Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Jesse Brown Veterans Administration Medical Center, Chicago, IL, USA.
Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Bone. 2018 Sep;114:278-284. doi: 10.1016/j.bone.2018.06.024. Epub 2018 Jul 3.
Preclinical data suggest that hypoxia stimulates fibroblast growth factor 23 (FGF23) transcription and cleavage in osteocytes, resulting in elevated circulating c-terminal (cFGF23) levels but normal intact FGF23 (iFGF23) levels. We conducted a case-control study within the Hispanic Community Health Study/Study of Latinos to investigate whether sleep disordered breathing, as a model of hypoxemia, is independently associated with elevated cFGF23 levels in the general population and with elevated cFGF23 and iFGF23 levels in patients with chronic kidney disease (CKD), in whom FGF23 cleavage may be impaired. Cases (n = 602) had severe sleep disordered breathing defined as an apnea/hypopnea index (AHI) of ≥30. Controls without severe sleep disordered breathing (n = 602) were matched for sex and CKD stage. The median AHI in the cases was 45.8 (IQR 35.5-62.5) compared to 2.6 (IQR 0.6-8.2) in the controls. Cases had higher cFGF23 levels than controls (66.2 RU/mL, IQR 52.8-98.4 vs. 61.2 RU/mL, IQR 49.5-80.1, p value <0.001). There were no differences in iFGF23 levels between cases and controls. In adjusted linear regression and multinomial regression analyses, body mass index attenuated the relationship between severe sleep disordered breathing and cFGF23 levels. No significant relationships were seen in analyses of severe sleep disordered breathing and iFGF23 levels or in analyses of iFGF23 and cFGF23 stratified by CKD status. Additional studies using other models of intermittent and chronic hypoxia are needed to confirm whether hypoxia stimulates FGF23 transcription in humans and to determine the impact on iFGF23 levels in CKD.
临床前数据表明，缺氧会刺激成骨细胞中纤维母细胞生长因子 23（FGF23）的转录和裂解，导致循环中 C 端（cFGF23）水平升高，但完整的 FGF23（iFGF23）水平正常。我们在西班牙裔社区健康研究/拉丁裔研究中进行了一项病例对照研究，以调查睡眠呼吸障碍（作为低氧血症的模型）是否与一般人群中 cFGF23 水平升高以及慢性肾脏病（CKD）患者中 cFGF23 和 iFGF23 水平升高独立相关，在这些患者中，FGF23 的裂解可能受损。病例（n=602）的睡眠呼吸障碍严重，定义为呼吸暂停/低通气指数（AHI）≥30。没有严重睡眠呼吸障碍的对照组（n=602）按性别和 CKD 分期匹配。病例组的中位数 AHI 为 45.8（IQR 35.5-62.5），对照组为 2.6（IQR 0.6-8.2）。病例组的 cFGF23 水平高于对照组（66.2 RU/mL，IQR 52.8-98.4 vs. 61.2 RU/mL，IQR 49.5-80.1，p 值<0.001）。病例组和对照组之间 iFGF23 水平没有差异。在调整后的线性回归和多项回归分析中，体重指数减弱了严重睡眠呼吸障碍与 cFGF23 水平之间的关系。在严重睡眠呼吸障碍与 iFGF23 水平之间的分析中，或在根据 CKD 状态对 iFGF23 和 cFGF23 进行分层的分析中，均未观察到显著关系。需要使用其他间歇性和慢性缺氧模型进行进一步研究，以证实缺氧是否刺激人类 FGF23 的转录，并确定其对 CKD 中 iFGF23 水平的影响。
