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) 的一种近乎普遍的并发症，与心血管疾病 (CVD)、CKD 进展、骨折和死亡的风险密切相关。磷酸盐过量会引起动脉钙化，这是 CKD 中 CVD 的重要表型。成纤维细胞生长因子 23 (FGF23) 升高可将 CKD 患者的血清磷酸盐维持在正常范围内，但 FGF23 过量会导致左心室肥厚 (LVH)。磷酸盐和 FGF23 过量对心血管系统的有害影响共同促进 CVD 事件和死亡。膳食磷酸盐吸收是磷酸盐和 FGF23 水平的一个可改变的决定因素。在动物中，高磷酸盐饮食会促进肾衰竭，并且在我们的初步数据中，它 升高磷酸盐和 FGF23 水平并诱导 LVH。相比之下，在 CKD 3-4 期患者的试点研究中，通过磷酸盐结合剂、低磷酸盐饮食或烟酰胺前体烟酸（可降低胃肠道 NPT2b 表达）来减少膳食磷酸盐吸收，可降低磷酸盐和 FGF23 水平。因此，针对磷酸盐和 FGF23 过量可能代表一种改善 CKD 临床结果的新治疗范例。然而，推进这种方法的一个关键障碍是缺乏磷酸盐和 FGF23 减少对 CKD 中间终点影响的证据。 NIDDK U01 支持的 COMBINE 研究提供了填补这一空白的独特机会。在这项对 200 名 CKD 3-4 期患者进行的随机、双盲、为期 18 个月的平行组研究中，U01 资助的母研究将检验联合烟酰胺和碳酸镧会降低血清磷酸盐和 FGF23 水平的假设。这项时间敏感的辅助提案的目的是通过在基线以及随机化后 9 个月和 18 个月时添加骨和矿物质代谢的纵向评估以及 CVD 和肾脏风险的替代测量来丰富母研究。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，积极治疗将减弱 PTH 上升的斜率，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，积极治疗将减少或抑制左心室质量的增加；减轻左心室舒张功能障碍并降低心血管疾病生物标志物的水平。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 来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，积极治疗将减缓 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进展 肾纤维化。这项 U01 批准的辅助研究提案的结果将产生新颖的机制见解，并提供为未来针对 CKD 磷酸盐和 FGF23 过量的最终 III 期结果试验选择终点所需的关键数据。