Pilot Studies Targeting Mineral Metabolism in Chronic Kidney Disease

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，可增加终末期肾脏疾病（ESRD）、心血管疾病（CVD）和死亡的风险。现有的CKD治疗方法仅能适度改善预后。目前迫切需要针对新的CKD特异性机制和CKD进展的治疗策略来改善健康。无论其潜在的病因如何，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中矿物质代谢紊乱的最早表现。FGF23在高磷酸盐饮食和磷酸盐排泄受损状态（如CKD）下升高。CKD中FGF23的升高维持了正常的血清磷酸盐，但也抑制了肾脏骨化三醇的产生，导致继发性甲状旁腺功能亢进，并降低了klotho的表达，加速了动脉钙化。FGF23升高可有效预测ESRD、CVD事件和死亡，本研究小组的数据经新的初步数据验证，提示潜在的致病机制：FGF23诱导左心室肥厚，加速CKD进展，磷酸盐过量和klotho缺乏诱导动脉钙化，不依赖于FGF23。基于这些数据，FGF23过量和矿物质代谢紊乱是结果试验的主要候选目标。我们的长期目标是通过随机试验证明，通过磷酸盐结合剂、膳食磷酸盐操纵和活性维生素D治疗FGF23过量和矿物质代谢紊乱，将降低慢性肾病3-4期ESRD、CVD事件和死亡的风险。在本临床中心申请中，我们提出两项试点研究，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期患者进行为期6个月的随机3 × 2研究。比较两组对FGF23、磷酸盐和其他矿物质代谢物的影响。研究结果将确定哪种粘结剂应该进入结局试验，以及是否应该伴随着饮食干预。在试点研究2中，我们将在220例CKD 3-4期患者中进行一项为期12个月的随机2 × 2研究，对“获胜”的磷酸盐结合剂+饮食组与安慰剂组，以及骨化三醇与安慰剂组进行研究，以检验联合积极治疗将协同改善心血管疾病和肾脏风险替代标志物的假设。在这个领域的十年工作和大量的初步数据支持了我们的假设。我们的团队在FGF23和维生素D方面有必要的临床研究专业知识来完成这些研究。迈阿密大学有在多中心试验中招募少数族裔参与者的记录，这对于慢性肾病等对少数族裔影响不成比例的疾病至关重要。在新的CTSA奖项激发的强大制度环境的支持下，我们参与U01联盟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患者所遭受的令人沮丧的临床结果的合作努力做出贡献。

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.