Phosphate binder therapy and chronic kidney disease in children

项目总结/摘要 成纤维细胞生长因子23（FGF 23）循环水平升高、血清磷酸盐升高和贫血是 与左心室肥大（LVH）、心血管疾病（CVD）和慢性肾脏疾病相关 (CKD)孩子的进步。CKD-矿物质骨疾病和CKD相关疾病的当前治疗策略 贫血包括1，25 D、结合剂、铁和促红细胞生成素刺激剂（ESA）。然而，1，25 D治疗 进一步增加循环和骨FGF 23水平，缺铁和ESA治疗也 刺激FGF 23产生。磷酸盐的使用为早期CKD提供了一个新的范例 当血清磷酸盐水平低于正常水平时， 在正常范围内，降低FGF 23和提高内源性1，25 D水平。然而，这种做法导致 不一致的结果。另一方面，柠檬酸铁（FC）治疗一直被证明可以 降低FGF 23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可降低血清磷水平，改善铁参数， 小儿透析患者。因此，FC可能具有附加价值，特别是对于透析前CKD儿童， 缺铁性贫血和FGF 23水平升高的人非常普遍。此外，缺铁是一种 FGF 23生产的有力驱动因素。因此，我们假设FC治疗会降低完整的FGF 23， 一项在160名儿童中进行的随机、双盲、双臂平行研究中， CKD 3-4期且血清磷酸盐水平正常的患者。多中心试验将追求以下目标 具体目的：具体目的1：确定FC降低血清完整FGF 23水平的功效（主要是降低血清完整FGF 23水平）。 在12个月内CKD 3-4的儿科患者中的终点）。具体目标2：确定 对贫血、肾功能以及骨和矿物质代谢指数进行干预（次要终点）。 此外，我们将进行治疗前和治疗后的骨活检，以评估骨组织形态计量学， 24名UCLA患者的子队列中的FGF 23表达。具体目标3：确定安全性和 儿童CKD 3-4患者的FC耐受性。如果我们的假设得到证实，那么一种新的治疗模式 将出现在CKD早期开始FC治疗，当患者血磷正常时， 减缓FGF 23的进行性增加并减弱FGF 23相关的不利的肾脏和CVD。

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.