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: 8841986
• 负责人: MYLES S WOLF
• 金额: $ 21.22万
• 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/8841986
• 关键词: Role; FGF23; Mineral; Metabolism; Across

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) 和慢性肾病 (CKD) 范围内死亡的独立危险因素。 FGF23 升高直接导致左心室肥厚的发病机制，这表明 FGF23 升高是 CVD 和死亡高风险的一种潜在机制。初步数据表明，FGF23 升高是充血性心力衰竭的一个强大危险因素，证实了 FGF23 介导的 LVH 的临床相关性。因此，在该奖项支持的前 4 年中产生的数据确立了 FGF23 升高作为 CKD 不良后果的新型生物标志物和机制，从而成为新的治疗靶点。我们小组的其他工作也是第一个提出活性维生素 D 对生存有益的研究 ESRD 的治疗。然而，活性维生素 D 会提高 FGF23，这可能会加速死亡率。调和这种潜在的悖论是该应用程序的中心主题。根据初步数据，我们假设尽管 FGF23 水平升高，维生素 D 仍可能减弱 FGF23 的心脏毒性，并且 CKD 患者对活性维生素 D 的不同 FGF23 反应（从最小到大幅增加）改变了他们的 CVD 风险和生存经历。在目标 1 中，我们将检验以下假设：在大量前瞻性血液透析患者队列中，FGF23 响应活性维生素 D 治疗而发生的变化幅度可调节死亡风险。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 与安慰剂随机试验的二次分析中分析 FGF23，以检验基线和随访 FGF23 水平改变心脏结构和功能反应的假设积极维生素D治疗。 既往研究表明，非钙基磷酸盐结合剂会降低 FGF23，但尚无持续时间超过 2 周的安慰剂对照研究，也没有研究探讨 FGF23 减少对 CKD 3-4 期患者 CVD 风险中间指标的影响。血清磷酸盐正常。此外，没有研究调查将磷酸盐结合剂与活性维生素 D 结合使用以最大限度地发挥其对矿物质代谢和 CVD 的双重益处的效用。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 x 2 析因随机研究，以测试活性维生素 D 和磷酸盐结合剂单独和组合对 FGF23、其他矿物质的影响代谢物，以及一套全面的 CVD 风险中间指标。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、观察队列和随机研究方面拥有必要的专业知识，并通过重复测量来成功完成这些目标。重新获得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 管理方面有意义的改进的长期目标。