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

描述(申请人提供)：童年和衰老是发展健康的骨骼和心血管系统的关键时期。慢性肾脏疾病(CKD)在年轻人中会导致代谢性骨病，由此导致的生长障碍和骨骼畸形，心血管异常，以及严重降低生活质量和寿命的血管钙化。然而，CKD儿童早期矿物质代谢紊乱的自然病史及其与心血管疾病(CVD)的相关性研究很少，特征也很差。传统上，慢性肾脏病继发性甲状旁腺功能亢进症(SHPT)被认为是1，25-二氢维生素D(1，25(OH)2D)缺乏并伴有高磷血症，导致骨代谢紊乱和矿化。这些异常现在被认为是CKD成人和儿童CVD和死亡率的新的危险因素。1，25(OH)2D缺乏在成人进展性CKD的早期发生，但关于其在儿童CKD中的紊乱演变或其与不利的肾脏和心血管结局的潜在关联，我们知之甚少。最近的数据表明，新激素成纤维细胞生长因子23(成纤维细胞生长因子23)的过量水平可能是SHPT发生发展的始动事件。成纤维细胞生长因子-23通过增加尿磷和抑制肾脏合成1，25(OH)2D来维持血磷浓度在正常范围内。在CKD患者中，随着肾小球滤过率(GFR)的下降，在高磷血症发生之前，FGF23水平逐渐升高，而且这种升高与左室肥厚、冠状动脉钙化和死亡率有关。然而，对于儿童CKD的患病率和决定因素，或其与CKD进展和CVD的潜在关联，我们知之甚少。在NIH赞助的儿童慢性肾脏疾病(CKiD)研究中，我们将确定成纤维细胞生长因子-23过多和1，25(OH)2D缺乏在594名透析前CKD儿童中作为SHPT、生长衰竭、肾脏疾病进展和不良心血管结局的危险因素的作用。CKiD对GFR、生长发育和详细的心血管参数进行了8年半的纵向测量，为研究CKD儿童矿物质代谢紊乱的自然历史及其与不良临床结果的关系提供了独特的机会。我们的研究将为了解成纤维细胞生长因子-23和维生素D代谢失调提供新的见解，从而为CKD儿童骨骼和心血管疾病的评估、预防和治疗提供新的策略。 公共卫生相关性：项目叙述儿童慢性肾脏疾病导致发育障碍、骨骼畸形以及严重影响他们生活质量和缩短寿命的心脏和血管疾病。然而，肾脏疾病儿童早期矿物质代谢紊乱的自然病史及其与心血管疾病的关系尚未得到很好的研究，也知之甚少。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。作为儿童慢性肾脏疾病(CKiD)研究的一部分，我们将研究儿童成纤维细胞生长因子23、维生素D和磷代谢的异常及其与生长障碍和心血管疾病的关系。CKiD研究是由NIH赞助的一项多中心研究，涉及600名早期慢性肾脏疾病儿童。

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.