Exercise, Nitric Oxide Bioavailability and Arteriovenous Fistula Maturation

描述（由申请方提供）：本研究的总体目标是评价增加一氧化氮（NO）生物利用度对人体动静脉瘘成熟的影响 为了发展更大规模研究的能力。 在美国，每年有超过100，000人开始血液透析作为终末期肾病的治疗。已证实动静脉瘘（AVF）是最可靠的透析通路形式，与其他血管通路方法相比，具有更长的功能通畅性，并降低了发病率和死亡率。然而，观察数据表明，超过50%的新创建AVF将无法成熟并可用于血液透析，导致需要多次外科手术来建立通路，并导致中心静脉导管的长期使用以及败血症和中心静脉狭窄的相关并发症。提高AVF创建的成功率将对透析患者的健康和生活质量产生重大影响。 AVF的成功成熟是通过血管重塑实现的，血管重塑导致静脉腔扩张、血管壁中膜增厚和血流充分增加以允许透析。成熟失败的标志是缺乏外向重塑、较低的血流速度和增殖性新生内膜增生，导致AVF狭窄和随后的血栓形成。以往的研究表明，NO信号和血管功能在AVF成熟过程中起重要作用。此外，我们还观察到，在门诊接受口服硝酸异山梨酯（NO供体）的患者中，达到功能性AVF的比例高于整体患者。根据这些观察，我们提出了一个假设，即增加NO的生物利用度将导致AVF成熟率的提高。 在拟议的研究中，我们将利用三种干预措施来增加接受AVF手术的患者中NO的生物利用度。本临床研究的四个组为1）标准治疗，2）握力运动训练，3）局部硝酸甘油糊剂治疗和4）握力运动训练和硝酸甘油糊剂治疗的联合治疗。每次干预将在手术前进行4周，并在AVF成熟后继续4周。将确定每个干预组的AVF成熟率。所有患者将在研究开始时和介入治疗4周后接受动脉功能、静脉功能和一氧化氮代谢物的生理学评估，并确定这些测量值的变化与AVF成熟率之间的关系。将通过分析用于创建AVF的静脉节段直接评估介入对静脉生物学的生物学效应。这项研究的完成将提供一个机械的理解，在AVF成熟的NO生物利用度的作用，并允许我们开发的权力，以执行一个更大的临床研究的长期目标，实现改善AVF成熟率增加NO生物利用度。

DESCRIPTION (provided by applicant): The overall goal of this study is to evaluate the effects of increasing the bioavailability of nitric oxide (NO) on arteriovenous fistula maturation in human subjects in order to develop power for a larger study. Each year over 100,000 people in the United States begin hemodialysis as treatment for end stage renal disease. The arteriovenous fistula (AVF) has been documented to provide the most reliable form dialysis access with longer functional patency, and decreased morbidity and mortality when compared to other vascular access methods. However, observational data has indicated that over 50% of newly created AVF will fail to mature and become usable for hemodialysis, resulting both in the necessity for multiple surgical procedures to establish access and in the prolonged use of central vein catheters and the associated complications of sepsis and central vein stenosis. Improving the success rate of AVF creation will have a significant impact on the health and quality of life of dialysis patients. Successful maturation of an AVF is achieved through vascular remodeling that result in dilation of the lumen of the vein, a medial thickening of the vascular wall, and a sufficient increase in blood flow to allow dialysis. Maturation failure is marked by a lack of outward remodeling, lower blood flow rates and proliferative neointimal hyperplasia that results in stenosis and subsequent thrombosis of the AVF. Previous studies have indicated that NO signaling and vascular function play an important role in AVF maturation. Moreover, we have observed that a higher percentage of patients presenting to clinic on oral isosorbide nitrates (NO donors) achieve a functional AVF than the patient population as a whole. From these observations we have developed the hypothesis that increasing the bioavailability of NO will result in improved rates of AVF maturation. In the proposed study, we will utilize three interventions to increase the bioavailability of NO in patients undergoing AVF surgery. The four arms of this clinical study are 1) standard of care, 2) handgrip exercise training 3) topical nitroglycerin paste therapy and 4) combination of both handgrip exercise training and nitroglycerin paste therapy. Each intervention will be performed for 4 weeks before surgery and continued 4 weeks after it while the AVF matures. The AVF maturation rates for each intervention arm will be determined. All patients will undergo physiologic assessment of arterial function, venous function and nitric oxide metabolites at the start of the study and after 4 weeks of intervention therapy, and relationships between changes in these measurements and AVF maturation rates will be determined. Biologic effects of the interventions on vein biology will be directly assessed through analysis of a segment of the vein used to create the AVF. Completion of this study will provide a mechanistic understanding of the role of NO bioavailability in AVF maturation and allow us to develop power to execute a larger clinical study with the long term goal of achieving an improvement in AVF maturation rates increased NO bioavailability.