FGF23 and Cardiovascular Disease in CKD

描述(申请人提供)：慢性肾脏病(CKD)是一种公共卫生流行病，它会显著增加患者患终末期肾脏疾病(ESRD)、心血管疾病和过早死亡的风险，从而给医疗保健系统带来巨大的经济损失，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建立的CKD的并发症，并且需要新的诊断策略来支持CKD本身在“高危”个体中的一级预防。在该奖项的第一期支持期间，我们在慢性肾功能不全队列(CRIC)研究中报告，磷酸调节激素-成纤维细胞生长因子23(FGF23)水平的升高可能是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，在CKD 2-3期患者中，升高的FGF23是终末期肾病的独立危险因素，也是CKD病死率的潜在危险因素：从2-4期到血液透析患者，甚至是肾移植受者。尽管这些数据证实FGF23升高是CKD患者不良临床结局的一个强有力的生物标志物，但我们最近报道，FGF23升高可能是直接导致左室肥厚发病的疾病机制，左室肥厚是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研究项目扩展到关键的新领域。在目标1中，我们将扩展我们在CRIC正在进行的工作，进行第一项纵向研究，每年重复测量FGF23和矿物质代谢物，这将使我们能够定义CKD中矿物质代谢紊乱的演变及其与临床结果的关系。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，调查基因 已知的矿物质代谢种族差异的基础。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升高是否是发生CKD的独立危险因素。如果FGF23升高是CKD发生的一个独立危险因素，它可以作为一种新的诊断方法来支持CKD的一级预防。初步数据支持我们的假设，我们的研究团队在FGF23、观察队列和群体遗传学方面拥有成功完成这些目标所需的专业知识。此外，该项目将继续成为肾病学受训人员的肥沃培训场地，其中包括几名K23奖获得者和由国际肾脏病协会指导的少数族裔补助金。最终，我们提出的创新研究将提供见解，帮助我们实现我们的长期目标：开发新的治疗和诊断策略，以改善CKD患者经历的令人沮丧的临床结果。

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.