More than 450,000 Americans have end stage kidney disease (ESKD), which requires dialysis or kidney transplantation for survival. The artriovenous fistula (AVF) represents a lifeline for hemodialysis patients because it offers substantially lower rates of infections and hospitalizations, and improved survival compared to other vascular access methods, such as artriovenous grafts or dialysis catheters. Unfortunately, as many as 50% of AVFs fail to mature within the toxic metabolic environment of kidney failure. Disturbances in mineral metabolism, which are common among ESKD patients, may be novel causes of AVF maturation failure. Early kidney disease leads to phosphorus retention, which is connected with arterial calcification in cell culture models and in individuals who have ESKD. Vascular calcification may contribute to AVF maturation failure through increased vessel stiffness and the prevention of adequate vasodilation in response to increased blood flow. Kidney dysfunction also leads to impaired vitamin D activation, which may interfere with successful AVF maturation by activating genes related to inflammation, hypertension, and thrombosis. The purpose of this application is to comprehensively evaluate associations of mineral metabolism markers with AVF maturation failure and vascular dysfunction within an established prospective study. We propose to add 6 mineral metabolism measurements to the Hemodialysis Fistula Maturation Consortium study: fibroblast growth factor-23, phosphorus, 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone. We will evaluate associations of these markers with clinical AVF maturation, longitudinal changes in blood flow and vessel diameter, and cross sectional differences in endothelial function, arterial stiffness, venous compliance, and calcification. The proposed research is designed to provide credible evidence that mineral metabolism disorders contribute to vascular dysfunction and AVF maturation and suggest potential targets for future interventions designed to improve AVF maturation rates.

Public Health Relevance

The purpose of this grant application is to add measurements of mineral metabolism biomarkers to the ongoing Hemodialysis Fistula Maturation Consortium study and to evaluate whether these markers are associated with fistula maturation and vascular dysfunction. Mineral metabolism measurements will be performed using gold- standard laboratory techniques and vascular function studies will be carried out using standardized methods. The studies proposed in this application are intended to discover new markers of fistula maturation in patients who have end stage kidney disease and to suggest possible targets for future trials.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cardiovascular and Sleep Epidemiology (CASE)
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Kusek, John W
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Kestenbaum, Bryan (2016) Con: Phosphate binders in chronic kidney disease. Nephrol Dial Transplant 31:189-94
de Boer, Ian H; Kestenbaum, Bryan (2013) Invited commentary: Quantifying salt in urine--a complex solution. Am J Epidemiol 177:1193-5; discussion 1196-8