Donation after brain death (DBD) organ donors remain an important source for kidney transplantation. However, brain death affects donor organs rendering them susceptible to ischemia reperfusion injury. It is vital to understand how kidneys are injured during brain death, as this will allow us to develop novel strategies protecting organs in the donor, especially in higher risk donors that are older and more marginal.

Using a brain death model in the rat (Fig.1) cellular and molecular pathways were found to be altered compared to sham controls and living donor controls, using novel proteomics and metabolomics techniques. Omics findings were further validated, characterising disturbances in metabolic pathways, mitochondrial function, oxidative stress and hypoxia response pathways.

Proteomics and metabolomics results demonstrated higher amounts of anaerobic metabolic intermediaries, including lactate (p=0.04) and higher dependency of brain dead donor kidneys on non-oxidative phosphorylation pathways. We also found a build-up of TCA cycle intermediaries. Mitochondria from brain dead donor kidneys showed decreased O₂ consumption (p=0.01), which correlated with decreased tissue ATP levels, compared to controls. Mitochondrial morphology in these kidneys also showed significant fragmentation. Mitochondrial dysfunction was associated with increased inflammatory response (NFkB mRNA levels, p=0.01) and increased oxidative stress (decreased mitochondrial aconitase activity, p=0.01), when compared to controls.

Brain death results in a concerted alteration of metabolic pathways in the donor kidney leading to dysregulated mitochondrial function and oxidative stress contributing to DBD-related injury of the graft-to-be. Metabolic conditioning or mitochondrial protective strategies are possible interventions during donor management and may reduce injury to donor organs and enhance outcomes after transplantation.

CITATION INFORMATION: Lo Faro M, Akhtar M, Huang H, Kaisar M, Robolledo R, Morten K, Heather L, Dona A, Leuvenink H, Fuggle S, Kessler B, Pugh C, Ploeg R. Metabolic Dysregulation and Mitochondrial Dysfunction Are Key Features of Injury Profiles of Donor Kidneys After Brain Death. Am J Transplant. 2016;16 (suppl 3).

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