FGF23 and Cardiovascular Disease in CKD

描述（由申请人提供）：慢性肾脏疾病（CKD）是一种公共卫生流行病，对卫生保健系统造成巨大的经济损失，对患者造成毁灭性的健康负担，显著增加终末期肾脏疾病（ESRD）、心血管疾病和过早死亡的风险。迫切需要新的治疗策略来预防慢性肾病的并发症，也需要新的诊断策略来支持“高危”个体对慢性肾病本身的一级预防。在该奖项支持的第一阶段，我们在慢性肾功能不全队列（CRIC）研究中报道，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，FGF23升高是CKD 2-3期患者发生ESRD的独立危险因素，也是整个CKD谱系（从2-4期到突发血液透析患者甚至肾移植患者）死亡的一个潜在危险因素。尽管这些数据表明FGF23升高是CKD不良临床结果的一个强有力的生物标志物，但我们最近报道FGF23升高可能是一种直接导致左心室肥厚发病的疾病机制，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FGF23研究的多产、多学科项目扩展到关键的新领域。在Aim 1中，我们将通过每年重复测量FGF23和矿物质代谢物的首次纵向研究来扩展我们在CRIC中正在进行的工作，这将使我们能够定义CKD中紊乱矿物质代谢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遗传发现研究，以调查遗传

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.