Brain Death Conditions Intensify Inflammation and Impair Metabolic Gene Expression

L. Zitur, P. Chlebeck, S. Odorico, T. Zens, J. Danobeitia, M. Eerhart, J. Reyes, A. D'Alessandro, K. Brunner, S. Capuano, L. Fernandez.

University of Wisconsin, Madison.

Meeting: 2018 American Transplant Congress

Abstract number: A46

Keywords: Anticoagulation, Brain death, Inflammation, Metabolic complications

Session Information

Session Name: Poster Session A: Biomarkers, Immune Monitoring and Outcomes

Session Type: Poster Session

Date: Saturday, June 2, 2018

Session Time: 5:30pm-7:30pm

Presentation Time: 5:30pm-7:30pm

Location: Hall 4EF

Rationale: Inflammation observed in Brain Death (BD) donors is linked to reduced graft function and survival compared to living donors (LD). Detailed analyses of non-human primate blood and tissue obtained in BD, LD and Sham donors (SD) revealed molecular signatures distinct from a general inflammatory response, yielding a new approach to improve transplant outcomes.

Methods: BD (n=9) and SD (n=4) were ventilated, monitored, and treated for 20 hours of standard ICU-level care. Blood/tissue collected from these and LD (n=6) were analyzed by ELISA, bead-array, and microarray. Statistics: student T-test, ANOVA (post-test: Bonferoni/Benjamini-Hochberg), gene expression threshold >2-fold, FDR<0.05.

Results: Expression analysis exhibited robust enrichment for inflammatory response in BD and SD (p=9.2e^-7, p=7.1e^-9) kidneys compared to LD. Compared to SD, BD kidneys upregulated angiogenesis (p=1.5e^-2) and stress response genes (p=4.5e^-2) and downregulated genes in metabolic processes, i.e. carbohydrate (p=2.1e^-5) and lipid (p=1.3e^-5). BD livers upregulated chemical response genes (p=2.6e^-2) and downregulated primary metabolism genes (p=9.7e^-5), including lipid, organic and carbohydrate (p=2.0e^-16, p=5.7e^-9, p=2.3e^-3) compared to LD. BD and SD livers exuded minimal expression differences.

BD and SD elicited profound neutrophilia and circulating IL-6 increased (BD: 300-fold, SD: 30-fold, p<0.005), along with circulating TNFα, IL-8, CCL-2 (3-, 3-, and 4-fold), and classical complement activity (125%). Lectin pathway activity increased in BD (120%) compared to SD (50%)(p<0.05). BD revealed increased circulation of VWF (200%, p<0.05), Thrombin (125%, p<0.05), and Plasminogen (150%, p<0.05) over SD. BD and SD increased circulating Fibrinogen (300%) and tPA (200%) over baseline. No changes were observed in coagulation times. Active Bradykinin, inflammatory molecule/vasodilator, increased 200% (p<0.05) in BD over SD.

Conclusion: BD and SD demonstrated general inflammatory responses, albeit with stronger intensity in BD, and dysregulation of coagulation and contact molecules. Transcription analysis of liver and kidney tissue unveiled dramatic BD-related down-regulation of genes involved in metabolic pathways for lipids, proteins, and carbohydrates. Addressing metabolic impairment and the inflammatory environment is key for therapeutic strategies that eradicate differences between BD and LD graft survival and improve transplant outcomes.

CITATION INFORMATION: Zitur L., Chlebeck P., Odorico S., Zens T., Danobeitia J., Eerhart M., Reyes J., D'Alessandro A., Brunner K., Capuano S., Fernandez L. Brain Death Conditions Intensify Inflammation and Impair Metabolic Gene Expression Am J Transplant. 2017;17 (suppl 3).

To cite this abstract in AMA style:

Zitur L, Chlebeck P, Odorico S, Zens T, Danobeitia J, Eerhart M, Reyes J, D'Alessandro A, Brunner K, Capuano S, Fernandez L. Brain Death Conditions Intensify Inflammation and Impair Metabolic Gene Expression [abstract]. https://atcmeetingabstracts.com/abstract/brain-death-conditions-intensify-inflammation-and-impair-metabolic-gene-expression/. Accessed November 21, 2024.

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