title: Chronic kidney disease accelerates endothelial barrier dysfunction in a mouse model of an arteriovenous fistula.
abstract: Hemodialysis patients depend on arteriovenous fistulas (AVF) for vascular access. Unfortunately, their 2-yr primary patency rate is only 60% because of AVF clog due to intimal hyperplasia at the venous anastomosis. Chronic kidney disease (CKD) can increase neointima formation by unknown mechanisms. A new AVF mouse model was created, and the mechanisms of CKD on neointima formation in AVFs were investigated. We created AVFs in mice by anastomosing the common carotid artery to the internal jugular vein. CKD was induced [BUN (blood urea nitrogen) in control and CKD mice, 33.3 ± 3.9 vs. 114.2 ± 12.1 mg/dl, P < 0.05]. After 1 day, there was endothelial cell loss and CD41-positive platelet aggregation, especially in the venous anastomosis. An invasion of macrophages and neutrophils peaked at 1 wk after surgery. Neointima formation (smooth muscle cell accumulation and extracellular matrix deposition) increased progressively over 4 wk. Mice with CKD had ~45% (P < 0.05) more neointima formation than control mice. CKD decreased vascular endothelial-cadherin expression in endothelial cells and delayed regeneration of the endothelium. CKD also increased inflammatory cells (Mac-2-positive or CD45-positive) in AVFs at 2 wk. Finally, AVFs were "leakier" (increased accumulation of Evans blue) in CKD mice at 7 and 14 days than control mice. We find that CKD increases neointima formation and endothelial barrier dysfunction. We have created a mouse model of AVF with characteristics similar to failed AVFs in patients. The model will allow testing of strategies directed at improving AVF function in CKD patients.
authors.affiliation: Division of Nephrology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Anlin
authors.initials: A
authors.lastname: Liang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Guofeng
authors.initials: G
authors.lastname: Han
authors.forename: Luan
authors.initials: L
authors.lastname: Truong
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001164:Arteriovenous Fistula / Q000503:physiopathology; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects; D017536:Carotid Artery, Common / Q000601:surgery; D004727:Endothelium / Q000503:physiopathology*; D007601:Jugular Veins / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D058426:Neointima / Q000209:etiology*; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000503:physiopathology*
keywords: arteriovenous fistula; chronic kidney disease; endothelial barrier; neointima