Brain Death Enhances Activation of the Innate Immune System and Leads to Reduced Renal Metabolic Gene Expression. Issue 9 (September 2019)

• Record Type: Journal Article
• Authors: Zitur, Laura J.; Chlebeck, Peter J.; Odorico, Scott K.; Danobeitia, Juan S.; Zens, Tiffany J.; Van Kooten, Cees; Eerhart, Michael; Reyes, Jose A.; Springer, Megan L.; Coonen, Jennifer M.; Brunner, Kevin G.; Capuano, Saverio V.; D'Alessandro, Anthony M.; Fernandez, Luis A.
• Is Part Of: Transplantation. Volume 103:Issue 9(2019)
• Publication Date: 2019-09
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000002744
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Background: Brain death (BD)–associated inflammation has been implicated in decreased kidney allograft function and survival, but the underlying mechanisms have not been well distinguished from the conditions of critical care itself. We have developed a clinically translatable model to separate and investigate strategies to improve donor management and critical care. Methods: Brain-dead (n = 12) and sham (n = 5) rhesus macaques were maintained for 20 hours under intensive care unit–level conditions. Samples were collected for immunophenotyping, analysis of plasma proteins, coagulation studies, and gene analysis for changes in immune and metabolic profile with comparison to naive samples (n = 10). Results: We observed an increase in circulating leukocytes and cytokines, activation of complement and coagulation pathways, and upregulation of genes associated with inflammation in both brain-dead and sham subjects relative to naïve controls. Sham demonstrated an intermediate phenotype of inflammation compared to BD. Analysis of gene expression in kidneys from BD kidneys revealed a similar upregulation of inflammatory profile in both BD and sham subjects, but BD presented a distinct reduction in metabolic and respiratory processes compared to sham and naïve kidneys. Conclusion: BD is associated with activation of specific pathways of the innate immune system and changes to metabolic gene expression in renal tissue itself; however, sham donors presented an intermediate inflammatory response attributable to the critical care environment. The early onset and penetrating impact of this inflammatory response underscores the need for early intervention to prevent perioperative tissue injury to transplantable organs. Abstract : Supplemental Digital Content is available in the text.