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

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Hameed, AM; Lu, DB; Burns, H; Byrne, N; Chew, YV; Julovi, S; Ghimire, K; Zanjani, NT; P'ng, CH; Meijles, D; et al. Hameed, AM; Lu, DB; Burns, H; Byrne, N; Chew, YV; Julovi, S; Ghimire, K; Zanjani, NT; P'ng, CH; Meijles, D; Dervish, S; Matthews, R; Miraziz, R; O'Grady, G; Yuen, L; Pleass, HC; Rogers, NM; Hawthorne, WJ (2020) Pharmacologic targeting of renal ischemia-reperfusion injury using a normothermic machine perfusion platform. Sci Rep, 10 (1). p. 6930. ISSN 2045-2322 https://doi.org/10.1038/s41598-020-63687-0

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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.

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Article

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre-ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per-mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2020

Journal or Publication Title:

Sci Rep

ISSN:

2045-2322

Language:

eng

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