Mineral metabolism disturbances and arteriovenous fistula maturation

描述(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存活。动静脉瘘(AVF)是血液透析患者的一条生命线，因为它提供的 与其他血管通路方法(如动静脉移植或透析导管)相比，感染和住院率更高，存活率更高。不幸的是，多达50%的动静脉瘘无法在肾功能衰竭的有毒代谢环境中成熟。矿物质代谢紊乱在ESKD患者中很常见，可能是AVF成熟失败的新原因。早期肾脏疾病导致磷滞留，在细胞培养模型和患有ESKD的个体中，这与动脉钙化有关。血管钙化可能通过增加血管僵硬和防止在血流增加时进行适当的血管扩张而导致AVF成熟失败。肾功能障碍还会导致维生素D活性受损，这可能会通过激活与炎症、高血压和血栓形成相关的基因来干扰AVF的成功成熟。这项应用的目的是在已建立的前瞻性研究中综合评估矿物质代谢标记物与动静脉瘘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成熟联盟研究中增加6项矿物质代谢指标：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。我们将评估这些标记物与临床动静脉瘘成熟度、血流和血管直径的纵向变化以及内皮功能、动脉僵硬、静脉顺应性和钙化的横断面差异的关系。这项拟议的研究旨在提供可靠的证据，证明矿物质代谢紊乱会导致血管功能障碍和动静脉瘘成熟，并为未来旨在提高动静脉动静脉瘘成熟率的干预措施提供潜在的靶点。

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.