Normothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39
We previously reported that normothermic ex vivo kidney perfusion (NEVKP) is superior in terms of organ protection compared to static cold storage (SCS), which is still the standard method of organ preservation, but the mechanisms are incompletely understood. We used a large animal kidney autotransplant model to evaluate mitochondrial function during organ preservation and after kidney transplantation, utilizing live cells extracted from fresh kidney tissue. Male porcine kidneys stored under normothermic perfusion showed preserved mitochondrial function and higher ATP levels compared to kidneys stored at 4 °C (SCS). Mitochondrial respiration and ATP levels were further enhanced when AP39, a mitochondria-targeted hydrogen sulfide donor, was administered during warm perfusion. Correspondingly, the combination of NEVKP and AP39 was associated with decreased oxidative stress and inflammation, and with improved graft function after transplantation. In conclusion, our findings suggest that the organ-protective effects of normothermic perfusion are mediated by maintenance of mitochondrial function and enhanced by AP39 administration. Activation of mitochondrial function through the combination of AP39 and normothermic perfusion could represent a new therapeutic strategy for long-term renal preservation.
Authors
- Ana C. Andreazza (ORCID: https://orcid.org/0000-0002-4323-7273)
- Samrat Ray
- Trevor Reichman (ORCID: https://orcid.org/0000-0002-2303-1606)
- Catherine Parmentier (ORCID: https://orcid.org/0000-0001-5026-4344)
- Ana Konvalinka (ORCID: https://orcid.org/0000-0001-6672-355X)
- Emmanuel Nogueira
- Sergi Clotet‐Freixas (ORCID: https://orcid.org/0000-0002-6965-4403)
- Rohan John (ORCID: https://orcid.org/0000-0001-7946-3013)
- Bhranavi Arulratnam
- Sharon Shui Yee Leung (ORCID: https://orcid.org/0000-0002-0194-7058)
- Yuki Noguchi (ORCID: https://orcid.org/0000-0003-3917-4369)
- Masataka Kawamura (ORCID: https://orcid.org/0000-0003-1454-0588)
- Laura Mazilescu (ORCID: https://orcid.org/0000-0003-4522-7295)
- Lisa A. Robinson (ORCID: https://orcid.org/0000-0003-1714-1929)
- Markus Selzner (ORCID: https://orcid.org/0000-0002-4326-0887)
- Sujani Ganesh
- Peter K. Kim (ORCID: https://orcid.org/0000-0001-6626-0575)
- Tomas Tamang
- Toru Goto (ORCID: https://orcid.org/0000-0002-8215-6839)
- Kaitlin Lees
Institutions
- University Health Network (CA)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Toronto General Hospital (CA)
- Osaka Prefectural Medical Center (JP)
- Osaka City General Hospital (JP)
- Essen University Hospital (DE)
- SickKids Foundation (CA)
- St. Joseph’s Healthcare Hamilton (CA)
- MRC Mitochondrial Biology Unit (GB)
- McMaster University (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-15
- DOI
- https://doi.org/10.1038/s41467-024-52140-9
- Citations
- 13
- Primary Topic
- Organ Transplantation Techniques and Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 7.45
Funders
- Canada Research Chairs
- Canadian Institutes of Health Research