Exercise, Nitric Oxide Bioavailability and Arteriovenous Fistula Maturation

描述(申请人提供)：本研究的总体目标是评估提高一氧化氮(NO)的生物利用度对人体动静脉瘘成熟的影响。 为了更大范围的研究而发展力量。在美国，每年有超过10万人开始血液透析，以治疗终末期肾病。动静脉瘘(AVF)已被证明是最可靠的透析途径，与其他血管途径相比，具有更长的功能通畅期，并降低了发病率和死亡率。然而，观察数据表明，超过50%的新创建的AVF将无法成熟并可用于血液透析，导致需要多次手术才能建立通路，并导致中心静脉导管的长期使用以及相关的脓毒症和中心静脉狭窄并发症。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，血管重塑导致静脉管腔扩张，血管壁中段增厚，以及足够的血流量增加以允许透析。成熟失败的特征是缺乏外向重塑、血流速度降低和增生性新生内膜增生，导致动静脉瘘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的成熟过程中起重要作用。此外，我们观察到，口服硝酸异山梨酯的患者(没有供体)在临床上实现功能性AVF的比例比整体患者高。从这些观察中，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。在这项拟议的研究中，我们将使用三种干预措施来增加动静脉瘘手术患者中NO的生物利用度。临床研究的四个方面是：1)标准护理，2)握力运动训练，3)外用硝酸甘油糊剂治疗，4)握力运动训练与硝酸甘油糊剂治疗相结合。每次干预在手术前进行4周，在AVF成熟后继续进行4周。将确定每个介入臂的AVF成熟率。所有患者都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产物的生理学评估，并将确定这些指标的变化与AVF成熟率之间的关系。干预措施对静脉生物学的生物学影响将通过分析用于产生AVF的静脉段来直接评估。这项研究的完成将提供对无生物利用度在AVF成熟中的作用的机械性理解，并使我们能够开发力量进行更大规模的临床研究，以实现改善AVF成熟率增加无生物利用度的长期目标。

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.