FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality
FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality
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DOI：
10.1172/jci61405
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发表时间：
2012-07-01
影响因子：
15.9
通讯作者：
Richards, William G.
中科院分区：
文献类型：
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作者：
Shalhoub, Victoria;Shatzen, Edward M.;Richards, William G.
慢性肾病-矿物质和骨病 (CKD-MBD) 与继发性甲状旁腺功能亢进 (HPT) 和血清磷酸激素 FGF23 升高有关，这可能会导致适应不良并导致发病率和死亡率增加。为了确定 FGF23 在 CKD-MBD 发病机制和继发性 HPT 发展中的作用，我们开发了一种单克隆 FGF23 抗体，以评估慢性 FGF23 中和对 CKD-MBD、继发性 HPT 以及 CKD-MBD 大鼠模型中相关合并症的影响。饲喂高磷酸盐饮食的 CKD-MBD 大鼠用低剂量或高剂量的 FGF23-Ab 或同种型对照抗体进行治疗。 FGF23的中和导致继发性HPT持续减少，包括甲状旁腺激素减少、维生素D增加、血清钙增加以及骨标志物如松质骨体积、小梁数量、成骨细胞表面、类骨表面和骨形成率的正常化。此外，我们观察到，在接受 FGF23-Ab 治疗的 CKD-MBD 大鼠中，血清磷酸盐和主动脉钙化呈剂量依赖性增加，与死亡风险增加相关。因此，FGF23 中和引起的矿物质紊乱限制了 FGF23-Ab 的功效，并可能导致该 CKD-MBD 大鼠模型中观察到的死亡率增加。
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.