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

• 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
• 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

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）：矿物质代谢紊乱是慢性肾脏病（CKD）的一种几乎普遍的并发症，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（FGF 23）使CKD患者的血清磷酸盐维持在正常范围内，但FGF 23过量会导致左心室肥大（LVH）。总之，磷酸盐和FGF 23过量对心血管系统的有害作用促进CVD事件和死亡。膳食磷酸盐吸收是磷酸盐和FGF 23水平的可改变决定因素。在动物中，高磷酸盐饮食会促进肾衰竭，而且，在我们的初步数据中， 升高磷酸盐和FGF 23水平并诱导LVH。相比之下，在CKD 3-4期患者的初步研究中，用磷酸盐结合剂、低磷酸盐饮食或烟酰胺前体烟酸减少膳食磷酸盐吸收，从而降低胃肠道NPT 2b表达，降低磷酸盐和FGF 23水平。因此，靶向磷酸盐和FGF 23过量可能代表了改善CKD临床结局的新治疗范式。然而，推进这一方法的一个关键障碍是缺乏磷酸盐和FGF 23减少对CKD中间终点影响的证据。NIDDK U 01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。在这项在200例CKD 3-4期患者中进行的随机、双盲、18个月、平行组研究中，U 01资助的母研究将检验烟酰胺和碳酸镧联合治疗将降低血清磷酸盐和FGF 23水平的假设。本时间敏感性辅助方案的目的是通过在基线和随机化后9个月和18个月时增加骨和矿物质代谢的纵向评估以及CVD和肾脏风险的替代指标来丰富母研究。在目标1中，通过获得骨转换标志物和矿物质代谢物的系列评估，我们将检验以下假设：与安慰剂相比，活性治疗将减弱PTH升高的斜率，减弱骨化三醇和klotho水平的下降，并改善骨转换标志物。在目标2中，我们将使用心脏MRI和CVD生物标志物的系列测量来检验以下假设：与安慰剂相比，活性治疗将减少或减弱LV质量的增加;减轻LV舒张功能障碍并降低CVD生物标志物的水平。在目标3中，使用系列血清学检测和无钆血氧水平依赖性MRI和弥散加权MRI监测肾内氧合和纤维化的变化，我们将检验以下假设：与安慰剂相比，活性治疗将减缓GFR下降的斜率以及蛋白尿和炎症标志物的上升，改善肾内氧合并稳定或减少肾纤维化的进展。这项U 01批准的辅助研究提案的结果将产生新的机制见解，并提供为未来确定性III期结局试验选择终点所需的关键数据，该试验针对CKD中的磷酸盐和FGF 23过量。