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Thrombotic Microangiopathic Glomerulopathy in Human Decay Accelerating Factor–Transgenic Swine-to-Baboon Kidney Xenografts

Akira Shimizu^*,,, Kazuhiko Yamada^*, Shin Yamamoto^*, John M. Lavelle^*, Rolf N. Barth^*, Simon C. Robson, David H. Sachs^* and Robert B. Colvin

^* Transplantation Biology Research Center, Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts; Department of Pathology, Nippon Medical School, Tokyo, Japan; and Center for Immunobiology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts

Address correspondence to: Dr. Robert B. Colvin, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street (Warren 225), Boston, MA 02114. Phone: 617-726-2966; Fax: 617-726-7533; E-mail: colvin@helix.mgh.harvard.edu

Received for publication December 29, 2004. Accepted for publication June 13, 2005.

Models of pig-to-baboon xenografting were examined to identify the mechanisms and pathologic characteristics of acute humoral xenograft rejection (AHXR). Thymus and kidney (composite thymokidney) from human decay accelerating factor–transgenic swine were transplanted into baboons (n = 16) that were treated with an immunosuppressive regimen that included extracorporeal immunoadsorption of anti-Gal antibody and inhibition of complement activation. Morphologic and immunohistochemical studies were performed on protocol biopsies and graftectomy samples. All renal xenografts avoided hyperacute rejection. However, graft rejection coincided with the increase of anti-Gal antibody in the recipient’s circulation. The 16 xenografts studied were divided into two groups dependent on the rapid return (group 1) or gradual return (group 2) of anti-Gal antibody after immunoadsorption. In group 1 (n = 6), grafts were rejected to day 27 with development of typical AHXR, characterized by marked interstitial hemorrhage and thrombotic microangiopathy in the renal vasculature. In group 2 (n = 10), grafts also developed thrombotic microangiopathy affecting mainly the glomeruli by day 30 but also showed minimal evidence of interstitial injury and hemorrhage. In the injured glomeruli, IgM and C4d deposition, subsequent endothelial cell death and activation with upregulation of von Willebrand factor and tissue factor, and a decrease of CD39 expression developed with the formation of fibrin-platelet multiple microthrombi. In this model, the kidney xenografts, from human decay accelerating factor–transgenic swine, in baboons undergo AHXR. In slowly evolving AHXR, graft loss is associated with the development of thrombotic microangiopathic glomerulopathy. Also, anti-Gal IgM deposition and subsequent complement activation play an important role in the mechanism of glomerular endothelial injury and activation and the formation of multiple microthrombi.

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