Several retrospective studies have helped support the 30% and 60% MaS thresholds for donor steatosis, although several reports have demonstrated safe utilization of these organs with comparable outcomes. clinical strategy to dampen reperfusion injury and reduce delayed graft function in liver transplantation. Targeting the complement cascade may be critical in donor livers with mild to moderate steatosis, where elevated AVE5688 lipid burden amplifies stress responses and increases hepatocyte turnover. Steatosis-driven complement activation in the donor liver may also have implications in rejection and thrombolytic complications following transplantation. This review focuses on the roles of complement activation in liver I/R injury, strategies to target complement activation in liver I/R, and potential opportunities to translate these strategies to transplanting donor livers with mild to moderate steatosis. strong class=”kwd-title” Keywords: complement, extended criteria donor, liver transplantation, steatosis 1. Introduction The United Network for Organ Sharing reported 7841 liver transplants performed for end-stage liver disease in 2016 . Although donation and utilization increased in 2016, the year ended with 11,140 active waitlist candidates, highlighting the stable deficit between waitlist candidates and the available donor pool. Given the disparity between recipient need and graft availability, transplant centers have increasingly utilized extended criteria donor (ECD) livers to address the deficit [2,3]. The ECD designation is assigned to livers that are considered marginal for transplantation due to known risk factors affecting graft function, transplant outcomes, and risk of transmitting infection. Common ECD designations include donation with advanced age, after cardiac death, positive for hepatitis B or C, prolonged ischemia time, or having lipid accumulation (steatosis) in hepatocytes. Managing risk is a critical factor in ECD transplantation, as these organs have increased susceptibility to hypoxia and reperfusion injury with increased risk for graft loss or delayed function [4,5]. Despite ongoing efforts to manage or reduce the risks associated with ECD grafts, utilization rates have remained stable at ~25% since 2005 . A recent retrospective study of patients with 15 model of end-stage liver disease (MELD) AVE5688 scores found that 50% of waitlist mortality patients declined at least one transplant offer . The reason for offer rejection in nearly 75% of these cases was due to concerns over donor quality or age. Surprisingly, many of these livers were successfully transplanted into lower priority patients. Increasing the safe utilization of ECD livers will require clarifying the molecular pathways associated with delayed graft function (DGF) or primary non-function (PNF) as well as strategies to quantify and manage these factors without influencing patient outcomes. Identifying specific Rabbit Polyclonal to SMUG1 mediators will allow centers to quantitatively ascertain high versus low risk ECD livers and therapeutically neutralize mediators to control DGF/PNF risk. Numerous reports have AVE5688 shown that when risks associated with ECD livers are identified and managed, these organs can be utilized with excellent patient outcomes [8,9,10]. Unfortunately, alarming trends in obesity and non-alcoholic fatty liver disease (NAFLD)  have already started to impact liver transplantation  and the donor liver pool [12,13]. The prevalence of steatosis in liver procurements ranges from 10C30% in the literature [12,13]. Obesity is a well-known risk factor for hepatic steatosis, and clinical profiles of waitlist registrants with consistent NAFLD continue to increase [1,11]. These trends suggest the prevalence of steatosis will increase in the coming years, and require centers to confidently assess and address donor steatosis or risk a widening gap between transplant candidates and available donor livers. In ECD AVE5688 steatosis, careful consideration must be given to both the degree of steatosis as well as the percentage of the liver affected. Steatosis is characterized as lipid accumulation within hepatocytes and can manifest as either microsteatosis (MiS) or macrosteatosis (MaS). Steatosis can lead to hepatic endoplasmic reticulum stress and mitochondrial dysfunction. Histologically, MiS exists as small lipid-containing vesicles within hepatocytes, and grafts with MiS are considered viable even with 100% of liver affected. MaS exists as large lipid-containing vesicles, which displace the hepatocyte nucleus , and grafts with MaS exceeding 30% are generally not utilized due to poor outcomes [14,15,16]. MaS AVE5688 is graded on a scale of mild.