Normothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39

Masataka Kawamura, Catherine Parmentier, Samrat Ray, Sergi Clotet-Freixas, Sharon Leung, Rohan John, Laura Mazilescu, Emmanuel Nogueira, Yuki Noguchi, Toru Goto, Bhranavi Arulratnam, Sujani Ganesh, Tomas Tamang, Kaitlin Lees, Trevor W. Reichman, Ana C. Andreazza, Peter K. Kim, Ana Konvalinka, Markus Selzner () and Lisa A. Robinson ()
Additional contact information
Masataka Kawamura: Toronto General Hospital
Catherine Parmentier: Toronto General Hospital
Samrat Ray: Toronto General Hospital
Sergi Clotet-Freixas: Toronto General Hospital
Sharon Leung: The Hospital for Sick Children Research Institute
Rohan John: University of Toronto
Laura Mazilescu: Toronto General Hospital
Emmanuel Nogueira: Toronto General Hospital
Yuki Noguchi: Toronto General Hospital
Toru Goto: Toronto General Hospital
Bhranavi Arulratnam: Toronto General Hospital
Sujani Ganesh: Toronto General Hospital
Tomas Tamang: Toronto General Hospital
Kaitlin Lees: Toronto General Hospital
Trevor W. Reichman: Toronto General Hospital
Ana C. Andreazza: University of Toronto
Peter K. Kim: The Hospital for Sick Children Research Institute
Ana Konvalinka: Toronto General Hospital
Markus Selzner: Toronto General Hospital
Lisa A. Robinson: The Hospital for Sick Children

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52140-9

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