CORM-401 reduces ischemia reperfusion injury in an ex vivo renal porcine model of the donation after cardiac death

Background Carbon monoxide (CO) inhalation protects organ by reducing inflammation and cell death during transplantation processes in animal model. However, using CO in clinical transplantation is difficult due to its delivery in a controlled manner. A manganese-containing CORM-401 has recently been synthesized which can efficiently deliver 3 molar equivalents of CO. We report the ability of this anti-inflammatory CORM-401 to reduce ischemia reperfusion injury associated with prolonged cold storage of renal allografts obtained from donation after cardiac death in a porcine model of transplantation. Methods To stimulate DCD condition, kidneys from large male Landrace pig were retrieved after 1h warm ischemia in situ by cross-clamping the renal pedicle. Procured kidneys, after a brief flushing with HTK solution were subjected to pulsatile perfusion at 4°C with UW solution for 4h and both kidneys were treated with either 200μM CORM-401 or inactive CORM-401 (iCORM-401) respectively. Kidneys were then reperfused with normothermic isogeneic porcine blood through oxygenated pulsatile perfusion for 10h. Urine was collected, vascular flow was assessed during reperfusion and histopathology was assessed after 10h of reperfusion. Results We have found that CORM-401 administration reduced urinary protein excretion, attenuated kidney damage markers (KIM-1 and NGAL), and reduced ATN and TUNEL staining in histopathologic sections. CORM-401 also prevented intrarenal hemorrhage and vascular clotting during reperfusion. Mechanistically, CORM-401 appeared to exert anti-inflammatory actions by suppressing Toll-like receptors 2, 4 and 6. Conclusions CORM-401 provides renal protection following cold storage of kidneys and provides a novel clinically relevant ex vivo organ preservation strategy. Correspondence: Patrick P.W. Luke, London Health Sciences, 339 Windermere Road, London, Ontario, Canada N6A 5A5. Email: patrick.luke@lhsc.on.ca Authorship R.N.B. participated in the performance of the research, data analysis, construction of figures and article writing. M.R.M participated in kidney perfusion and preparation of perfusion circuit. A.H participated in data analysis and pathological evaluation of tissue sections. G.A. participated in surgical procedures. P.B participated in kidney perfusion and urine collection. R.M. participated in kidney perfusion and blood collection. I.A. participated in surgical procedures. K.P.S participated in surgical procedures. Q. S., H.A and L.J. participated in data analysis. M.S. participated in performing RT-PCR experiments of TLR data. E.P. participated in measuring CO from CORM-401. A.S. participated in article editing. G.C participated in technical support regarding CORM-401 release. A.M.J. participated in intellectual conception of project, article editing and approval of the article. P.P.L participated in the intellectual conception of project, extensive literature review, partial article writing, editing and final approval of the article. Conflicts of Interest. All the authors declared no competing interests. Funding We would like to thank the Canadian National Transplantation Research Program sponsored by Canadian Institutes for Health Research (PPL), Physicians Services Incorporated Foundation (PSIF) (PPL, RNB), Academic Medical Organization of Southwestern Ontario (PPL, RNB), HSFO grant (G-17-0018622) to GC and Internal Research Fund (RNB, PPL), Department of Surgery at LHSC for financial support. HTK and UW solutions were provided by Methapharm Inc. and Bridge to life respectively. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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