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CKD Accelerates Development of Neointimal Hyperplasia in Arteriovenous Fistulas

Taku Kokubo^*,, Noriyuki Ishikawa^*,, Hisashi Uchida^*,, Sara E. Chasnoff, Xun Xie, Suresh Mathew, Keith A. Hruska and Eric T. Choi^,

^* Department of Cardiovascular Surgery, Asahikawa Medical University, Hokkaido, Japan; Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Departments of Medicine and Pediatric, Renal Divisions, Washington University School of Medicine, St. Louis, Missouri; and Department of Surgery, John Cochran VA Hospital, St. Louis, Missouri

Correspondence: Dr. Eric T. Choi, 660 S. Euclid Avenue, Campus Box 8109, Saint Louis, Missouri 63110. Phone: 314-362-6490; Fax: 314-362-4615; E-mail: choie{at}wustl.edu

Received for publication December 10, 2007. Accepted for publication January 28, 2009.

Arteriovenous (AV) access failure resulting from venous neointimal hyperplasia is a major cause of morbidity in patients with ESRD. To understand the role of chronic kidney disease (CKD) in the development of neointimal hyperplasia, we created AV fistulae (common carotid artery to jugular vein in an end-to-side anastomosis) in mice with or without CKD (renal ablation or sham operation). At 2 and 3 wk after operation, neointimal hyperplasia at the site of the AV anastomosis increased 2-fold in animals with CKD compared with controls, but cellular proliferation in the neointimal hyperplastic lesions did not significantly differ between the groups, suggesting that the enhanced neointimal hyperplasia in the setting of CKD may be secondary to a migratory phenotype of vascular smooth muscle cells (VSMC). In ex vivo migration assays, aortic VSMC harvested from mice with CKD migrated significantly greater than VSMC harvested from control mice. Moreover, animals with CKD had higher serum levels of osteopontin, which stimulates VSMC migration. When we treated animals with bone morphogenic protein-7, which promotes VSMC differentiation, before creation of the AV anastomosis, the effect of CKD on the development of neointimal hyperplasia was eliminated. In summary, CKD accelerates development of neointimal hyperplasia at the anastomotic site of an AV fistula, and administration of bone morphogenic protein-7 neutralizes this effect.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673