Pilot Studies Targeting Mineral Metabolism in Chronic Kidney Disease

描述（由申请人提供）：慢性肾脏病（CKD）是一种公共卫生流行病，可增加终末期肾脏病（ESRD）、心血管疾病（CVD）和死亡的风险。CKD的现有疗法仅适度改善结局。迫切需要针对CVD和CKD进展的新CKD特异性机制的治疗策略来改善健康。矿物质代谢紊乱是CKD的一种几乎普遍的并发症，无论其潜在病因如何。成纤维细胞生长因子23（FGF 23）水平升高是CKD矿物质代谢紊乱的最早表现。FGF 23在高磷酸盐饮食和磷酸盐排泄受损的状态下（如CKD）升高。CKD中FGF 23升高可维持正常的血清磷酸盐，但也可抑制肾骨化三醇的产生，从而导致继发性甲状旁腺功能亢进，并降低klotho表达，从而加速动脉钙化。FGF 23升高有力地预测ESRD、CVD事件和死亡，我们组的数据经新的初步数据验证，表明潜在的潜在致病机制：FGF 23诱导左心室肥大并加速CKD进展，磷酸盐过量和klotho缺乏诱导独立于FGF 23的动脉钙化。 基于这些数据，FGF 23过量和紊乱的矿物质代谢是导致候选人在结果试验中靶向的目标。我们的长期目标是通过随机试验证明，用磷酸盐结合剂、膳食磷酸盐控制和活性维生素D治疗FGF 23过量和矿物质代谢紊乱，将降低3-4期CKD患者ESRD、CVD事件和死亡的风险。在本临床中心申请中，我们提出了两项试点研究，以填补剩余的知识空白，为结局试验的设计提供信息。在初步研究1中，我们将在150例CKD 3-4期患者中进行一项为期6个月的随机化3 x 2研究，分别比较镧与司维拉姆与。安慰剂，单独和与膳食磷酸盐操作组合，以比较它们对FGF 23、磷酸盐和其他矿物质代谢物的作用。研究结果将确定哪种粘合剂应该进入结果试验，以及是否应该伴随饮食干预。在初步研究2中，我们将在220例CKD 3-4期患者中进行一项为期12个月的随机化2 x 2研究，比较初步研究1中“获胜”的磷结合剂+饮食组与安慰剂组，以及骨化三醇与安慰剂组，以检验联合活性治疗将协同改善CVD和肾脏风险的替代标志物的假设。在该领域的十年工作和广泛的初步数据支持我们的假设。我们的团队在FGF 23和维生素D方面拥有必要的临床研究专业知识，以完成这些研究。迈阿密大学在多中心试验中招募少数族裔参与者方面有着良好的记录，这对于不成比例地影响少数族裔的疾病（如CKD）至关重要。 在新CTSA奖项激励下的强大机构环境的支持下，我们参与U 01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局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.