Phosphate binder therapy and chronic kidney disease in children

磷酸盐结合剂治疗与儿童慢性肾病

基本信息

批准号：
10393594
负责人：
ISIDRO B. SALUSKY
金额：
$ 200万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393594
关键词：
Adult Aftercare Age Anemia Biochemical Biopsy Bone Diseases Calcitriol Cardiovascular Diseases Cessation of life Child Childhood Chronic Kidney Failure Citrates Clinical Combined Modality Therapy Data Development Dialysis patients Dialysis procedure Disease Progression Dose Double-Blind Method Early Intervention Enteral Erythropoietin Ferrous Sulfate Future Hemoglobin Hormonal Infrastructure Iron Iron deficiency anemia Kidney Kidney Diseases Lead Left Ventricular Hypertrophy Link Metabolism Minerals Normal Range Patients Pharmaceutical Preparations Physiologic calcification Physiological Placebos Plague Plasma Population Production Randomized Renal function Replacement Therapy Safety Secondary Hyperparathyroidism Serum absorption active method arm bone bone metabolism bone turnover calcium phosphate cardiovascular effects cohort design fibroblast growth factor 23 improved indexing inhibitor inorganic phosphate intervention effect iron deficiency iron metabolism lanthanum carbonate multi-site trial novel novel strategies novel therapeutic intervention pediatric patients premature prevent primary endpoint randomized placebo controlled trial randomized trial secondary analysis secondary endpoint standard of care treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Elevated circulating levels of fibroblast growth factor 23 (FGF23), increased serum phosphate, and anemia are associated with left ventricular hypertrophy (LVH), cardiovascular disease (CVD), and chronic kidney disease (CKD) progression in children. Current treatment strategies for CKD-mineral bone disorder and CKD-related anemia include 1,25D, binders, iron, and erythropoietin stimulating agents (ESA). However, 1,25D therapy further increases circulating and bone FGF23 levels, and iron deficiency and ESA treatment both also stimulate FGF23 production. A novel paradigm in earlier CKD has been suggested with the use of phosphate binders with or without an inhibitor of enteral phosphate absorption, when serum phosphate levels are within the normal range, to lower FGF23 and to raise endogenous 1,25D levels. However, such approach led to inconsistent results. Therapy with ferric citrate (FC), on the other hand, has been shown consistently to lower FGF23 and phosphate levels while improving indices of iron metabolism in adults with CKD stages 3-4. Furthermore, FC decreased serum phosphate levels, improved iron parameters and was well tolerated in pediatric dialysis patients. Thus, FC may have added value especially for children with pre-dialysis CKD in whom iron deficiency anemia and elevated FGF23 levels are highly prevalent. Moreover, iron deficiency is a potent driver of FGF23 production. Therefore, we hypothesize that treatment with FC will lower intact FGF23 levels during a 12-month period in a randomized, double-blinded, two -arms parallel study in 160 pediatric patients with CKD stages 3-4 and normal serum phosphate levels. The multi-site trial will pursue the following specific aims: Specific Aim 1: To determine the efficacy of FC to lower serum intact FGF23 levels (primary endpoint) in pediatric patients with CKD 3–4 over 12 months. Specific Aim 2: To determine the effects of the interventions on anemia, kidney function, and indices of bone and mineral metabolism (secondary end-points). Additionally, we will perform pre- and post-treatment bone biopsies to assess bone histomorphometry and FGF23 expression in a sub-cohort of 24 UCLA patients. Specific Aim 3: To determine the safety and tolerability of FC in pediatric CKD 3-4 patients. If our hypothesis is confirmed, then a new treatment paradigm would emerge in which therapy with FC will be initiated early in CKD, when patients are normophosphatemic, slowing progressive increases in FGF23 and blunting FGF23-associated adverse renal and CVD.

项目摘要/摘要成纤维细胞生长因子23（FGF23）的循环水平升高，血清磷酸盐和贫血增加是与左心室肥大（LVH），心血管疾病（CVD）和慢性肾脏疾病有关（CKD）儿童进展。 CKD时段骨疾病和CKD相关的当前治疗策略贫血包括1,25D，粘合剂，铁和红细胞生成素刺激剂（ESA）。但是，1,25D疗法进一步增加了循环和骨FGF23水平，铁缺乏症和ESA治疗也刺激FGF23产生。使用磷酸盐的较早CKD中的一种新型范式当血清磷酸盐水平为或没有肠磷酸盐滥用抑制剂时，血清磷酸盐水平为在正常范围内，降低FGF23并提高内源性1,25D水平。但是，这种方法领导不一致的结果。另一方面，用柠檬酸铁酸酯（FC）治疗一直被证明降低FGF23和磷酸盐水平，同时改善了CKD阶段3-4的成年人铁代谢指标。此外，FC改善了血清磷酸盐水平，改善了铁参数，并且在小儿透析患者。这是FC可能增加了价值缺乏铁缺乏贫血和FGF23水平升高的人非常普遍。而且，铁缺乏是 FGF23生产的有效驱动力。因此，我们假设使用FC的治疗将降低完整的FGF23 在160个小儿的随机，双盲，两臂平行研究中，在12个月的时间里的水平 CKD阶段3-4和正常血清磷酸盐水平的患者。多站点审判将进行以下具体目的：特定目的1：确定FC对降低血清完整FGF23水平的效率（主要终点）在12个月内CKD 3-4的小儿患者中。特定目的2：确定对贫血，肾功能以及骨骼和矿物质代谢指标的干预措施（次要终点）。此外，我们将执行治疗前和后的骨活检，以评估骨骼组态法和 FGF23在24例UCLA患者的亚州中表达。特定目标3：确定安全性和 FC在小儿CKD 3-4例患者中的耐受性。如果确认我们的假设，则是新的治疗范式会出现在CKD早期开始使用FC的治疗的患者，当患者患有正常磷酸化时，会开始使用。 FGF23和FGF23相关的不良肾脏和CVD的渐进降低增加。