Disordered Mineral Metabolism in the CKiD Children: Role of FGF-23

CKiD 儿童矿物质代谢紊乱：FGF-23 的作用

• 批准号: 7987208
• 负责人: ANTHONY A PORTALE
• 金额: $ 40.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987208
• 关键词: 25-hydroxyvitamin D; Adolescence; Adult; Affect; Area; Basic Science; Biological Markers; Blood Vessels; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Child; Childhood; Chronic Kidney Failure; Clinical; Data; Deformity; Development; Dialysis procedure; Disease; Disease Progression; Enrollment; Event; Evolution; Excretory function; Failure; Glomerular Filtration Rate; Growth; Heart Diseases; Homeostasis; Hormones; Kidney; Kidney Diseases; Lead; Left Ventricular Hypertrophy; Left Ventricular Mass; Longevity; Measurement; Measures; Mediating; Metabolic Bone Diseases; Metabolism; Minerals; Natural History; Nephrons; Outcome; Physiologic calcification; Prevalence; Prevention; Preventive; Production; Quality of life; Risk Factors; Role; Secondary Hyperparathyroidism; Serum; Severities; Staging; Structure; Testing; Therapeutic; Thick; Time; United States National Institutes of Health; Vascular calcification; Vitamin D; Youth; arterial stiffness; bone; cohort; coronary artery calcification; fibroblast growth factor 23; indexing; inorganic phosphate; insight; intima media; mortality; novel; novel strategies; phosphorus metabolism; prevent; public health relevance; skeletal; treatment strategy

DESCRIPTION (provided by applicant): Childhood and dolescence are crucial times for the development of a healthy skeletal and cardiovascular system. Chronic kidney disease (CKD) in youth results in metabolic bone disease, resultant growth failure and bone deformities, cardiovascular abnormalities, and vascular calcification that severely diminish quality-of-life and lifespan. However, the natural history of disordered mineral metabolism and its association with cardiovascular disease (CVD) in children with CKD in its early stages is little studied and poorly characterized. Traditionally, secondary hyperparathyroidism (sHPT) in CKD has been attributed to 1,25-dihyroxyvitamin D (1,25(OH)2D) deficiency combined with hyperphosphatemia, leading to disordered turnover and mineralization of bone. These abnormalities are now accepted as novel risk factors for CVD and mortality in adults and children with CKD. Deficiency of 1,25(OH)2D occurs early in the course of progressive CKD in adults, but little is known regarding the evolution of its disorder in children with CKD or its potential association with adverse renal and cardiovascular outcomes. Recent data suggests that excess levels of the novel hormone, fibroblast growth factor 23 (FGF-23), may be the initiating event in the development of sHPT. FGF-23 maintains serum phosphate concentrations within normal limits by augmenting phosphaturia and inhibiting renal synthesis of 1,25(OH)2D. FGF-23 levels increase progressively as glomerular filtration rate (GFR) declines in adults with CKD, before the development of hyperphosphatemia, and the increased FGF-23 levels are associated with left ventricular hypertrophy, coronary artery calcification, and mortality. However, little is known about the prevalence and determinants of FGF-23 excess across the spectrum of CKD in children or its potential association with CKD progression and CVD. We will characterize the role of FGF-23 excess and 1,25(OH)2D deficiency as risk factors for the development of sHPT, growth failure, kidney disease progression, and adverse cardiovascular outcomes in 594 children with pre-dialysis CKD who are enrolled in the NIH-sponsored Chronic Kidney Disease in Children (CKiD) study. With 8 1/2 years of longitudinal measurements of GFR, growth, and detailed cardiovascular parameters, CKiD provides a unique opportunity to examine the natural history of disordered mineral metabolism and its relationship to adverse clinical outcomes in children with CKD. Our study will provide novel insights into the dysregulation of FGF-23 and vitamin D metabolism and thus suggest novel strategies for the assessment, prevention, and treatment of skeletal and cardiovascular disorders in children with CKD. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic kidney disease in children results in growth failure, skeletal deformities, and disease of the heart and blood vessels that severely affect their quality-of-life and shorten lifespan. However, the natural history of disordered mineral metabolism and its association with cardiovascular disease in children with kidney disease in its early stages has not been well studied and is poorly understood. As a result, our ability to develop more effective preventive and treatment strategies is severely hampered. We will study abnormalities in fibroblast growth factor 23, vitamin D, and phosphorus metabolism and their relationship to growth failure and cardiovascular disease in children as part of the Chronic Kidney Disease in Children (CKiD) study, an NIH- sponsored multi-center study of 600 children with early stage chronic kidney disease.

描述（由申请人提供）：童年和青少年时期是健康骨骼和心血管系统发育的关键时期。青少年慢性肾病 (CKD) 会导致代谢性骨病、由此导致的生长障碍和骨骼畸形、心血管异常和血管钙化，严重降低生活质量和寿命。然而，早期 CKD 儿童矿物质代谢紊乱的自然史及其与心血管疾病 (CVD) 的关系却鲜有研究，且特征也较差。传统上，CKD 中的继发性甲状旁腺功能亢进 (sHPT) 归因于 1,25-二羟基维生素 D (1,25(OH)2D) 缺乏和高磷血症，导致骨转换和矿化紊乱。这些异常现在被认为是 CKD 成人和儿童 CVD 和死亡的新危险因素。 1,25(OH)2D 缺乏发生在成人进行性 CKD 病程的早期，但有关 CKD 儿童疾病的演变或其与不良肾脏和心血管结局的潜在关联知之甚少。最近的数据表明，新型激素成纤维细胞生长因子 23 (FGF-23) 水平过高可能是 sHPT 发展的起始事件。 FGF-23 通过增加磷酸盐尿和抑制 1,25(OH)2D 的肾脏合成来将血清磷酸盐浓度维持在正常范围内。在发生高磷血症之前，成人 CKD 患者的 FGF-23 水平随着肾小球滤过率 (GFR) 下降而逐渐升高，并且 FGF-23 水平升高与左心室肥厚、冠状动脉钙化和死亡率相关。然而，对于儿童 C​​KD 范围内 FGF-23 过量的患病率和决定因素，或其与 CKD 进展和 CVD 的潜在关联，人们知之甚少。我们将描述 FGF-23 过量和 1,25(OH)2D 缺乏作为 594 名入组的透析前 CKD 儿童发生 sHPT、生长障碍、肾脏疾病进展和不良心血管结局的危险因素的作用在 NIH 资助的儿童慢性肾病 (CKiD) 研究中。通过对 GFR、生长和详细心血管参数进行 8 1/2 年的纵向测量，CKiD 提供了一个独特的机会来检查 CKD 儿童矿物质代谢紊乱的自然史及其与不良临床结果的关系。我们的研究将为 FGF-23 和维生素 D 代谢失调提供新的见解，从而提出评估、预防和治疗 CKD 儿童骨骼和心血管疾病的新策略。 公共健康相关性：项目叙述儿童慢性肾病会导致生长障碍、骨骼畸形以及心脏和血管疾病，严重影响他们的生活质量并缩短寿命。然而，早期肾病儿童矿物质代谢紊乱的自然史及其与心血管疾病的关系尚未得到充分研究和了解。结果，我们制定更有效的预防和治疗策略的能力受到严重阻碍。我们将研究成纤维细胞生长因子 23、维生素 D 和磷代谢的异常及其与儿童生长障碍和心血管疾病的关系，作为儿童慢性肾病 (CKiD) 研究的一部分，该研究是 NIH 资助的一项多中心研究600 名患有早期慢性肾病的儿童。