Role of FGF23 in Mineral Metabolism Across the Spectrum of Chronic Kidney Disease

FGF23 在慢性肾病矿物质代谢中的作用

• 批准号: 8728815
• 负责人: MYLES S WOLF
• 金额: $ 19.86万
• 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/8728815
• 关键词: 1,25 (OH) vitamin D; Address; Adult; Affect; Attenuated; Award; Biological Markers; Calcitriol; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic Kidney Failure; Clinical; Cohort Studies; Congestive Heart Failure; Data; Double-Blind Method; Early treatment; End stage renal failure; Enrollment; Fibroblast Growth Factor Receptors; Future; Goals; Heart Atrium; Hemodialysis; Hormones; Hypertrophy; Individual; Inflammation; Interleukin-6; Intervention; Kidney Failure; Lanthanum; Left; Left Ventricular Hypertrophy; Left Ventricular Mass; Measures; Mediating; Metabolism; Minerals; Natriuretic Peptides; Observational Study; Outcome; Pathogenesis; Patients; Physiological; Placebo Control; Placebos; Population; Public Health; Randomized; Rattus; Reporting; Research; Residual state; Risk; Risk Factors; Role; Serum; Staging; Structure; Testing; Time; Translating; Troponin T; Vitamin D; Work; adverse outcome; arm; base; cardiovascular disorder risk; clinically relevant; cohort; design; experience; fibroblast growth factor 23; follow-up; high risk; improved; innovation; inorganic phosphate; lanthanum carbonate; mortality; new therapeutic target; novel; novel therapeutics; placebo controlled study; prevent; prospective; public health relevance; randomized trial; response

DESCRIPTION (provided by applicant): An elevated level of the phosphate regulating hormone fibroblast growth factor 23 (FGF23) is an independent risk factor for cardiovascular disease (CVD) and mortality across the spectrum of chronic kidney disease (CKD). Elevated FGF23 contributes directly to the pathogenesis of left ventricular hypertrophy, suggesting one potential mechanism for the high risk of CVD and death that is attributable to elevated FGF23. Preliminary data that demonstrate that elevated FGF23 is a powerful risk factor for congestive heart failure confirms the clinical relevance of FGF23-mediated LVH. Thus, data generated during the first 4 years of support under this award established elevated FGF23 as a novel biomarker and mechanism of adverse outcomes in CKD, and thus, novel therapeutic target. Additional work from our group was also the first to suggest a survival benefit of active vitamin D therapy in ESRD. However, active vitamin D raises FGF23, which might be expected to accelerate mortality. Reconciling this potential paradox is a central theme of this application. Based on preliminary data, we hypothesize that vitamin D may attenuate cardiac toxicity of FGF23 despite raising FGF23 levels, and that CKD patients' variable FGF23 response to active vitamin D, ranging from minimal to large increases, modifies their CVD risk and survival experience. In Aim 1, we will test the hypothesis that the magnitude of change in FGF23 in response to active vitamin D therapy modulates risk of mortality in a large prospective cohort of incident hemodialysis patients. In Aim 2, we will analyze FGF23 in a secondary analysis of a recently completed randomized trial of active vitamin D versus placebo in CKD stage 3-4 patients to test the hypothesis that baseline and follow-up FGF23 levels modify the cardiac structural and functional response to active vitamin D therapy. Previous studies suggest that non-calcium based phosphate binders lower FGF23, but there have been no placebo-controlled studies >2 weeks duration, and no studies examined the impact of FGF23 reduction on intermediate measures of CVD risk in CKD stage 3-4 patients with normal serum phosphate. Furthermore, no studies investigated the utility of combining phosphate binders with active vitamin D to potentially maximize their dual benefits on mineral metabolism and CVD. In Aim 3, we will conduct a one- year, placebo-controlled, 2 x 2 factorial, randomized study of CKD stage 3-4 patients to test the effects of active vitamin D and phosphate binders alone and in combination on FGF23, other mineral metabolites, and a comprehensive set of intermediate measures of CVD risk. Extensive preliminary data support our hypotheses, and our research team has the requisite expertise in FGF23, vitamin D, observational cohorts, and randomized studies with repeated measures to successfully complete these Aims. Renewed support will enable us to generate data that are critical for the rational design of larger trials in the futureand thereby support our long- term goal of translating FGF23 research into meaningful improvements in the management of CKD.

描述(由申请人提供)：磷酸盐调节激素成纤维细胞生长因子23(FGF23)水平升高是心血管疾病(CVD)和慢性肾脏疾病(CKD)病死率的独立危险因素。FGF23升高直接参与了左心室肥厚的发病机制，提示FGF23升高是心血管疾病高风险和死亡的一个潜在机制。初步数据表明，FGF23升高是充血性心力衰竭的一个强大的危险因素，证实了FGF23介导的LVH的临床相关性。因此，在该奖项下支持的头4年期间产生的数据确立了FGF23作为CKD不良结果的新的生物标记物和机制，从而成为新的治疗靶点。我们小组的另一项研究也首次表明活性维生素D对生存有好处 终末期肾病的治疗。然而，活性维生素D会增加FGF23，这可能会加速死亡率。调和这一潜在的悖论是本应用程序的一个中心主题。根据初步数据，我们假设，尽管FGF23水平升高，但维生素D可能减轻FGF23的心脏毒性，CKD患者对活性维生素D的可变FGF23反应，从轻微到大量增加，改变了他们的心血管风险和生存经验。在目标1中，我们将检验这样一个假设，即对主动维生素D治疗的反应中，FGF23的变化幅度调节了发生血液透析患者的大量前瞻性队列中的死亡风险。在目标2中，我们将在最近完成的一项针对CKD 3-4期患者的活性维生素D与安慰剂的随机试验的二次分析中分析FGF23，以测试基线和后续FGF23水平改变心脏对活性维生素D治疗的结构和功能反应的假设。以前的研究表明，非钙基磷酸盐结合剂降低FGF23，但还没有安慰剂对照研究&持续2周，也没有研究考察降低FGF23对血磷正常的CKD期3-4期患者心血管疾病风险的中间指标的影响。此外，没有研究调查磷酸盐结合剂与活性维生素D结合的效用，以潜在地最大化它们在矿物质代谢和心血管疾病方面的双重好处。在目标3中，我们将对CKD 3-4期患者进行为期一年的安慰剂对照、2×2因素随机研究，以测试活性维生素D和磷酸盐结合剂单独和联合使用对FGF23、其他矿物质代谢物以及一套全面的心血管风险中间指标的影响。大量的初步数据支持我们的假设，我们的研究团队在FGF23、维生素D、观察队列和重复测量的随机研究方面拥有必要的专业知识，以成功实现这些目标。新的支持将使我们能够生成对未来更大规模试验的合理设计至关重要的数据，从而支持我们将FGF23研究转化为CKD管理中有意义的改进的长期目标。