FGF23 and Cardiovascular Disease in CKD

FGF23 与 CKD 中的心血管疾病

• 批准号: 9462546
• 负责人: MYLES S WOLF
• 金额: $ 38.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-07 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9462546
• 关键词: FGF23; Cardiovascular; Disease; CKD

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a public health epidemic that exacts an enormous financial toll on the health care system and a devastating health burden on affected patients by markedly increasing their risk of end- stage renal disease (ESRD), cardiovascular disease and premature death. Novel therapeutic strategies are desperately needed to prevent complications of established CKD, and novel diagnostic strategies are needed to support the primary prevention of CKD itself in "at-risk" individuals. During the first period of support under this award, we reported in the Chronic Renal Insufficiency Cohort (CRIC) Study that an elevated level of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), may be the earliest detectable abnormality of disordered mineral metabolism in CKD. We further demonstrated that elevated FGF23 is an independent risk factor for ESRD in patients suffering from CKD stages 2-3, and a potent risk factor for mortality across the spectrum of CKD: from stages 2-4 to incident hemodialysis patients and even kidney transplant recipients. Although these data established elevated FGF23 as a powerful biomarker of adverse clinical outcomes in CKD, we recently reported that elevated FGF23 is likely a mechanism of disease that contributes directly to the pathogenesis of left ventricular hypertrophy, which is a common manifestation of cardiovascular disease in CKD and a leading risk factor for major cardiovascular events and death. In this renewal application, we will expand our productive, multidisciplinary program of FGF23 research into critical new areas. In Aim 1, we will extend our ongoing work in CRIC by performing the first longitudinal study with annual repeated measures of FGF23 and mineral metabolites that will allow us to define the evolution of disordered mineral metabolism over time in CKD and its association with clinical outcomes. In Aim 2, we will capitalize on CRIC's completed genome-wide association study and its rich phenotype data to perform efficient genetic discovery studies that investigate the genetic basis underlying known racial differences in mineral metabolism. We anticipate these studies will suggest novel therapeutic targets for the future. In Aim 3, we will test whether an elevated FGF23 is an independent risk factor for incident CKD in an ancillary study to the ACCORD Trial of type 2 diabetes. If elevated FGF23 is an independent risk factor for incident CKD, it could serve as a novel diagnostic to support primary prevention of CKD. Preliminary data support our hypotheses, and our research team has the requisite expertise in FGF23, observational cohorts and population genetics to successfully complete these Aims. In addition, this project will continue to be a fertile training ground for nephrology trainees, including several recipients of K23 awards and a Minority Supplement mentored by the PI. Ultimately, the innovative studies we propose will provide insight that will help us realize our long-term goal: to develop novel therapeutic and diagnostic strategies to improve the dismal clinical outcomes experienced by patients with CKD.

描述（由申请人提供）：慢性肾病（CKD）是一种公共卫生流行病，它会显着增加患者患终末期肾病（ESRD）、心血管疾病和过早死亡的风险，给医疗保健系统造成巨大的经济损失，并给受影响的患者带来毁灭性的健康负担。迫切需要新的治疗策略来预防已确定的 CKD 并发症，并且需要新的诊断策略来支持“高危”个体中 CKD 本身的一级预防。在该奖项的第一个支持期间，我们在慢性肾功能不全队列 (CRIC) 研究中报告称，磷酸盐调节激素、成纤维细胞生长因子 23 (FGF23) 水平升高可能是 CKD 中最早可检测到的矿物质代谢紊乱异常。我们进一步证明，升高的 FGF23 是 CKD 2-3 期患者 ESRD 的独立危险因素，也是整个 CKD 范围内死亡的有效危险因素：从 2-4 期到血液透析患者，甚至肾移植受者。尽管这些数据表明 FGF23 升高是 CKD 不良临床结果的有力生物标志物，但我们最近报道，FGF23 升高可能是直接导致左心室肥厚发病机制的一种疾病机制，左心室肥厚是 CKD 心血管疾病的常见表现，也是主要心血管事件和死亡的主要危险因素。在这次更新申请中，我们将把我们富有成效的、多学科的 FGF23 研究计划扩展到关键的新领域。在目标 1 中，我们将扩展 CRIC 正在进行的工作，通过每年重复测量 FGF23 和矿物质代谢物进行首次纵向研究，这将使我们能够定义 CKD 中矿物质代谢紊乱随时间的演变及其与临床结果的关联。在目标2中，我们将利用CRIC已完成的全基因组关联研究及其丰富的表型数据来进行有效的基因发现研究，以调查遗传 矿物质代谢中已知种族差异的基础。我们预计这些研究将为未来提出新的治疗靶点。在目标 3 中，我们将在 2 型糖尿病 ACCORD 试验的辅助研究中测试 FGF23 升高是否是 CKD 事件的独立危险因素。如果 FGF23 升高是 CKD 事件的独立危险因素，那么它可以作为支持 CKD 一级预防的新诊断方法。初步数据支持我们的假设，我们的研究团队拥有 FGF23、观察队列和群体遗传学方面所需的专业知识，可以成功完成这些目标。此外，该项目将继续成为肾病学学员的肥沃培训基地，其中包括几位 K23 奖项的获得者和 PI 指导的少数派补充品。最终，我们提出的创新研究将提供见解，帮助我们实现长期目标：开发新的治疗和诊断策略，以改善 CKD 患者所经历的令人沮丧的临床结果。