The Impact of Ischemia/Reperfusion Injury on Liver Allografts from Deceased after Cardiac Death versus Deceased after Brain Death Donors

Abstract

Background and aimsThe shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD). The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD), we aimed to understand how ischemia/reperfusion (I/R) injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration.MethodsHepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13) and DBD (n = 10) livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22) and DBD (n = 13) livers.ResultsWhen examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p<0.05) and C22 ceramide (p<0.05) were more pronounced for DCD. C18 ceramide is correlated to bilirubin, INR, and creatinine after transplant in DCD. Prior to transplantation, DCD livers have reduced leukocyte infiltration compared to DBD allografts. Following reperfusion, the neutrophil infiltration and platelet deposition was less prevalent in DCD grafts while cell death and recipients levels of serum aspartate aminotransferase (AST) of DCD allografts had significantly increased.ConclusionThese data suggest that I/R injury generate necrosis in the absence of a strong inflammatory response in DCD livers with an appreciable effect on early graft function. The long-term consequences of increased inflammation in DBD and increased cell death in DCD allografts are unknown and warrant further investigation.

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

“…NHBD donor livers demonstrate increased levels of ceramide18, a pro‐apoptotic activator correlating with increased cell death from IRI. VWF is also elevated in NHBD donor livers indicating higher risk of microthrombi formation and loss of sinusoidal blood flow contributing to ongoing IRI during organ recovery …”

“…VWF is also elevated in NHBD donor livers indicating higher risk of microthrombi formation and loss of sinusoidal blood flow contributing to ongoing IRI during organ recovery. 33,34 Increasing donor age is a risk factor for IRI in liver transplantation. Livers from donors over the age of 70 experience more injury at prolonged cold ischaemic times as compared to livers from younger donors.…”

Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase3 pathway regulation

“…This procedure is currently accepted and performed by many transplant centres worldwide, but organ shortages remain a prevalent problem [2] which is reflected in the median time to transplant among waiting-listed candidates. For example, in the United States, the median time increased from 14.8 months in 2004 to 19.5 months in 2011 [3]. As a result, death rates among patients on the waiting list have increased over the past two decades [2].…”

Normothermic Machine Perfusion (NMP) Inhibits Proinflammatory Responses in the Liver and Promotes Regeneration

“…However, this increase is mainly limited to high‐risk, so‐called marginal donors, which largely comprise donors deceased after circulatory death (DCD), older donors, and fatty livers . There is evidence that marginal organs have greater vulnerability to ischemia reperfusion injury (IRI), an inevitable process of organ transplantation …”

“…(3) There is evidence that marginal organs have greater vulnerability to ischemia reperfusion injury (IRI), an inevitable process of organ transplantation. (4) A number of experimental and clinical studies have shown that reperfusion of allografts is associated with organ inflammation characterized by the release of inflammatory mediators, up-regulation of adhesion molecules, immune cell infiltration, and increased cell death. (5)(6)(7) This damage affects short-and longterm organ outcome by contributing to development of primary nonfunction and ischemic cholangiopathy, respectively.…”