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

Peter Urbanellis, MD, PhD,; Caitriona M. McEvoy, MD, PhD; Marko Škrtić, MD, PhD; J. Moritz Kaths, MD,; Dagmar Kollmann, MD, PhD; Ivan Linares, MD, PhD; Sujani Ganesh, MSc; Fabiola Oquendo, MD; Manraj Sharma, BSc (Hons); Laura Mazilescu, MD; Toru Goto, MD; Yuki Noguchi, MD, PhD; Rohan John, MD; Istvan Mucsi, MD, PhD; Anand Ghanekar, MD, PhD; Darius Bagli, MD; Ana Konvalinka, MD, PhD; Markus Selzner, MD; Lisa A. Robinson, MD

doi:10.1097/TXD.0000000000001157

Transplantation Direct (Aug 2021)

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

Peter Urbanellis, MD, PhD,,
Caitriona M. McEvoy, MD, PhD,
Marko Škrtić, MD, PhD,
J. Moritz Kaths, MD,,
Dagmar Kollmann, MD, PhD,
Ivan Linares, MD, PhD,
Sujani Ganesh, MSc,
Fabiola Oquendo, MD,
Manraj Sharma, BSc (Hons),
Laura Mazilescu, MD,
Toru Goto, MD,
Yuki Noguchi, MD, PhD,
Rohan John, MD,
Istvan Mucsi, MD, PhD,
Anand Ghanekar, MD, PhD,
Darius Bagli, MD,
Ana Konvalinka, MD, PhD,
Markus Selzner, MD,
Lisa A. Robinson, MD

Affiliations

Peter Urbanellis, MD, PhD,: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Caitriona M. McEvoy, MD, PhD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Marko Škrtić, MD, PhD: 5 Division of Nephrology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
J. Moritz Kaths, MD,: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Dagmar Kollmann, MD, PhD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Ivan Linares, MD, PhD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Sujani Ganesh, MSc: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Fabiola Oquendo, MD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Manraj Sharma, BSc (Hons): 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Laura Mazilescu, MD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Toru Goto, MD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Yuki Noguchi, MD, PhD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Rohan John, MD: 7 Laboratory Medicine and Pathobiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada.
Istvan Mucsi, MD, PhD: 2 Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada.
Anand Ghanekar, MD, PhD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Darius Bagli, MD: 8 Departments of Surgery (Urology) and Physiology, The Hospital for Sick Children, Toronto, ON, Canada.
Ana Konvalinka, MD, PhD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Markus Selzner, MD: 1 Soham and Shaila Ajmera Family Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Lisa A. Robinson, MD: 6 Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON, Canada.

DOI: https://doi.org/10.1097/TXD.0000000000001157
Journal volume & issue: Vol. 7, no. 8
p. e719

Abstract

Read online

Background. 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.

Published in Transplantation Direct

ISSN: 2373-8731 (Online)
Publisher: Wolters Kluwer
Country of publisher: United States
LCC subjects: Medicine: Surgery
Website: http://journals.lww.com/transplantationdirect/Pages/default.aspx

About the journal