Therapeutic to improve maturation and performance of arteriovenous fistulae

DESCRIPTION (provided by applicant): Patients with kidney failure must undergo regular external blood filtering, known as hemodialysis, in order to remove metabolic byproducts from their blood. Hemodialysis requires creation of access sites in the body for connection to hemodialysis machines. The primary types of chronic access sites are ArterioVenous Fistulae (AVF - a vein attached directly to an artery) and ArterioVenous Grafts (AVGs - an artery and vein connected by a segment of artificial tubing). Access sites often are difficult to create and are prone to failure that can result in treatment interruption, hospitalization, costly corrective surgical procedures, and premature death. Access site maintenance is a large and growing market with significant unmet medical needs. Acute thrombosis and neointimal hyperplasia share an underlying pathology - damage to the endothelium of the vein segment induced by ischemia/reperfusion, traumatic endothelial cell loss due to manipulation, and exposure to arterial pressures post-installation. Other research has shown that maturation of AVF correlates with dilation of the venous component. Nitric oxide (NO) is an important vasodilative and cell-signaling molecule that also has been shown to limit, by several mechanisms, both thrombosis and neointimal hyperplasia. Short oligomers of arginine - such as nona-L-arginine - effectively cross biological membranes and are cleaved enzymatically to produce monomeric L-arginine, which in turn results in therapeutic levels of NO that persist at 2X normal for a minimum of three days. Nona-L-arginine (R9) has demonstrated benefit in reducing short and long-term injury to interpositioned vein grafts in preclinical studies, and there is potential for utility of R9 treatment in improving the maturation and performance of vascular access sites. The specific aims for this project are to: 1. Generate proof-of-efficacy for nona-L-arginine to improve the maturation and performance of AVF and determine optimal concentration. 2. Execute a definitive study of nona-L-arginine at the optimal concentration. PUBLIC HEALTH RELEVANCE: If successful, this project will provide the first therapeutic option to improve AVF for the hemodialysis population. This easy to implement treatment option will impact significantly the clinical practice paradigms for vascular access procedures, as exemplified by arteriovenous fistulae created to enable hemodialysis.