Mineral metabolism disturbances and arteriovenous fistula maturation

描述（由申请人提供）：超过45万美国人患有终末期肾病（ESKD），需要透析或肾移植才能生存。动静脉内瘘（AVF）代表了血液透析患者的生命线，因为它提供了显著降低 与其他血管通路方法（如动静脉移植物或透析导管）相比，感染率和住院率降低，生存率提高。不幸的是，多达50%的AVF不能在肾衰竭的毒性代谢环境中成熟。在ESKD患者中常见的矿物质代谢紊乱可能是AVF成熟失败的新原因。早期肾脏疾病导致磷潴留，这与细胞培养模型和ESKD患者的动脉钙化有关。血管钙化可能通过增加血管硬度和阻止血流增加引起的血管充分舒张而导致AVF成熟失败。肾功能障碍还导致维生素D活化受损，这可能通过激活与炎症、高血压和血栓形成相关的基因而干扰AVF的成功成熟。本申请的目的是在一项既定的前瞻性研究中全面评价矿物质代谢标志物与AVF成熟失败和血管功能障碍的相关性。我们建议在血液透析瘘管成熟联盟研究中增加6项矿物质代谢测量：成纤维细胞生长因子-23、磷、25-羟基维生素D、24，25-二羟基维生素D、1，25-二羟基维生素D和甲状旁腺激素。我们将评估这些标志物与临床AVF成熟、血流和血管直径的纵向变化以及内皮功能、动脉硬度、静脉顺应性和钙化的横截面差异的相关性。拟议的研究旨在提供可靠的证据，证明矿物质代谢障碍有助于血管功能障碍和AVF成熟，并为未来旨在提高AVF成熟率的干预措施提出潜在目标。 公共卫生相关性：本基金申请的目的是在正在进行的血液透析瘘管成熟联盟研究中增加矿物质代谢生物标志物的测量，并评估这些标志物是否与瘘管成熟和血管功能障碍相关。将使用金标准实验室技术进行矿物质代谢测量，并使用标准化方法进行血管功能研究。本申请中提出的研究旨在发现终末期肾病患者中瘘管成熟的新标志物，并为未来试验提出可能的目标。

DESCRIPTION (provided by applicant): 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.