Nephrology Therapeutic Area, Global Medical Affairs, Amgen, Inc., Thousand Oaks, California.
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
J Am Soc Nephrol. 2022 Jan;33(1):201-212. doi: 10.1681/ASN.2021060825. Epub 2021 Nov 3.
Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands . Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels.
To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia.
Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds.
These findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.
在接受透析的患者中，临床所见范围内的磷水平已被报道可减弱钙受体的激活，并改变甲状旁腺激素（PTH）从分离的甲状旁腺中的释放。因此，一些临床医生和透析提供者建议，当血清磷浓度超过某些阈值水平时，钙敏感受体激动剂对于管理接受透析的患者的继发性甲状旁腺功能亢进症无效，不应使用。
为了确定高磷血症是否降低了钙敏感受体激动剂的治疗反应，我们使用来自大型临床试验的数据来分析依替膦酸钙和西那卡塞降低继发性甲状旁腺功能亢进且存在不同程度高磷血症的血液透析患者的血浆 PTH 水平的效果。
在接受依替膦酸钙或西那卡塞治疗的 26 周期间，无论基线时高磷血症的程度如何，血浆 PTH 水平都逐渐下降。然而，与每种钙敏感受体激动剂一样，与血清磷水平低于这些阈值的患者相比，在试验期间，血清磷水平高于三个预设阈值之一的患者中，每个随访间隔的 PTH 从基线下降的幅度较小。
这些发现是人类中第一个支持高磷血症减弱钙离子和钙敏感受体激动剂对钙受体激活的观点的发现。然而，高磷血症对钙敏感受体激动剂反应性的影响相对较小，并且在治疗上可能没有显著意义。钙敏感受体激动剂治疗继发性甲状旁腺功能亢进症降低血浆 PTH 水平的疗效仍然很强，尽管血清磷显著升高。
