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Brain Death Enhances Activation of the Innate Immune System and Leads to Reduced Renal Metabolic Gene Expression

Zitur, Laura J. MS1; Chlebeck, Peter J. BS1; Odorico, Scott K. BS1; Danobeitia, Juan S. MD, PhD1; Zens, Tiffany J. MD1; Van Kooten, Cees PhD2; Eerhart, Michael MD1; Reyes, Jose A. MD1; Springer, Megan L.1; Coonen, Jennifer M. DVM3; Brunner, Kevin G. DVM3; Capuano, Saverio V. DVM3; D’Alessandro, Anthony M. MD1; Fernandez, Luis A. MD1

doi: 10.1097/TP.0000000000002744
Original Basic Science—General
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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.

1 Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI.

2 Department of Nephrology, Leiden University Medical Centre, Leiden, Netherlands.

3 Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI.

Received 27 August 2018. Revision received 14 March 2019.

Accepted 16 March 2019.

This work was supported by the NIH under award R01AI110617. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors declare no funding or conflicts of interest.

L.Z., P.C., S.O., J.D., T.Z., M.S., and C.V.K. conducted this research under the mentorship and guidance of L.A.F. M.L.S., S.V.C., J.M.C., A.M.D., M.E., and J.A.R. provided meaningful guidance with regard to methodological approach, data analysis, data interpretation, and article writing and revisions. L.J.Z. and P.J.C. contributed equally to this work.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Luis A. Fernandez, MD, FACS, Professor Department of Surgery, Division of Transplantation, 600 Highland Ave BX7375 Clinical Science CNTR-H4 Madison, WI 53792-3284. (luisf@surgery.wisc.edu).

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