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CORM-401 Reduces Ischemia Reperfusion Injury in an Ex Vivo Renal Porcine Model of the Donation After Circulatory Death

Bhattacharjee, Rabindra N., PhD1,2,4; Richard-Mohamed, Mahms, MSc2,3; Sun, Qizhi, PhD1; Haig, Aaron, MD1,4; Aboalsamh, Ghaleb, MD2,3; Barrett, Peter, MSc2,3; Mayer, Richard, MSc3; Alhasan, Ibrahim, MD2,3; Pineda-Solis, Karen, MD2,3; Jiang, Larry, MSc1; Alharbi, Hajed, MSc1; Saha, Manujendra, PhD1; Patterson, Eric, PhD5; Sener, Alp, MD1,2,3; Cepinskas, Gediminas, PhD5; Jevnikar, Anthony M., MD1,2,3,6; Luke, Patrick P.W., MD1,2,3,4

doi: 10.1097/TP.0000000000002201
Original Basic Science—General

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 CO releasing molecules (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 circulatory death in a porcine model of transplantation.

Methods To stimulate donation after circulatory death condition, kidneys from large male Landrace pig were retrieved after 1 hour warm ischemia in situ by cross-clamping the renal pedicle. Procured kidneys, after a brief flushing with histidine-tryptophan-ketoglutarate solution were subjected to pulsatile perfusion at 4°C with University of Wisconsin solution for 4 hours and both kidneys were treated with either 200 μM CORM-401 or inactive CORM-401, respectively. Kidneys were then reperfused with normothermic isogeneic porcine blood through oxygenated pulsatile perfusion for 10 hours. Urine was collected, vascular flow was assessed during reperfusion and histopathology was assessed after 10 hours of reperfusion.

Results We have found that CORM-401 administration reduced urinary protein excretion, attenuated kidney damage markers (kidney damage marker-1 and neutrophil gelatinase-associated lipocalin), and reduced ATN and dUTP nick end labeling 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 Carbon monoxide releasing molecules-401 provides renal protection after cold storage of kidneys and provides a novel clinically relevant ex vivo organ preservation strategy.

The authors demonstrate that perfusate infused CORM-401 protects the kidney from postreperfusion injury through reduction of vascular resistance, apoptosis and necrosis in a porcine DCD model.

1 Matthew Mailing Centre for Translational Transplantation Studies, Western University, London, Canada.

2 Multi Organ Transplant Program, Western University, London, Canada.

3 Department of Surgery, Western University, London, Canada.

4 Department of Pathology and Laboratory Medicine, Western University, London, Canada.

5 Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada.

6 Division of Nephrology, London Health Sciences Centre, London, Ontario, Canada.

Received 6 October 2017. Revision received 1 March 2018.

Accepted 2 March 2018.

The Canadian National Transplantation Research Program is 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 financial support was received from the Internal Research Fund (RNB, PPL), Department of Surgery at LHSC. HTK and UW solutions were provided by Methapharm Inc. and Bridge to life, respectively.

The authors declare no conflicts of interest.

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 the surgical procedures. P.B. participated in kidney perfusion and urine collection. R.M. participated in kidney perfusion and blood collection. I.A. participated in the surgical procedures. K.P.-S. participated in the 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.W.L. participated in the intellectual conception of project, extensive literature review, partial article writing, editing and final approval of the article.

Correspondence: Patrick P.W. Luke, London Health Sciences, 339 Windermere Road, London, Ontario, Canada N6A 5A5. (patrick.luke@lhsc.on.ca).

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