Phosphate Binders in Children with Chronic Kidney Disease-Mineral Bone Disorder

 描述(由申请人提供)：慢性肾脏疾病(CKD)患者的血磷和成纤维细胞生长因子23(FGF23)水平升高与心血管疾病、肾脏疾病进展和过早死亡有关。FGF23水平在CKD儿童早期升高，而血磷水平正常，是CKD进展的预测因子，并与左心室肥厚独立相关。目前CKD-矿物性骨病(CKD-MBD)的治疗方案是：当FGF23水平显著升高时，使用磷酸盐结合物纠正高磷血症，并使用1，25D治疗进一步提高FGF23水平。一个新的范例是在CKD中当血清磷正常时更早开始磷酸盐结合，以降低已经升高的FGF23。然而，使用磷酸盐粘结剂的干预研究显示出不一致的结果；大多数研究规模小、持续时间短，并且使用单一干预措施。此外，使用粘合剂的单一治疗可能会受到肠道钠磷联合转运体NPT2b上调的阻碍。烟酰胺(NAM)通过下调NPT2b的表达而不是通过结合饮食中的磷来降低CKD患者的血磷和FGF23水平。正如最近一次关于磷酸盐稳态的研讨会所强调的那样，定义新的方法来逆转CKD中磷酸盐和FGF23的干扰是一个高度优先的任务。因此，拟议的U34将制定必要的研究基础设施、研究计划以及科学、后勤和监管文件，以在从8个参与地点招募的168名患有CKD 3-4期的儿童患者中进行为期12个月的随机、双盲、四臂碳酸酯(SC)和NAM平行试验。拟议的U34将为随后的U01提供基础设施，以实现以下目标：具体目标1：确定SC和NAM在降低血磷和FGF23水平(共同主要终点)方面的有效性。具体目标2：确定SC和NAM的安全性和耐受性。具体目标3：除了这些主要终点外，我们还将评估与安慰剂相比，积极干预对下列变量的影响：a)骨转换和磷酸盐稳态的生物标志物，我们将在25名加州大学洛杉矶分校患者中进行治疗前和治疗后的骨活检研究，以评估骨矿化及FGF23的表达；b)通过心脏磁共振成像评估左心室重量，以及c)通过血浆碘己醇消失(IGFR)直接测量GFR的下降率。如果我们的假设得到证实，CKD-MBD的治疗将出现新的范式转变，因为当血清磷水平在正常范围内时，磷酸盐结合剂将被用作一线治疗，而不是用活性维生素D纠正1，25D缺乏症，后者进一步增加FGF23水平。

 DESCRIPTION (provided by applicant): Elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease, kidney disease progression, and premature death in patients with chronic kidney disease (CKD). FGF23 levels increases early in children with CKD while serum phosphate levels are normal, are predictors of CKD progression, and are independently associated with left ventricular hypertrophy. Current treatment paradigms of CKD-Mineral Bone Disorder (CKD-MBD) are: phosphate binders to correct hyperphosphatemia when FGF23 levels are markedly elevated and 1,25D therapy that further raise FGF23 levels. A novel paradigm is to start phosphate binders earlier in CKD when serum phosphate is normal to lower already elevated FGF23. However, interventional studies with phosphate binders have demonstrated inconsistent results; most of them were small, short duration and used single interventions. Moreover, monotherapy with binders may be hampered by up-regulation of the intestinal sodium-phosphate co-transporter NPT2b. Nicotinamide (NAM) lowers serum phosphate and FGF23 levels in CKD patients by down-regulating NPT2b expression, rather than by binding dietary phosphate. As highlighted by a recent Symposium on Phosphate Homeostasis, defining novel approaches to reverse disturbances in phosphate and FGF23 in CKD is a high priority. Thus, the proposed U34 will develop the necessary study infrastructure, research plan, and scientific, logistic, and regulatory documents to conduct a 12-month randomized double blinded, four-arm parallel trial of sevelamer carbonate (SC) and NAM in 168 pediatric patients with CKD stages 3-4 recruited from eight participating sites. The proposed U34 will provide the infrastructure for the subsequent U01 that will pursue the following aims: Specific Aim 1: To determine the efficacy of SC and NAM to lower serum phosphate and FGF23 levels (co-primary endpoints). Specific Aim 2: To determine the safety and tolerability of SC and NAM. Specific Aim 3: In addition to these primary endpoints, we will evaluate the effects of the active interventions compared to placebo on the following variables: a) biomarkers of bone turnover and phosphate homeostasis and we will perform pre- and post-treatment bone biopsies study in a sub-cohort of 25 UCLA patients to assess bone mineralization and expression of FGF23; b) on left ventricular mass, as assessed by cardiac magnetic resonance imaging and c) on the rate of decline in GFR, directly measured by the plasma disappearance of iohexol (iGFR). If our hypotheses are confirmed, a new paradigm shift would emerge in the therapy of CKD- MBD, because phosphate binders will be used as first-line of treatment when serum phosphate levels are within the normal range rather than correcting 1,25D deficiency with active vitamin D which further increases FGF23 levels.