Real Time Nitric Oxide Measurements as a Determinant of AV Fistula Maturation

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DESCRIPTION (provided by applicant): Although arteriovenous fistulae (AVFs) are the preferred mode of dialysis vascular access, over 50% fail to "mature" (achieve adequate blood flow and luminal diameter for dialysis), resulting in significant clinical morbidity and economic cost. In order to address this problem, the NIH has initiated a multi-center study (6 centers including Cincinnati), called the Hemodialysis Fistula Maturation Consortium (HFMC; parent study for this ancillary proposal), with the goal of identifying clinical and biological predictors of AVF maturation failure. At a pathogenetic level, AVF maturation is dependent on the release of nitric oxide (NO) by vascular endothelial cells in response to increased blood flow, which then results in dilation of the AVF due to positive (expansive) remodeling and also inhibits smooth muscle cell proliferation and migration (neointimal hyperplasia). Unfortunately, due to the inherent analytical difficulties associated with the measurement of NO, the parent HFMC study does not include a direct assessment of NO or its metabolites/carriers (S-nitrosothiols [RSNO] and S-nitrosohemoglobin [HbSNO]). We have recently developed a novel, innovative and simple technology for the real-time bedside evaluation of RSNO/HbSNO, using catalyst-based electrochemical sensors which has the potential to become a future point-of-care technology similar to bedside measurements of glucose. We believe that the combination of access to these novel catalyst-based sensors, together with our involvement in the parent NIH funded study on AVF maturation, provides us with a unique opportunity to test out the predictive value of RSNO/HbSNO measurements in the clinical setting of AVF maturation. The central hypothesis for this proposal is that poor NO availability in the form of (a) a stunted rise in RSNO levels following flow mediated dilation (FMD) and (b) low average basal RSNO and HbSNO levels will influence (i) physiological end points such as FMD (ii) functional end points such as AVF blood flow and diameter and clinical endpoints such as usability of the AVF for hemodialysis. In Specific Aim 1 we will measure RSNO/HbSNO levels, prior to and following an FMD study and at the time of mandated ultrasound examinations for AVF blood flow and diameter as part of the parent study (1d, 2wk, 6wk and 26wk). In Specific Aim 2 we will quantify associations between RSNO/HbSNO levels and physiological (FMD), functional (flow and diameter) and clinical (usability for hemodialysis) end points of AVF maturation. The results from this study could allow us to develop a simple, cheap, reliable, point of care test for identification of "at risk" patients for AVF maturation failure who could then be stratified for more aggressive follow up and intervention. The successful use of this technology to predict AVF maturation failure could also result in the future application of this real time sensor to other clinical settings, thought to be dependent on nitric oxide release and availability, such as coronary, carotid and peripheral vascular disease. ) PUBLIC HEALTH RELEVANCE: The best form of vascular access (to take blood out from a dialysis patient, purify it and then return it to the patient), is a connection between the artery and vein in the forearm called an arteriovenous fistula (AVF). Unfortunately over 50% of these AVFs will not work due to vessel narrowing. The current proposal aims to develop a simple blood test that can be performed at the bedside to identify which patients have an increased chance of AVF failure. ) )