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Therapeutic Strategy with a Membrane-Localizing Complement Regulator to Increase the Number of Usable Donor Organs after Prolonged Cold Storage

Hetal Patel^*, Richard A.G. Smith, Steven H. Sacks^* and Wuding Zhou^*

^* King’s College London School of Medicine at Guy’s, King’s College and St. Thomas’ Hospitals, Department of Nephrology and Transplantation, Guy’s Hospital, London, United Kingdom; and Inflazyme Pharmaceuticals Ltd., Richmond, British Columbia, Canada

Address correspondence to: Dr. Wuding Zhou, Department of Nephrology and Transplantation, 5th Floor, Thomas Guy House, Guy’s Hospital, London SE1 9RT, UK. Phone: +44-0-207-188-1528; Fax: +44-0-207-188-5660; E-mail: wuding.zhou{at}kcl.ac.uk

Received for publication October 25, 2005. Accepted for publication January 18, 2006.

A shortage of donor organs and increasing dependence on marginal grafts with prolonged ischemic times have meant that new methods are needed to prevent postischemic damage. Herein is reported a new strategy aimed to protect donor kidney from complement-mediated postischemic damage and therefore increase the number of successful transplants. Rat donor kidneys were perfused with a membrane-localizing complement regulator derived from human complement receptor type 1 (APT070) and then subjected to prolonged periods of cold storage (at 4°C). A relationship was found between the duration of cold ischemia and the extent of complement-mediated tubule damage and loss of graft function. After 16 h of cold storage, APT070-treated kidneys that were transplanted into syngeneic recipients showed a significant increase in the number of surviving grafts, compared with control-treated grafts (63.6 versus 26.3%). Surviving grafts also displayed less acute tubular injury and better preservation of renal function. These results not only enhance the understanding of the mechanism by which prolonged cold ischemia reduces immediate graft survival but also provide essential information about the effectiveness of membrane-localizing complement regulator with prolonged cold storage. This could lead to more effective strategies for improving the use of severely ischemic donor organs.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673