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: 8110042
• 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/8110042
• 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）：儿童和性能是发展健康骨骼和心血管系统的关键时期。慢性肾脏疾病（CKD）在青年中导致代谢骨病，导致的生长衰竭和骨骼畸形，心血管异常以及血管钙化严重降低了生活质量和寿命。然而，在其早期阶段的CKD儿童中，矿物质代谢无序的自然历史及其与心血管疾病（CVD）的联系很少，而且特征很差。传统上，CKD中的继发性甲状旁腺功能亢进症（SHPT）归因于1,25-二羟基维生素D（1,25（OH）2D）缺乏症与高磷酸盐血症相结合，导致骨骼失调和骨骼的矿物质。现在，这些异常被认为是成人和CKD儿童中CVD和死亡率的新风险因素。 1,25（OH）2D的缺乏发生在成年人进行性CKD的早期，但对于CKD儿童的疾病的演变或潜在的与不良肾脏和心血管结局的关联，其疾病的演变鲜为人知。最近的数据表明，新型激素的过量水平，成纤维细胞生长因子23（FGF-23）可能是SHPT发展的起始事件。 FGF-23通过增加磷酸化并抑制1,25（OH）2d的肾合成，在正常极限内保持血清磷酸盐浓度。 FGF-23水平随着CKD成年人的肾小球滤过率（GFR）的下降，在过度磷酸血症的发展之前逐渐增加，而FGF-23水平的增加与左心室肥大，冠状动脉钙化和死亡率有关。然而，对于儿童中FGF-23过量的流行率和决定因素知之甚少，或其与CKD进展和CVD的潜在关联。我们将表征FGF-23过度和1,25（OH）2D缺陷的作用，是SHPT发展，生长衰竭，肾脏疾病进展和心血管不良后果的风险因素，在594名透析前CKD儿童中，该儿童在NIH复发的儿童（CKID）研究中均纳入NIH复发的慢性肾脏疾病。 CKID具有8 1/2年的纵向测量，生长和详细的心血管参数，提供了一个独特的机会，可以检查矿物质代谢无序的自然历史及其与CKD儿童不良临床结果的关系。我们的研究将为FGF-23和维生素D代谢的失调提供新的见解，从而提出了CKD儿童骨骼和心血管疾病的评估，预防和治疗的新型策略。 公共卫生相关性：儿童的项目叙事慢性肾脏疾病会导致生长失败，骨骼畸形以及心脏和血管疾病严重影响其生活质量和寿命。然而，在早期阶段的肾脏疾病儿童中矿物质代谢混乱的自然史及其与心血管疾病的关联尚未得到很好的研究，并且知之甚少。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，Vitamin D和磷代谢的异常，及其与儿童的生长衰竭和心血管疾病的关系，这是儿童慢性肾脏疾病（CKID）研究的一部分，这是NIHSPSONE的NIH肾脏疾病，一项对600名早期患有慢性肾脏疾病的儿童的多中心研究。