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: 8287179
• 负责人: ANTHONY A PORTALE
• 金额: $ 32.08万
• 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/8287179
• 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; Clinical Sciences; 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; Prevention strategy; Production; Quality of life; Risk Factors; Role; Secondary Hyperparathyroidism; Serum; Severities; Skeletal system; 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; skeletal disorder; 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）：童年和衰老是健康骨骼和心血管系统发育的关键时期。青年慢性肾病（CKD）导致代谢性骨病，导致生长衰竭和骨畸形，心血管异常和血管钙化，严重降低生活质量和寿命。然而，CKD儿童早期矿物质代谢紊乱的自然史及其与心血管疾病（CVD）的相关性研究很少，特征也不明确。传统上，CKD继发性甲状旁腺功能亢进（sHPT）被归因于1，25-二羟基维生素D（1，25（OH）2D）缺乏与高磷酸盐血症，导致骨代谢紊乱和矿化。这些异常现在被认为是成人和儿童CKD患者CVD和死亡率的新风险因素。1，25（OH）2D缺乏发生在成人进展性CKD的早期，但关于其在CKD儿童中的疾病进展或其与不良肾脏和心血管结局的潜在相关性知之甚少。最近的数据表明，过量的新激素，成纤维细胞生长因子23（FGF-23），可能是在发展中的sHPT的起始事件。FGF-23通过增加磷酸尿和抑制肾合成1，25（OH）2D来维持血清磷酸盐浓度在正常范围内。在CKD成人患者中，在高磷酸盐血症发生之前，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大、冠状动脉钙化和死亡率相关。然而，关于儿童CKD谱中FGF-23过量的患病率和决定因素及其与CKD进展和CVD的潜在相关性知之甚少。我们将在594例入选NIH申办的儿童慢性肾脏病（CKiD）研究的透析前CKD儿童中，描述FGF-23过量和1，25（OH）2D缺乏作为sHPT、生长衰竭、肾脏疾病进展和不良心血管结局发生风险因素的作用。通过8 1/2年的GFR、生长和详细心血管参数的纵向测量，CKiD提供了一个独特的机会来检查矿物质代谢紊乱的自然史及其与CKD儿童不良临床结局的关系。我们的研究将为FGF-23和维生素D代谢的失调提供新的见解，从而为CKD儿童骨骼和心血管疾病的评估、预防和治疗提出新的策略。 公共卫生相关性：儿童慢性肾脏病会导致生长衰竭、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，早期肾脏疾病患儿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很好的研究，而且了解甚少。因此，我们制定更有效的预防和治疗战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衰竭和心血管疾病的关系，作为儿童慢性肾脏病（CKiD）研究的一部分，这是一项由NIH申办的多中心研究，共有600名早期慢性肾脏病儿童参加。