Impact of phosphate and FGF23 reduction on intermediate end points in CKD

磷酸盐和 FGF23 减少对 CKD 中间终点的影响

基本信息

批准号：
8748271
负责人：
Tamara Isakova
金额：
$ 63.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8748271
关键词：
Ancillary Study Animals Attenuated Biological Markers Bone Diseases Calcitriol Cardiac Cardiovascular Diseases Cardiovascular system Cessation of life Cholesterol Chronic Kidney Failure Clinical Complication Congestive Heart Failure Data Diet Diffusion Magnetic Resonance Imaging Disease Disease Progression Double-Blind Method End stage renal failure Epidemic Event Fibrosis Fracture Functional disorder Funding Future Gadolinium Healthcare Heart Atrium Homeostasis Hormones Inflammation Inflammatory Institutional Review Boards Interleukin-6 Kidney Kidney Diseases Kidney Failure Laboratories Left Left Ventricular Hypertrophy Left Ventricular Mass Link Longevity Magnetic Resonance Imaging Measures Metabolism Minerals Monitor National Institute of Diabetes and Digestive and Kidney Diseases Niacinamide Nicotinic Acids Normal Range Observational Study Outcome Parathyroid gland Parents Pathogenesis Patients Phase Phenotype Physical Function Pilot Projects Placebo Control Placebos Proteinuria Public Health Randomized Reporting Research Research Infrastructure Resources Risk Risk Factors Safety Secondary Hyperparathyroidism Serologic tests Serum Staging Testing Time Troponin T Vascular calcification Weight absorption adverse outcome arterial stiffness blood oxygen level dependent bone bone turnover calcification calcium phosphate cardiovascular disorder risk cognitive function cost effective design experience fibroblast growth factor 23 follow-up gadolinium oxide gastrointestinal human data improved indexing inflammatory marker inorganic phosphate insight lanthanum carbonate novel novel therapeutics public health relevance randomized trial

项目摘要

DESCRIPTION (provided by applicant): Disordered mineral metabolism is a near-universal complication of chronic kidney disease (CKD) that is strongly linked to risks of cardiovascular disease (CVD), CKD progression, fractures, and death. Phosphate excess induces arterial calcification, which is an important phenotype of CVD in CKD. Elevated fibroblast growth factor 23 (FGF23) maintains serum phosphate in the normal range in CKD, but FGF23 excess contributes mechanistically to left ventricular hypertrophy (LVH). Together, the deleterious effects of phosphate and FGF23 excess on the cardiovascular system promote CVD events and death. Dietary phosphate absorption is a modifiable determinant of phosphate and FGF23 levels. In animals, a high phosphate diet promoted kidney failure, and, in our preliminary data, it raised phosphate and FGF23 levels and induced LVH. In contrast, reducing dietary phosphate absorption with phosphate binders, low phosphate diets or the nicotinamide precursor, niacin, which reduces gastrointestinal NPT2b expression, lowered phosphate and FGF23 levels in pilot studies of CKD stage 3-4 patients. Thus, targeting phosphate and FGF23 excess may represent a novel therapeutic paradigm to improve clinical outcomes in CKD. However, a key road block to advancing this approach is the lack of evidence on the effects of phosphate and FGF23 reduction on intermediate end points in CKD. The NIDDK U01-supported COMBINE Study provides a unique opportunity to fill this gap. In this randomized, double-blinded, 18-month, parallel-group study in 200 CKD stage 3-4 patients, the U01-funded parent study will test the hypothesis that combining nicotinamide and lanthanum carbonate will lower serum phosphate and FGF23 levels. The purpose of this time-sensitive ancillary proposal is to enrich the parent study by adding longitudinal assessments of bone and mineral metabolism and surrogate measures of CVD and renal risks at baseline and at 9 and 18 months post-randomization. In Aim 1, by obtaining serial assessments of bone turnover markers and mineral metabolites, we will test the hypothesis that compared with placebo, active therapy will blunt the slope of PTH rise, attenuate the decline of calcitriol and klotho levels, and improve bone turnover markers. In Aim 2, we will use serial measures of cardiac MRI and CVD biomarkers to test the hypothesis that compared with placebo, active therapy will reduce or blunt the increase in LV mass; attenuate LV diastolic dysfunction and reduce levels of CVD biomarkers. In Aim 3, using serial serologic testing and gadolinium-free blood oxygenation level dependent MRI and diffusion-weighted MRI to monitor changes in intra-renal oxygenation and fibrosis, we will test the hypothesis that compared with placebo, active therapy will blunt the slope of decline in GFR and the rise in proteinuria and inflammatory markers, improve intra-renal oxygenation and stabilize or reduce progression of renal fibrosis. The results of this U01-approved ancillary study proposal will yield novel mechanistic insights and provide critical data needed to select the endpoints for the future definitive phase-III outcomes trial targeting phosphate and FGF23 excess in CKD.

