FGF23 and Cardiovascular Disease in CKD

FGF23 与 CKD 中的心血管疾病

• 批准号: 8702151
• 负责人: MYLES S WOLF
• 金额: $ 59.21万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702151
• 关键词: 1,25 (OH) vitamin D; Address; Admixture; Affect; African; African American; Albuminuria; Ancillary Study; Architecture; Area; Award; Biological; Biological Markers; Biology; Cardiovascular Diseases; Cardiovascular system; Caucasians; Caucasoid Race; Cessation of life; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Cohort Studies; Complication; Computer Simulation; Data; Data Set; Diagnostic; Diet; Dihydroxycholecalciferols; Disease; End stage renal failure; Epidemic; Epidemiology; European; Event; Evolution; Excretory function; Future; Gene Frequency; Genes; Genetic; Genotype; Goals; Health; Healthcare Systems; Hemodialysis; Hispanics; Homeostasis; Hormones; Individual; Kidney Diseases; Kidney Transplantation; Left Ventricular Hypertrophy; Link; Linkage Disequilibrium; Longitudinal Studies; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolism; Microalbuminuria; Minerals; Minority; National Health and Nutrition Examination Survey; Nephrology; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Parathyroid gland; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Population Genetics; Primary Prevention; Prospective Studies; Public Health; Relative (related person); Reporting; Research; Risk; Risk Factors; Sampling; Secondary Hyperparathyroidism; Serum; Staging; Testing; Time; Training; Transplant Recipients; Variant; Vitamin D; Work; base; burden of illness; calcium phosphate; cardiovascular disorder risk; cohort; computerized tools; diabetic; experience; fibroblast growth factor 23; follow-up; genetic variant; genome wide association study; high risk; improved; innovation; inorganic phosphate; insight; mortality; multidisciplinary; new therapeutic target; novel; novel diagnostics; novel therapeutics; premature; prevent; programs; public health relevance; racial difference; trait; urinary

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）：慢性肾脏疾病（CKD）是一种公共卫生流行病，可以通过明显增加其最终阶段肾脏疾病（ESRD），心血管疾病，心血管疾病和早期死亡的风险，对受影响的患者产生巨大的财务损失，并给受影响的患者带来毁灭性的健康负担。迫切需要新颖的治疗策略来防止已建立的CKD并发症，并且需要采取新颖的诊断策略来支持“处于危险”个体中CKD本身的主要预防。在该奖项下的第一个支持期间，我们在慢性肾功能不全队列（CRIC）研究中报告说，调节激素的磷酸盐水平升高，成纤维细胞生长因子23（FGF23）可能是CKD中无序矿物质代谢的最早可检测到的异常。我们进一步证明，FGF23升高是患有CKD阶段2-3的患者ESRD的独立危险因素，并且是CKD频谱中死亡率的有效危险因素：从2-4阶段到事件血液透析患者甚至肾脏移植者。尽管这些数据将FGF23升高为CKD中不良临床结果的有力生物标志物，但我们最近报道说，FGF23升高可能是一种疾病的机制，它可能直接促进左心室肥大的发病机理，这是CKD中心血管疾病的常见表现，是CKD中最领先的风险因素和重大事件和死亡事件。在此续订应用程序中，我们将将FGF23研究的富有成效的多学科计划扩展到关键的新领域。在AIM 1中，我们将通过每年的FGF23和矿物代谢产物的年度重复度量进行首次纵向研究，从而扩展我们在CRIC的正在进行的工作，这将使我们能够定义CKD中矿物质代谢无序代谢的演变及其与临床结果的关联。在AIM 2中，我们将利用CRIC完成的全基因组联想研究及其丰富的表型数据，以进行有效的遗传发现研究，以研究遗传 矿物质代谢中已知的种族差异的基础。我们预计这些研究将为未来提供新的治疗靶标。在AIM 3中，我们将测试升高的FGF23是否是2型糖尿病协定试验的辅助研究中事件CKD的独立危险因素。如果升高的FGF23是事件CKD的独立危险因素，则可以作为支持CKD初级预防的新型诊断。初步数据支持我们的假设，我们的研究团队在FGF23，观察人群和人群遗传学方面具有必要的专业知识，以成功完成这些目标。此外，该项目将继续是肾脏病学员的肥沃培训场所，其中包括几名K23奖项和PI指导的少数族裔补充剂。最终，我们提出的创新研究将提供洞察力，这将有助于我们实现我们的长期目标：开发新颖的治疗和诊断策略，以改善CKD患者所经历的令人沮丧的临床结果。