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Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes


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Date
2021

Authors
Urbanellis P, McEvoy CM, Škrtić M, Kaths JM, Kollmann D, Linares I, Ganesh S, Oquendo F, Sharma M, Mazilescu L, Goto T, Noguchi Y, John R, Mucsi I, Ghanekar A, Bagli D, Konvalinka A, Selzner M, Robinson LA.

Subject
Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes

Abstract
Normothermic ex vivo kidney perfusion (NEVKP) has demonstrated superior outcomes for donation-after-cardiovascular death grafts compared with static cold storage (SCS). To determine the mechanisms responsible for this, we performed an unbiased genome-wide microarray analysis. Methods: Kidneys from 30-kg Yorkshire pigs were subjected to 30 min of warm ischemia followed by 8 h of NEVKP or SCS, or no storage, before autotransplantation. mRNA expression was analyzed on renal biopsies on postoperative day 3. Gene set enrichment analysis was performed using hallmark gene sets, Gene Ontology, and pathway analysis. Results: The gene expression profile of NEVKP-stored grafts closely resembled no storage kidneys. Gene set enrichment analysis demonstrated enrichment of fatty acid metabolism and oxidative phosphorylation following NEVKP, whereas SCS-enriched gene sets were related to mitosis, cell cycle checkpoint, and reactive oxygen species (q < 0.05). Pathway analysis demonstrated enrichment of lipid oxidation/metabolism, the Krebs cycle, and pyruvate metabolism in NEVKP compared with SCS (q < 0.05). Comparison of our findings with external data sets of renal ischemia-reperfusion injury revealed that SCS-stored grafts demonstrated similar gene expression profiles to ischemia-reperfusion injury, whereas the profile of NEVKP-stored grafts resembled recovered kidneys. Conclusions: Increased transcripts of key mitochondrial metabolic pathways following NEVKP storage may account for improved donation-after-cardiovascular death graft function, compared with SCS, which promoted expression of genes typically perturbed during IRI.