FGF23 neutralization improves chronic kidney disease–associated hyperparathyroidism yet increases mortality
Victoria Shalhoub, … , Michael Eschenberg, William G. Richards
Victoria Shalhoub, … , Michael Eschenberg, William G. Richards
Published June 25, 2012
Citation Information: J Clin Invest. 2012;122(7):2543-2553. https://doi.org/10.1172/JCI61405.
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FGF23 neutralization improves chronic kidney disease–associated hyperparathyroidism yet increases mortality

Abstract

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.

Authors

Victoria Shalhoub, Edward M. Shatzen, Sabrina C. Ward, James Davis, Jennitte Stevens, Vivian Bi, Lisa Renshaw, Nessa Hawkins, Wei Wang, Ching Chen, Mei-Mei Tsai, Russell C. Cattley, Thomas J. Wronski, Xuechen Xia, Xiaodong Li, Charles Henley, Michael Eschenberg, William G. Richards

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Figure 1

Characterization of FGF23-Abs in normal rodents.

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Characterization of FGF23-Abs in normal rodents. (A) Rat FGF23 dose-resp...
(A) Rat FGF23 dose-response in CHO–Kl–ELK-1 luciferase reporter cells. §P < 0. 001 versus CHO–ELK-1 and parental CHO cells and FGF23, ANOVA plus Tukey’s post test. (B) Rat anti-rat FGF23 hybridoma-conditioned medium inhibited FGF23 binding to FGFR-Kl. Each bar represents the mean result from duplicate wells. Blank, no FGF23 control. (C) FGF23-Ab inhibited binding to FGFRs 1c, 3c, and 4. (D) FGF23-Ab inhibited FGF23 ELK-1 signaling in CHO-Kl cells. *P < 0.05, **P < 0.01 versus FGF23-Ab; #P < 0.05, ##P < 0.01 versus FGF23-Ab, t test. (E) A single FGF23-Ab injection increased serum phosphate in normal mice. Balb/c male mice were injected with FGF23-Ab, control Ab or PBS vehicle (n = 3 PBS, n = 7 control Ab, n = 10 FGF23-Ab; mean ± SEM; *P < 0. 05 versus PBS or control Ab, ANOVA plus Tukey’s post-test). (F) A single FGF23-Ab injection increased serum phosphate in normal rats. Serum phosphate was measured daily for 4 days. (n = 4/group; mean ± SEM; **P < 0.01, §P < 0.001, §§P < 0.0001 versus respective day control Ab, unpaired t test. ###P < 0.001 versus baseline, ANOVA plus Dunnett’s multiple comparison test). BL, baseline (time 0) before each treatment was administered.