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.

项目概要/摘要成纤维细胞生长因子 23 (FGF23) 循环水平升高、血清磷酸盐升高和贫血与左心室肥厚 (LVH)、心血管疾病 (CVD) 和慢性肾脏疾病相关 (CKD) 儿童进展的当前治疗策略。贫血包括1,25D、结合剂、铁和红细胞生成素刺激剂(ESA)，但1,25D疗法。进一步增加循环和骨 FGF23 水平，缺铁和 ESA 治疗也同样有效已提出使用磷酸盐刺激早期 CKD 的新范例。当血清磷酸盐水平为然而，这种方法导致了在正常范围内降低 FGF23 并提高内源性 1,25D 水平。另一方面，柠檬酸铁 (FC) 治疗已被证明始终存在不一致的结果。降低 FGF23 和磷酸盐水平，同时改善 CKD 3-4 期成人的铁代谢指数。此外，FC 降低了血清磷酸盐水平，改善了铁参数，并且在患者中具有良好的耐受性。因此，FC 可能具有附加值，特别是对于透析前 CKD 的儿童。缺铁性贫血和 FGF23 水平升高的情况非常普遍。 FGF23 产生的有力驱动因素因此，我们追求 FC 治疗会降低完整的 FGF23。一项针对 160 名儿科患者的随机、双盲、双组平行研究在 12 个月期间的水平 CKD 3-4 期且血清磷酸盐水平正常的患者多中心试验将进行以下研究。具体目标：具体目标 1：确定 FC 降低血清完整 FGF23 水平的功效（主要终点）在 12 个月内患有 CKD 3-4 的儿科患者中。具体目标 2：确定治疗的效果。对贫血、肾功能以及骨和矿物质代谢指数（次要终点）的干预措施。此外，我们将进行治疗前和治疗后骨活检，以评估骨组织形态学和 24 名 UCLA 患者亚组中的 FGF23 表达具体目标 3：确定安全性和有效性。如果我们的假设得到证实，那么就会出现新的治疗模式。将出现在 CKD 早期、当患者血磷正常时开始 FC 治疗，减缓 FGF23 的进行性增加并减弱 FGF23 相关的肾脏和心血管疾病。