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）：慢性肾病（CKD）是一种公共卫生流行病，会增加终末期肾病（ESRD）、心血管疾病（CVD）和死亡的风险。现有的 CKD 疗法只能有限地改善预后。为了改善健康，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。无论其根本病因如何，矿物质代谢紊乱几乎是 CKD 的普遍并发症。成纤维细胞生长因子 23 (FGF23) 水平升高是 CKD 矿物质代谢紊乱的最早表现。 FGF23 会因高磷酸盐饮食和磷酸盐排泄受损的状态（例如 CKD）而升高。 CKD 中 FGF23 的升高可维持正常的血清磷酸盐，但也会抑制肾脏骨化三醇的产生，从而导致继发性甲状旁腺功能亢进，并减少 klotho 表达，从而加速动脉钙化。 FGF23 升高可有力地预测 ESRD、CVD 事件和死亡，并且我们小组的数据经过新的初步数据验证，表明潜在的潜在致病机制：FGF23 诱导左心室肥大并加速 CKD 进展，磷酸盐过量和 klotho 缺乏诱导动脉钙化，与FGF23。 根据这些数据，FGF23 过量和矿物质代谢紊乱是结果试验中的主要候选目标。我们的长期目标是通过随机试验证明，通过磷酸盐结合剂、膳食磷酸盐控制和活性维生素 D 治疗 FGF23 过量和矿物质代谢紊乱，将降低 CKD 3-4 期的 ESRD、CVD 事件和死亡风险。在此临床中心申请中，我们提出了两项​​试点研究，以填补剩余的知识空白，为结果试验的设计提供信息。在试点研究 1 中，我们将对 150 名 CKD 3-4 期患者进行一项为期 6 个月的随机 3 x 2 研究，分别使用镧与司维拉姆。安慰剂，单独使用以及与膳食磷酸盐控制相结合，比较它们对 FGF23、磷酸盐和其他矿物质代谢物的影响。结果将确定哪种粘合剂应进入结果试验，以及是否应伴随饮食干预。在试点研究 2 中，我们将在 220 名 CKD 3-4 期患者中进行为期 12 个月的随机 2 x 2 研究，比较试点研究 1 中“获胜的”磷酸盐结合剂 + 饮食组与安慰剂的比较，以及骨化三醇与安慰剂的比较。检验以下假设：结合积极疗法将协同改善 CVD 和肾脏风险的替代标志物。十年的该领域工作和广泛的初步数据支持了我们的假设。我们的团队拥有完成这些研究所需的 FGF23 和维生素 D 临床研究专业知识。迈阿密大学在多中心试验中招募少数族裔参与者有着良好的记录，这对于慢性肾病等对少数族裔影响较大的疾病至关重要。 在新的 CTSA 奖项激励下的强大机构环境的支持下，我们对 U01 联盟的参与将丰富其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 患者所遭受的惨淡临床结果的合作努力做出贡献。