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

磷酸盐结合剂治疗慢性肾病-矿物质骨疾病儿童

• 批准号: 9020138
• 负责人: ISIDRO B. SALUSKY
• 金额: $ 39.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020138
• 关键词: Adult; Aftercare; Alkaline Phosphatase; Binding; Biological Markers; Biopsy; Bone Diseases; Calcitriol; Calcium; Carbonates; Cardiac; Cardiovascular Diseases; Cessation of life; Child; Chronic Kidney Failure; Clinical; Cohort Studies; Data; Development; Diet; Disease; Disease Progression; Double-Blind Method; Early Intervention; Excretory function; Future; Glomerular Filtration Rate; Grant; Heart; Homeostasis; Intake; Intervention; Intestines; Iohexol; Kidney; Kidney Diseases; Lead; Left Ventricular Hypertrophy; Left Ventricular Mass; Logistics; Magnetic Resonance Imaging; Measures; Minerals; Multi-Institutional Clinical Trial; N-terminal; National Institute of Diabetes and Digestive and Kidney Diseases; Niacinamide; Normal Range; Patients; Physiologic calcification; Placebos; Plague; Plasma; Population; Procollagen; Production; Proteins; Randomized; Recruitment Activity; Replacement Therapy; Research Infrastructure; Safety; Secondary Hyperparathyroidism; Serum; Site; Staging; Testing; Therapeutic; United States National Institutes of Health; Up-Regulation; Vitamin D; absorption; active method; arm; bone; bone metabolism; bone turnover; cohort; design; fibroblast growth factor 23; inorganic phosphate; intervention effect; novel; novel strategies; pediatric patients; premature; public health relevance; sevelamer; sodium phosphate; symporter; symposium; tartrate-resistant acid phosphatase; urinary

 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.

 描述（由申请方提供）：血清磷酸盐和成纤维细胞生长因子23（FGF 23）水平升高与慢性肾脏疾病（CKD）患者的心血管疾病、肾脏疾病进展和过早死亡相关。FGF 23水平在CKD儿童早期升高，而血清磷酸盐水平正常，是CKD进展的预测因子，并与左心室肥大独立相关。目前CKD-矿物质骨障碍（CKD-MBD）的治疗范例是：当FGF 23水平显著升高时，磷酸盐结合剂纠正高磷酸盐血症，以及进一步升高FGF 23水平的1，25 D治疗。一个新的范例是在CKD早期血清磷酸盐正常时开始磷酸盐结合剂，以降低已经升高的FGF 23。然而，磷酸盐结合剂的干预性研究显示了不一致的结果;其中大多数是小的，持续时间短，使用单一干预。此外，结合剂单药治疗可能会受到肠道钠-磷酸盐协同转运蛋白NPT 2b上调的阻碍。烟酰胺（NAM）通过下调NPT 2b表达而不是通过结合膳食磷酸盐来降低CKD患者的血清磷酸盐和FGF 23水平。正如最近的磷酸盐稳态研讨会所强调的那样，定义新的方法来逆转CKD中磷酸盐和FGF 23的紊乱是一个高度优先事项。因此，拟定的U3 - 4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，以便在8家参与研究中心招募的168例3-4期CKD儿童患者中开展一项为期12个月的碳酸司维拉姆（SC）和NAM的随机双盲、四组平行试验。拟定的U34将为后续U 01提供基础设施，U 01将追求以下目标：具体目标1：确定SC和NAM降低血清磷酸盐和FGF 23水平的疗效（共同主要终点）。具体目标2：确定SC和NAM的安全性和耐受性。具体目标3：a）骨转换和磷酸盐稳态的生物标志物，并且我们将在25名UCLA患者的子队列中进行治疗前和治疗后骨活检研究以评估骨矿化和FGF 23的表达; B）通过心脏磁共振成像评估的左心室质量和c）通过碘海醇（iGFR）的血浆消失直接测量的GFR下降速率。如果我们的假设得到证实，在CKD-MBD的治疗中将出现新的范式转变，因为当血清磷酸盐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1，25 D缺乏症，这进一步增加了FGF 23水平。