描述（由申请人提供）：无序的矿物质代谢是慢性肾脏疾病（CKD）的几乎全额并发症，与心血管疾病（CVD），CKD进展，骨折和死亡的风险密切相关。磷酸盐过量诱导动脉钙化，这是CKD中CVD的重要表型。升高的成纤维细胞生长因子23（FGF23）在CKD的正常范围内保持血清磷酸盐，但FGF23过量的过量对左心室肥大（LVH）的机械贡献。共同，磷酸盐和FGF23过量对心血管系统的有害影响促进了CVD事件和死亡。饮食中的磷酸盐吸收是磷酸盐和FGF23水平的可修改决定因素。在动物中，高磷酸盐饮食促进了肾脏衰竭，在我们的初步数据中磷酸盐和FGF23水平升高，并诱导LVH。相反，在CKD阶段3-4例患者的PILOT研究中，使用磷酸盐结合剂，低磷酸盐饮食或烟酰胺前体降低了饮食中的磷酸盐吸收，可降低胃肠道NPT2B表达，降低胃肠道NPT2B表达，降低磷酸盐和FGF23水平。因此，靶向磷酸盐和FGF23过量可能代表一种新型的治疗范式，以改善CKD中的临床结果。但是，推进这种方法的关键路线是缺乏证据表明磷酸盐和FGF23降低对CKD中间端点的影响。 NIDDK U01支持的联合收割机研究为填补这一空白提供了独特的机会。在这项200 CKD阶段3-4例患者的随机，双盲，18个月的平行组研究中，U01资助的父母研究将检验以下假设：将烟酰胺和碳酸盐酸盐结合起来将降低磷酸血清和FGF23水平。这项时间敏感的辅助建议的目的是通过增加对基线时CVD和CVD和肾脏风险的纵向评估以及在随机后的9个月和18个月时对CVD和肾脏风险进行纵向评估来丰富父母研究。在AIM 1中，通过获得骨转换标记和矿物代谢产物的系列评估，我们将检验以下假设，即与安慰剂相比，主动疗法将钝化PTH的斜率，减轻钙三醇和Klotho水平的下降，并改善骨转倍倍数。在AIM 2中，我们将使用心脏MRI和CVD生物标志物的串行测量来测试与安慰剂相比，主动治疗将减少或钝化LV质量的假设；减弱LV舒张功能障碍并降低CVD生物标志物的水平。在AIM 3中，使用串行血清学检测和无血液氧合水平依赖于MRI和扩散加权MRI来监测肾脏内氧合和纤维化的变化，我们将测试的假设与安慰剂相比，主动治疗将使稳定牛的稳定性和稳定性分化为蛋白尿，并改善了蛋白尿的稳定性，并改善了蛋白尿素的稳定性，并改善了蛋白尿的稳定性，并将其改善。肾纤维化。该U01批准的辅助研究建议的结果将产生新的机械见解，并提供至关重要的数据，以选择针对CKD中磷酸盐和FGF23过量的未来确定的III结果试验的终点。