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

描述(申请人提供)：尽管动静脉瘘(AVF)是首选的透析血管通路模式，但超过50%的患者未能“成熟”(达到足够的血流量和管腔直径进行透析)，导致显著的临床发病率和经济成本。为了解决这个问题，美国国立卫生研究院发起了一项多中心研究(包括辛辛那提在内的6个中心)，名为血液透析瘘成熟联盟(HFMC；这项辅助提案的母公司研究)，目的是确定AVF成熟失败的临床和生物学预测因素。在发病水平上，AVF的成熟依赖于血管内皮细胞在血流增加时释放一氧化氮(NO)，从而导致AVF因正(扩张性)重塑而扩张，并抑制平滑肌细胞的增殖和迁移(新生内膜增生)。不幸的是，由于与NO测量相关的固有分析困难，母公司HFMC的研究不包括对NO或其代谢物/载体(S亚硝硫醇和S亚硝基血红蛋白)的直接评估。我们最近开发了一种新颖、创新和简单的技术，用于实时床边评估RSNO/HbSNO，使用基于催化剂的电化学传感器，该技术有可能成为未来类似于床边血糖测量的护理点技术。我们相信，获得这些基于催化剂的新型传感器，再加上我们参与母公司NIH资助的AVF成熟研究，为我们提供了一个独特的机会来测试RSNO/HbSNO测量在AVF成熟的临床环境中的预测价值。这一建议的中心假设是：(A)血流介导扩张(FMD)后RSNO水平迟缓上升，以及(B)基础RSNO和HbSNO平均水平较低，表现为NO供应不良，将影响(I)生理终点，如FMD；(Ii)功能终点，如AVF血流和直径；以及临床终点，如AVF用于血液透析的可用性。在具体目标1中，我们将在FMD研究之前和之后以及作为母体研究的一部分(1d、2wk、6wk和26wk)对AVF血流和直径进行强制超声检查时，测量RSNO/HbSNO水平。在具体目标2中，我们将量化RSNO/HbSNO水平与AVF成熟度的生理(FMD)、功能(流量和直径)和临床(可用于血液透析)终点之间的关系。这项研究的结果可以让我们开发一种简单、廉价、可靠的护理点测试来识别动静脉瘘成熟失败的“高危”患者，然后对这些患者进行分层，以便进行更积极的随访和干预。成功地使用这项技术来预测AVF成熟失败也可能导致这种实时传感器未来应用于其他临床环境，被认为依赖于一氧化氮的释放和可用性，如冠状动脉、颈动脉和外周血管疾病。) 与公共卫生相关：血管通路的最佳形式(从透析患者身上取出血液，对其进行净化，然后将其返还给患者)是前臂动脉和静脉之间的连接，称为动静脉瘘(AVF)。不幸的是，由于血管变窄，超过50%的AVF将无法工作。目前的提议旨在开发一种简单的血液测试，可以在床边进行，以确定哪些患者发生AVF失败的机会增加。))

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. ) )