Inhibition of Lysyl Oxidase with b-aminopropionitrile Improves Venous Adaptation after Arteriovenous Fistula Creation

Abstract

Background The arteriovenous fistula (AVF) is the preferred hemodialysis access for patients with ESKD. Yet, establishment of a functional AVF presents a challenge, even for the most experienced surgeons, because postoperative stenosis frequently occludes the AVF. Stenosis results from the loss of compliance in fibrotic areas of the fistula, which turns intimal hyperplasia into an occlusive feature. Fibrotic remodeling depends on deposition and crosslinking of collagen by lysyl oxidase (LOX), an enzyme that catalyzes the deamination of lysine and hydroxylysine residues, facilitating intra/intermolecular covalent bonds. We postulate that pharmacologic inhibition of LOX increases postoperative venous compliance and prevents stenosis in a rat AVF model. Methods LOX gene expression and vascular localization were assayed in rat AVFs and human preaccess veins, respectively. Collagen crosslinking was measured in humans AVFs that matured or failed, and in rat AVFs treated with β-aminopropionitrile (BAPN), an irreversible LOX inhibitor. BAPN was either injected systemically or delivered locally around rat AVFs using nanofiber scaffolds. The major endpoints were AVF blood flow, wall fibrosis, collagen crosslinking, and vascular distensibility. Results Nonmaturation of human AVFs was associated with higher LOX deposition in preaccess veins (n20, P0.03), and increased trivalent crosslinks (n18, P0.03) in human AVF tissues. Systemic and local inhibition of LOX increased AVF distensibility, while reducing wall fibrosis and collagen crosslinking in rat fistulas. Conclusions Our results demonstrate that BAPN-mediated inhibition of LOX significantly improves vascular remodeling in experimental fistulas.