FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality

• Published in: The Journal of clinical investigation Vol. 122; no. 7; pp. 2543 - 2553
• Main Authors: Shalhoub, Victoria, Shatzen, Edward M, Ward, Sabrina C, Davis, James, Stevens, Jennitte, Bi, Vivian, Renshaw, Lisa, Hawkins, Nessa, Wang, Wei, Chen, Ching, Tsai, Mei-Mei, Cattley, Russell C, Wronski, Thomas J, Xia, Xuechen, Li, Xiaodong, Henley, Charles, Eschenberg, Michael, Richards, William G
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-07-2012
• Subjects: Animals; Antibodies, Monoclonal, Murine-Derived - pharmacology; Aorta - pathology; Biomarkers - metabolism; Biomedical research; Bone diseases; Calcification; Calcitriol - blood; Calcium - blood; Cardiovascular disease; CHO Cells; Chronic Kidney Disease-Mineral and Bone Disorder - blood; Chronic Kidney Disease-Mineral and Bone Disorder - metabolism; Chronic Kidney Disease-Mineral and Bone Disorder - physiopathology; Complications and side effects; Cricetinae; Development and progression; Fibroblast Growth Factors - antagonists & inhibitors; Fibroblast Growth Factors - immunology; Fibroblast Growth Factors - metabolism; Genes, Reporter; Glomerular Filtration Rate; Health aspects; Hemodynamics; Hyperparathyroidism; Hyperparathyroidism, Secondary - blood; Hyperparathyroidism, Secondary - metabolism; Hyperparathyroidism, Secondary - physiopathology; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Luciferases - biosynthesis; Luciferases - genetics; Male; Mice; Mice, Inbred BALB C; Mortality; Myocardium - pathology; Parathyroid Hormone - blood; Phosphates - blood; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - physiopathology; Risk factors; Tibia - metabolism; Tibia - pathology; United States; Vascular Calcification - pathology; Vitamin D; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI61405

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is associated with secondary hyperparathyroidism (HPT) and serum elevations in the phosphaturic hormone FGF23, which may be maladaptive and lead to increased morbidity and mortality. To determine the role of FGF23 in the pathogenesis of CKD-MBD and development of secondary HPT, we developed a monoclonal FGF23 antibody to evaluate the impact of chronic FGF23 neutralization on CKD-MBD, secondary HPT, and associated comorbidities in a rat model of CKD-MBD. CKD-MBD rats fed a high-phosphate diet were treated with low or high doses of FGF23-Ab or an isotype control antibody. Neutralization of FGF23 led to sustained reductions in secondary HPT, including decreased parathyroid hormone, increased vitamin D, increased serum calcium, and normalization of bone markers such as cancellous bone volume, trabecular number, osteoblast surface, osteoid surface, and bone-formation rate. In addition, we observed dose-dependent increases in serum phosphate and aortic calcification associated with increased risk of mortality in CKD-MBD rats treated with FGF23-Ab. Thus, mineral disturbances caused by neutralization of FGF23 limited the efficacy of FGF23-Ab and likely contributed to the increased mortality observed in this CKD-MBD rat model.