Pilot Studies Targeting Mineral Metabolism in CKD

针对 CKD 矿物质代谢的试点研究

• 批准号: 8829382
• 负责人: MYLES S WOLF
• 金额: $ 34.38万
• 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: 2014-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829382
• 关键词: Pilot; Studies; Targeting; Mineral; Metabolism

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a public health epidemic that increases risks of end-stage renal disease (ESRD), cardiovascular disease (CVD) and death. Existing therapies for CKD improve outcomes only modestly. Therapeutic strategies that target novel CKD-specific mechanisms of CVD and CKD progression are desperately needed to improve health. Disordered mineral metabolism is a nearly universal complication of CKD, regardless of its underlying etiology. An elevated level of fibroblast growth factor 23 (FGF23) is the earliest manifestation of disordered mineral metabolism in CKD. FGF23 rises in response to high phosphate diets and in states of impaired phosphate excretion, such as CKD. Rising FGF23 in CKD maintains normal serum phosphate, but also inhibits renal calcitriol production, which causes secondary hyperparathyroidism, and reduces klotho expression, which accelerates arterial calcification. Elevated FGF23 powerfully predicts ESRD, CVD events and death, and data from our group, validated by new preliminary data, suggest potential underlying pathogenic mechanisms: FGF23 induces left ventricular hypertrophy and accelerates CKD progression, and phosphate excess and klotho deficiency induce arterial calcification independent of FGF23. Based on these data, FGF23 excess and disordered mineral metabolism are leading candidates to target in an outcomes trial. Our long-term goal is to prove by randomized trial that treatment of FGF23 excess and disordered mineral metabolism with phosphate binders, dietary phosphate manipulation, and active vitamin D, will reduce risks of ESRD, CVD events and death in CKD stages 3-4. In this Clinical Center application, we propose two pilot studies to fill remaining knowledge gaps that will inform the design of an outcomes trial. In Pilot Study 1, we will conduct a 6-month, randomized, 3 x 2 study of 150 CKD stage 3-4 patients of lanthanum versus sevelamer versus. placebo, alone and combined with dietary phosphate manipulation to compare their effects on FGF23, phosphate and other mineral metabolites. The results will define which binder should be advanced to an outcomes trial, and whether it should be accompanied by a dietary intervention. In Pilot Study 2, we will conduct a 12-month, randomized, 2 x 2 study of the "winning" phosphate binder + diet arm in Pilot Study 1 versus placebo, and calcitriol vs. placebo in 220 CKD stage 3-4 patients to test the hypothesis that combining active therapies will synergistically improve surrogate markers of CVD and renal risk. A decade of work in the field and extensive preliminary data support our hypotheses. Our team has the requisite clinical research expertise in FGF23 and vitamin D to complete these studies. The University of Miami has a track record of recruiting minority participants in multi-center trials, which is critical in diseases that disproportionately affect minorities, such as CKD. Backed by a strong institutional environment energized by a new CTSA award, our participation in the U01 Consortium will enrich the diversity of study populations it recruits and allow us to contribute to the collaborative effort aimed at improving dismal clinical outcomes suffered by millions of patients with CKD.

描述（由申请人提供）：慢性肾脏疾病（CKD）是一种公共卫生流行病，可增加终阶段肾脏疾病（ESRD），心血管疾病（CVD）和死亡的风险。现有的CKD疗法仅适度改善结果。迫切需要针对CVD和CKD进展的新型CKD特异性机制的治疗策略以改善健康。无序的矿物质代谢是CKD几乎普遍的并发症，无论其潜在的病因如何。成纤维细胞生长因子23（FGF23）的水平升高是CKD中矿物质代谢无序的最早表现。 FGF23响应于高磷酸盐饮食和磷酸盐排泄受损状态（例如CKD）。 CKD中的FGF23升高可维持正常的血清磷酸盐，但也抑制肾骨化三醇产生，这会导致继发性甲状旁腺功能亢进，并降低了klotho表达，从而加速了动脉钙化。 Elevated FGF23 powerfully predicts ESRD, CVD events and death, and data from our group, validated by new preliminary data, suggest potential underlying pathogenic mechanisms: FGF23 induces left ventricular hypertrophy and accelerates CKD progression, and phosphate excess and klotho deficiency induce arterial calcification independent of FGF23. 基于这些数据，FGF23过量和无序的矿物质代谢是候选人在结果试验中的目标。我们的长期目标是通过随机试验证明，用磷酸盐粘合剂，饮食中的磷酸盐操纵和活性维生素D治疗FGF23过量和无序的矿物代谢，将降低CKD阶段3-4的ESRD，CVD事件和死亡的风险。在此临床中心应用程序中，我们提出了两项​​试点研究，以填补剩余的知识差距，这将为结果试验的设计提供信息。在试点研究1中，我们将对150 ckd阶段的3-4例兰塔努姆与Sevelamer与Sevelamer与Sevelamer vess的患者进行6个月，随机，3 x 2的研究。安慰剂，单独使用饮食磷酸盐操纵，以比较其对FGF23，磷酸盐和其他矿物代谢产物的影响。结果将定义哪种粘合剂应采用结果试验，以及是否应伴随饮食干预。在试点研究2中，我们将在试点研究1对安慰剂中进行12个月，随机的2 x 2研究，对220 CKD阶段的3-4名患者的Calcitriol vs.安慰剂进行测试，以测试现有主动疗法的假设将表达cvd和肾脏的CVD和肾脏替代品的替代标记。该领域的十年工作和广泛的初步数据支持我们的假设。我们的团队具有FGF23和维生素D的必要临床研究专业知识，以完成这些研究。迈阿密大学有招募少数群体参与者的往绩，这对于对少数群体（例如CKD）的疾病至关重要。 在由新的CTSA奖充满活力的强大机构环境的支持下，我们参与U01财团将丰富IT招募的研究人群的多样性，并使我们能够为旨在改善数百万CKD患者遭受的惨淡临床成果做出贡献。