Pilot Studies Targeting Mineral Metabolism in CKD

描述(申请人提供)：慢性肾脏病(CKD)是一种公共卫生流行病，会增加终末期肾脏疾病(ESRD)、心血管疾病(CVD)和死亡的风险。现有的治疗慢性肾脏病的方法只能略微改善结果。为了改善健康，迫切需要针对CVD和CKD进展的新的CKD特异性机制的治疗策略。矿物质代谢紊乱是CKD的一种几乎普遍的并发症，无论其潜在的病因如何。成纤维细胞生长因子23(FGF23)水平升高是慢性肾脏病矿物质代谢紊乱的最早表现。FGF23在高磷饮食和磷酸盐排泄受损的状态下(如慢性肾脏病)会升高。CKD患者FGF23升高维持正常血磷水平，但也抑制肾组织骨化三醇的产生，从而导致继发性甲状旁腺功能亢进，并减少Klotho的表达，从而加速动脉钙化。FGF23升高有力地预测了ESRD、CVD事件和死亡，来自我们小组的数据，经新的初步数据验证，提出了潜在的致病机制：FGF23诱导左室肥厚并加速CKD进展，而磷酸盐过量和Klotho缺乏诱导动脉钙化，而不依赖FGF23。基于这些数据，FGF23过量和紊乱的矿物质代谢是导致候选结果试验的目标。我们的长期目标是通过随机试验证明，使用磷酸盐结合剂、饮食磷酸盐操纵和活性维生素D治疗FGF23过量和紊乱的矿物质代谢，将降低CKD 3-4期ESRD、CVD事件和死亡的风险。在这个临床中心的应用中，我们提出了两项试验性研究，以填补剩余的知识空白，这将为结果试验的设计提供信息。在先导研究1中，我们将对150名CKD 3-4期患者进行为期6个月的随机3x2对照研究。安慰剂，单独和联合饮食磷酸盐操作，比较他们对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该进入结果试验，以及是否应该伴随着饮食干预。在先导研究2中，我们将进行为期12个月的随机2×2研究，在先导研究1中“获胜”的磷酸盐粘合剂+减肥药与安慰剂，以及骨化三醇与安慰剂在220名CKD 3-4期患者中的对比，以检验结合积极治疗将协同改善心血管疾病和肾脏风险的替代标记物的假设。十年的实地工作和广泛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方面拥有完成这些研究所需的临床研究专业知识。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，这在CKD等对少数族裔影响不成比例的疾病中至关重要。在一个由新的CTSA奖项激励的强大机构环境的支持下，我们参与U01联合会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患者悲惨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.