Vascular access dysfunction is associated with patient morbidity and mortality, is a leading reason for hospitalization among dialysis patients, and is estimated to have annual associated costs in the United States that exceed 1 billion dollars. The arteriovenous fistula (AVF) is the preferred type of vascular access due to substantially lower thrombosis rates, infection rates, and total health care expenditures. Recognition of these advantages is reflected in clinical practice guidelines as well as clinical performance measures utilized by the Centers for Medicare and Medicaid Services (CMS). Indeed, CMS has launched a major initiative to increase the prevalence of AVF (Fistula First). However, the numerous advantages associated with functional AVF are counterbalanced by the recognition that a substantially higher proportion of fistulas than grafts are never able to be used for dialysis due to failure to mature adequately to support the blood flows needed for effective hemodialysis. There is now substantial evidence that uremia is accompanied by increased oxidative stress, and inflammation, leading to endothelial dysfunction and structural changes in the vascular system which includes aggressive development of venous intimal hyperplasia. However, the extent to which these uremia-related functional and structural changes in the vasculature contribute to failure of AVF maturation is currently unknown. The central hypothesis of this proposal is that uremia-related functional and structural alterations in the vasculature can be identified which will predict the probability of AV fistula maturation. To examine this hypothesis, we propose the following Specific Aims: 1. To determine whether physiologic measures of endothelial function can predict outcomes of newly created native AV fistulae. For this aim, vascular function will be evaluated prior to surgical creation of native fistulae using well- established, non-invasive methods: a) assessment of brachial artery flow mediated and nitroglycerin-induced dilation, b) fingertip tonometric measurement of pulse amplitude, c) arterial pulse wave velocity as a measure of arterial stiffness, and d) forearm venous distensibility by strain-gauge plethysmography;2. To determine whether venous structural changes can predict outcomes of newly created native AV fistulae;and 3. To determine whether plasma biomarkers of oxidative stress and endothelial dysfunction can predict outcomes of newly created native AV fistulae.
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