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

描述（由申请方提供）：磷酸盐调节激素成纤维细胞生长因子23（FGF 23）水平升高是心血管疾病（CVD）和慢性肾脏疾病（CKD）范围内死亡率的独立风险因素。升高的FGF 23直接导致左心室肥大的发病机制，提示CVD和死亡的高风险的一种潜在机制可归因于升高的FGF 23。初步数据表明，升高的FGF 23是充血性心力衰竭的一个强有力的危险因素，证实了FGF 23介导的LVH的临床相关性。因此，在该奖项的前4年支持期间产生的数据将升高的FGF 23确定为CKD不良结局的新生物标志物和机制，因此是新的治疗靶点。我们小组的其他工作也首次表明活性维生素D对生存有益 治疗ESRD。然而，活性维生素D会增加FGF 23，这可能会加速死亡率。消除这种潜在的矛盾是本申请的中心主题。基于初步数据，我们假设维生素D可能会减弱FGF 23的心脏毒性，尽管增加了FGF 23水平，并且CKD患者对活性维生素D的可变FGF 23反应，从最小到大的增加，改变了他们的CVD风险和生存经验。在目标1中，我们将在一个大型的前瞻性血液透析患者队列中检验活性维生素D治疗后FGF 23变化幅度调节死亡风险的假设。在目标2中，我们将在最近完成的活性维生素D与安慰剂在CKD 3-4期患者中的随机试验的次要分析中分析FGF 23，以检验基线和随访FGF 23水平改变对活性维生素D治疗的心脏结构和功能反应的假设。 以前的研究表明，非钙基磷结合剂降低FGF 23，但没有安慰剂对照研究>2周的持续时间，也没有研究检查FGF 23降低对血清磷酸盐正常的CKD 3-4期患者中CVD风险的中间测量的影响。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，以最大限度地发挥其对矿物质代谢和CVD的双重益处。在目标3中，我们将对CKD 3-4期患者进行一项为期一年、安慰剂对照、2 x 2析因、随机化研究，以测试活性维生素D和磷结合剂单独和联合对FGF 23、其他矿物质代谢产物以及一组全面的CVD风险中间指标的影响。广泛的初步数据支持我们的假设，我们的研究团队在FGF 23，维生素D，观察性队列和随机研究方面拥有必要的专业知识，并通过重复测量成功完成这些目标。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FGF 23研究转化为CKD管理的有意义的改善的长期目标。

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.