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.

Public Health Relevance

The goal of this study is to evaluate two interventions in end stage renal disease patients for the improvement of the success rate of arteriovenous fistula maturation. The arteriovenous fistula is the safest and most reliable type of access for hemodialysis, but they only mature into a working fistula about 50% of the time. Success of this project will provide the basis for a larger trial of these interventions, which could lead to a significant improvement in the health and well-being of patients who require hemodialysis for survival.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kusek, John W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Zhang, Lisheng; Wu, Jiao-Hui; Otto, James C et al. (2017) Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells. Cardiovasc Res 113:1551-1559