FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality.
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.
Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
Victoria
V
Shalhoub
Edward M
EM
Shatzen
Sabrina C
SC
Ward
James
J
Davis
Jennitte
J
Stevens
Vivian
V
Bi
Lisa
L
Renshaw
Nessa
N
Hawkins
Wei
W
Wang
Ching
C
Chen
Mei-Mei
MM
Tsai
Russell C
RC
Cattley
Thomas J
TJ
Wronski
Xuechen
X
Xia
Xiaodong
X
Li
Charles
C
Henley
Michael
M
Eschenberg
William G
WG
Richards
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D001011:Aorta / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D016466:CHO Cells; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000097:blood / Q000378:metabolism / Q000503:physiopathology; D006224:Cricetinae; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D017930:Genes, Reporter; D005919:Glomerular Filtration Rate; D006439:Hemodynamics; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D013977:Tibia / Q000378:metabolism / Q000473:pathology; D061205:Vascular Calcification / Q000473:pathology
D058846:Antibodies, Monoclonal, Murine-Derived; D015415:Biomarkers; C000717428:Fgf23 protein, mouse; C505605:Fgf23 protein, rat; D010281:Parathyroid Hormone; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D008156:Luciferases; D002117:Calcitriol; D002118:Calcium