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Pharmacologic targeting of renal ischemia-reperfusion injury using a normothermic machine perfusion platform.

Authors :
Hameed, Ahmer M.
Lu, David B.
Burns, Heather
Byrne, Nicole
Chew, Yi Vee
Julovi, Sohel
Ghimire, Kedar
Zanjani, Negar Talaei
P'ng, Chow H.
Meijles, Daniel
Dervish, Suat
Matthews, Ross
Miraziz, Ray
O'Grady, Greg
Yuen, Lawrence
Pleass, Henry C.
Rogers, Natasha M.
Hawthorne, Wayne J.
Source :
Scientific Reports; 4/24/2020, Vol. 10 Issue 1, p1-17, 17p
Publication Year :
2020

Abstract

Normothermic machine perfusion (NMP) is an emerging modality for kidney preservation prior to transplantation. NMP may allow directed pharmacomodulation of renal ischemia-reperfusion injury (IRI) without the need for systemic donor/recipient therapies. Three proven anti-IRI agents not in widespread clinical use, CD47-blocking antibody (αCD47Ab), soluble complement receptor 1 (sCR1), and recombinant thrombomodulin (rTM), were compared in a murine model of kidney IRI. The most effective agent was then utilized in a custom NMP circuit for the treatment of isolated porcine kidneys, ascertaining the impact of the drug on perfusion and IRI-related parameters. αCD47Ab conferred the greatest protection against IRI in mice after 24 hours. αCD47Ab was therefore chosen as the candidate agent for addition to the NMP circuit. CD47 receptor binding was demonstrated by immunofluorescence. Renal perfusion/flow improved with CD47 blockade, with a corresponding reduction in oxidative stress and histologic damage compared to untreated NMP kidneys. Tubular and glomerular functional parameters were not significantly impacted by αCD47Ab treatment during NMP. In a murine renal IRI model, αCD47Ab was confirmed as a superior anti-IRI agent compared to therapies targeting other pathways. NMP enabled effective, direct delivery of this drug to porcine kidneys, although further efficacy needs to be proven in the transplantation setting. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20452322
Volume :
10
Issue :
1
Database :
Complementary Index
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
142886943
Full Text :
https://doi.org/10.1038/s41598-020-63687-0