Dataset Information

Complement Activation in Liver Transplantation: Role of Donor Macrosteatosis and Implications in Delayed Graft Function.

ABSTRACT: The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation may be a critical variable controlling the balance between regenerative and destructive inflammation following sterile injury. Recent studies in kidney transplantation suggest that aberrant complement activation may play a significant role in delayed graft function following transplantation, confirming results obtained from rodent models of renal ischemia/reperfusion (I/R) injury. Deactivating the complement cascade through targeting anaphylatoxins (C3a/C5a) might be an effective 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 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.

SUBMITTER: Nunez K

PROVIDER: S-EPMC6032339 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Complement Activation in Liver Transplantation: Role of Donor Macrosteatosis and Implications in Delayed Graft Function.

Núñez Kelley K Thevenot Paul P Alfadhli Abeer A Cohen Ari A

International journal of molecular sciences 20180613 6

The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation may be a critical variable controlling the balance between regenerative and destructive inflammation following sterile injury. Recent studies in kidney transplantation ...[more]

PMID: 29899265

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Project description:BackgroundAs prevalence of nonalcoholic fatty liver disease increases in the population, livers with steatosis will continue to infiltrate the donor pool. Safe utilization of these extended criteria grafts is paramount given the increased risk associated with their use in transplantation. Prognostic factors that can predict liver dysfunction immediately after transplantation with macrosteatotic grafts are lacking.AimTo understand the relationship between interleukin-33 (IL-33) and complement in recipients immediately following liver reperfusion as a marker of liver dysfunction.MethodsCohort consisted of patients who received a liver transplant from September 2016-September 2019 at our institution. Clinical variables were retrospectively extracted from the electronic medical record. Back-table donor biopsies were obtained with donor steatosis percentage retrospectively determined by a board-certified pathologist. Blood samples were available immediately following liver transplantation. Quantification of plasma IL-33 and complement proteins, C3a and C5a, were determined by enzyme-linked immunosorbent assay. For mRNA expression, RNA was extracted from donor biopsies and used against a 780 gene panel.ResultsCohort consisted of 99 donor and recipients. Donor median age was 45 years and 55% male. Recipients had a median age of 59 years with 62% male. The main etiologies were alcoholic hepatitis, nonalcoholic steatohepatitis, and hepatocellular carcinoma. Median MELD-Na at transplant was 21. Donors were grouped based on moderate macrosteatosis (≥ 30%). Recipients implanted with moderate macrosteatotic grafts had significantly higher peak alanine aminotransferase/aspartate aminotransferase (P < 0.001 and P < 0.004), and increased incidence of early allograft dysfunction (60% compared to 18%). Circulating IL-33 levels were significantly elevated in recipients of ≥ 30% macrosteatotic grafts (P < 0.05). Recipients with detectable levels of circulating IL-33 immediately following reperfusion had significantly higher alanine aminotransferase/aspartate aminotransferase (P < 0.05 and P < 0.01). Activated complement (C3a and C5a) were elevated in recipients implanted with moderate macrosteatotic grafts. RNA expression analysis of donor biopsies revealed moderate steatotic grafts upregulated genes inflammatory processes while downregulated hepatocyte-produced complement factors.ConclusionCirculating IL-33 and activated complement levels immediately following liver reperfusion in recipients of moderate macrosteatotic grafts may identify which patients are at risk of early allograft dysfunction.

Project description:Background and objectivesIncreased donor age is one of the most important risk factors for delayed graft function (DGF), and previous studies suggest that the harmful effect of cold ischemia time is increased in kidneys from older donors. Our aim was to study the association of increased donor age and cold ischemia time with the risk of delayed graft function in a large cohort kidney transplants from the current era.Design, setting, participants, & measurementsThe Scientific Registry of Transplant Recipients was used for this observational, retrospective registry analysis to identify all deceased donor kidney transplantations in the United States between 2010 and September 2018, who were on dialysis pretransplantation (n=90,810). The association of donor age and cold ischemia time with the risk of DGF was analyzed in multivariable models adjusted for recipient characteristics (age, race, sex, diabetes, calculated panel-reactive antibodies, pretransplant dialysis duration) and donor characteristics (cause of death, sex, race, body mass index, creatinine, donation after circulatory death status, history of hypertension, and HLA mismatch).ResultsCold ischemia time and donor age were independently associated with the risk of DGF, but the risk of DGF was not statistically significantly lower in donor age categories between 50 and 64 years, compared with donors ≥65 years. The harmful association of cold ischemia time was not higher in kidneys from older donors in any age category, not even among donation after circulatory death donors. When donor risk was assessed with kidney donor profile index, although a statistically significant interaction with cold ischemia time was found, no practically meaningful increase in cold-ischemia susceptibility of kidneys with a high kidney donor profile index was found.ConclusionsWe were unable to demonstrate an association between donor age and DGF. The association of longer cold ischemia time with the risk of DGF was not magnified in older or more marginal donors.

Dataset Information

Complement Activation in Liver Transplantation: Role of Donor Macrosteatosis and Implications in Delayed Graft Function.

Publications

Complement Activation in Liver Transplantation: Role of Donor Macrosteatosis and Implications in Delayed Graft Function.

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