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

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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.