Cardiotrophin 1 improves kidney preservation, graft function, and survival in transplanted rats

Background Cold ischemia-reperfusion injury is unavoidable during organ transplantation, and prolonged preservation is associated with poorer function recovery. Cardiotrophin-1 (CT-1) is an IL-6 family cytokine with cytoprotective properties. This preclinical study in rats tested whether CT-1 mitigates cold renal ischemia-reperfusion injury in the context of the transplantation of long-time preserved kidneys. Methods Kidneys were flushed with cold (4°C) University of Wisconsin solution (UW) containing 0.2 μg/mL CT-1 and stored for several periods of time at 4 °C in the same solution. In a second approach, kidneys were first cold-preserved for 6 hours and then were perfused with UW containing CT-1 (0, 16, 32, or 64 μg/mL) and further cold-preserved. Organ damage markers were measured in the kidneys at the end of the storage period. For renal transplantation, recipient consanguineous Fischer rats underwent bilateral nephrectomy and received a previously cold-preserved (24 hours) kidney as described above. Survival and creatinine clearance were monitored over 30 days. Results CT-1 in perfusion and preservation fluids reduced oxidative stress markers (SOA and iNOS), inflammation markers (NF-κB and TNF-α), and vascular damage (VCAM-1) and activated LIFR and STAT-3 survival signaling. Transplantation of kidneys cold-preserved with CT-1 increased rat survival and renal function (ie, lower plasma creatinine and higher creatinine clearance) and improved kidney damage markers after transplantation (ie, lower SOA, TNF-α, ICAM-1, and VCAM-1 and higher NF-κB). Conclusions CT-1 represents a novel therapeutic strategy to reduce ischemia-reperfusion and cold preservation injury, to rescue suboptimal kidneys and, consequently, to improve the clinical outcomes of renal transplantation. Received 13 January 2018. Revision received 30 April 2018. Accepted 24 May 2018. *These authors share first authorship. Correspondence: José M. Lopez-Novoa, Department of Physiology and Pharmacology, University of Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain. E-mail: jmlnovoa@usal.es. Fax number: +34 923294669 AUTHORSHIP PAGE 1. Authorship: BG-C, VB-G, JML-N, and FJL-H participated in the research design and writing of the paper. BG-C, VB-G, DL-M, and JRSG-R participated in the performance of the research. BG-C, VB-G, JML-N, and FJL-H participated in the data analysis. 2. Disclosure: The authors have no conflicts of interest to declare. 3. Funding: This study was supported by funds from Digna Biotech, Instituto de Salud Carlos III (grants DT15S/00166 and PI15/01055), and the European Commission (FEDER). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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