Exercise, Nitric Oxide Bioavailability and Arteriovenous Fistula Maturation

运动、一氧化氮生物利用度和动静脉瘘成熟

• 批准号: 8771393
• 负责人: Jeffrey H. Lawson
• 金额: $ 22.7万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771393
• 关键词: Address; Adherence; Animal Model; Arginine; Arteriovenous fistula; Bioavailable; Biological Availability; Biological Markers; Biology; Blood Vessels; Blood flow; Catheters; Central Vein; Clinic; Clinical; Clinical Research; Data; Dialysis patients; Dialysis procedure; Electric Capacitance; End stage renal failure; Endothelium; Exercise; Exhibits; Failure; Feasibility Studies; Fistula; Goals; Health; Hemodialysis; Hyperplasia; Infection; Inflammation; Intervention; Intervention Trial; Isosorbide; Lead; Measurement; Measures; Medial; Mediating; Methods; Morbidity - disease rate; Myofibroblast; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Nitroglycerin; Operative Surgical Procedures; Oral; Outcome; Paste substance; Patients; Personal Satisfaction; Physiological; Pilot Projects; Plasma; Play; Production; Protocols documentation; Quality of life; Records; Recruitment Activity; Relative (related person); Rest; Role; Sepsis; Severities; Signal Transduction; Stenosis; Testing; Therapeutic Intervention; Thrombosis; Time; Tissues; Training; United States; Vascular remodeling; Vascular resistance; Veins; Venous; Visit; Work; arm; base; brachial artery; design; group intervention; human subject; improved; inhibitor/antagonist; intervention effect; mortality; patient population; pressure; prevent; public health relevance; response; shear stress; standard of care; success

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.

描述（由申请人提供）：这项研究的总体目标是评估一氧化氮（NO）对人类瘘管成熟的生物利用度的影响 受试者为了开发大型研究的力量。 每年，美国每年有100,000人开始血液透析作为治疗末期肾脏疾病的治疗。与其他血管通道方法相比，动静脉瘘（AVF）已被记录在功能通畅的情况下，提供最可靠的透析透析功能，并降低发病率和死亡率。但是，观察数据表明，超过50％的新创建的AVF将无法成熟，并且可用于血液透析，这既需要进行多项外科手术来建立访问权限，并长期使用中央静脉导管以及相关的脓毒症和中静脉炎症的并发症。提高AVF创造的成功率将对透析患者的健康和生活质量产生重大影响。 通过血管重塑实现了AVF的成功成熟，从而导致静脉腔的扩张，血管壁的内侧增厚，并充分增加血液流动以允许透析。成熟失败的特征是缺乏外部重塑，较低的血液流速和增生的新内膜增生，从而导致狭窄和随后的AVF血栓形成。先前的研究表明，没有信号传导和血管功能在AVF成熟中起重要作用。此外，我们已经观察到，与整个患者人群相比，在口服异肌硝酸盐（无供体）上出现在诊所的患者的比例更高。从这些观察结果中，我们提出了一个假设，即增加无生物利用度将导致AVF成熟率提高。 在拟议的研究中，我们将利用三种干预措施来增加接受AVF手术的患者的生物利用度。这项临床研究的四个臂是1）护理标准，2）手工锻炼训练3）局部硝酸甘油糊疗法和4）手工夹运动训练和硝酸甘油糊疗法的结合。每种干预措施将在手术前进行4周，并在AVF成熟后持续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对动脉功能，静脉功能和一氧化氮代谢产物进行生理评估，并在干预治疗4周后进行生理评估，并确定这些测量结果的变化与AVF成熟率之间的关系。干预措施对静脉生物学的生物学作用将通过分析用于创建AVF的静脉的一部分进行直接评估。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理解，并使我们能够开发能力执行更大的临床研究，其长期目标是提高AVF成熟率，而没有增加生物利用度。