Brain Death Activates Donor Organs and Is Associated with a Worse I/R Injury After Liver Transplantation

Abstract

The majority of transplants are derived from donors who suffered from brain injury. There is evidence that brain death causes inflammatory changes in the donor. To define the impact of brain death, we evaluated the gene expression of cytokines in human brain dead and ideal living donors and compared these data to organ function following transplantation.Hepatic tissues from brain dead (n = 32) and living donors (n = 26) were collected at the time of donor laparotomy. Additional biopsies were performed before organ preservation, at the time of transplantation and one hour after reperfusion. Cytokines were assessed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and cytometric bead array. Additionally, immunohistological analysis of tissue specimens was performed. Inflammatory cytokines including IL-6, IL-10, TNF-a , TGF-b and MIP-1a were significantly higher in brain dead donors immediately after laparotomy compared to living donors. Cellular infiltrates significantly increased in parallel to the soluble cytokines IL-6 and IL-10. Enhanced immune activation in brain dead donors was reflected by a deteriorated I/R injury proven by elevated alanin-aminotransferase (ALT), aspartat-amino-transferase (AST) and bilirubin levels, increased rates of acute rejection and primary nonfunction. Based on our clinical data, we demonstrate that brain death and the events that †Authors contributed equally to this manuscript.precede it are associated with a significant upregulation of inflammatory cytokines and lead to a worse ischemia/reperfusion injury after transplantation.

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

“…Plasma HMGB1 levels were slightly elevated in organ donors already before graft procurement, reflecting a systemic proinflammatory response induced by brain death. [28][29][30] Furthermore, surgical manipulation of the liver during procurement activates Kupffer cells, leading to hepatic expression of proinflammatory mediators. 30,31 Indeed, weak hepatocyte HMGB1 staining was already evident in biopsies taken immediately before graft perfusion during procurement.…”

“…[28][29][30] Furthermore, surgical manipulation of the liver during procurement activates Kupffer cells, leading to hepatic expression of proinflammatory mediators. 30,31 Indeed, weak hepatocyte HMGB1 staining was already evident in biopsies taken immediately before graft perfusion during procurement. Inflammatory responses related to both brain death and surgical stress likely enhanced hepatic HMGB1 expression.…”

Treatment With Tetrahydrobiopterin Overcomes Brain Death–Associated Injury in a Murine Model of Pancreas Transplantation

“…Consequently, the combination of donor BD and IRI causes enhanced immunogenicity of the graft, which accelerates the recipient's immune response after transplantation. This is clinically reflected by a higher incidence of delayed graft function (DGF) and impaired long‐term outcome in kidney transplantation 7, 13, 14 and even more in pancreas transplantation, IRI‐associated pancreatitis with subsequent pro‐thrombogenicity is one of the leading causes of early graft failure 2.…”

Brain death and its implications for management of the potential organ donor

“…63 In summary, brain death is associated with the release of proinflammatory substances and inflammatory responses are detected in all organs suitable for transplantation leading to immunologically activated organs before engraftment, resulting in histological damage, decreased function, and lower graft survival compared with organs from living donors. 58,[64][65][66][67][68] …”