischemia reperfusion injury occurs during clamping of vascular inflow during prolonged liver resections and during a donation after cardiac death organ retrieval procedure. Cold ischemia reperfusion injury results from maintenance of the liver in cold preservation and subsequent reperfusion of the graft during transplantation. Apart from its pivotal role in the pathogenesis of the liver’s post reperfusion injury, it has also been involved as an underlying mechanism responsible for the dysfunction and injury of other organs as well. Liver ischemia and reperfusion in settings of liver transplant represent an event with consequences that influence the function of many organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organ injuries can ultimately lead to multiple organ dysfunction syndrome. The objective of this thesis is to give a full and comprehensive analysis of ischemic reperfusion injury in liver transplantation.