Phosphate binder therapy and chronic kidney disease in children

项目摘要/摘要 循环中成纤维细胞生长因子23(FGF23)水平升高、血磷升高和贫血 与左心室肥厚(LVH)、心血管疾病(CVD)和慢性肾病相关 (CKD)儿童的进展。慢性肾脏病矿物性骨病及相关疾病的治疗现状 贫血包括1，25D、粘合剂、铁和促红细胞生成素刺激剂(ESA)。然而，1，25D疗法 进一步增加循环和骨FGF23水平，缺铁和ESA治疗也 刺激FGF23的生产。在早期的CKD中，使用磷酸盐提出了一种新的范式 含或不含肠内磷吸收抑制剂的粘合剂，当血清磷水平为 在正常范围内，降低FGF23，升高内源性1，25D水平。然而，这种方法导致了 导致不一致的结果。另一方面，使用柠檬酸铁(FC)的治疗一直被证明是有效的 降低FGF23和磷酸盐水平，同时改善CKD 3-4期成人的铁代谢指标。 此外，FC可降低血磷水平，改善铁参数，并在 儿童透析患者。因此，FC可能具有附加值，特别是对于患有透析前CKD的儿童 缺铁性贫血和FGF23水平升高在世界卫生组织中非常普遍。此外，缺铁是一种 FGF23生产的强大推动力。因此，我们假设FC治疗将降低完整的FGF23 一项为期12个月的随机、双盲、双臂平行研究：160名儿童的血药浓度 CKD分期3-4，血磷水平正常的患者。多个地点的试验将进行以下几个方面 特定目标：特定目标1：确定FC降低血清完整FGF23水平(初级)的疗效 终点)在12个月以上的CKD 3-4的儿童患者中。具体目标2：确定 对贫血、肾功能、骨骼和矿物质代谢指数(次级终点)的干预。 此外，我们将在治疗前和治疗后进行骨活检，以评估骨组织形态计量学和 24例加州大学洛杉矶分校患者中FGF23的表达。具体目标3：确定安全和 儿童慢性肾脏病3~4岁患者对FC的耐受性。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治疗的情况下，当患者血磷正常时， 减缓FGF23的进行性增加和钝化FGF23相关的不良肾脏和心血管疾病。

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.