摘要

BACKGROUND:Emerging data in chronic kidney disease (CKD) patients suggest that iron deficiency and higher circulating levels of erythropoietin (EPO) stimulate the expression and concomitant cleavage of the osteocyte-derived, phosphate-regulating hormone fibroblast growth factor 23 (FGF23), a risk factor for premature mortality. To date, clinical implications of iron deficiency and high EPO levels in the general population, and the potential downstream role of FGF23, are unclear. Therefore, we aimed to determine the associations between iron deficiency and higher EPO levels with mortality, and the potential mediating role of FGF23, in a cohort of community-dwelling subjects. METHODS AND FINDINGS:We analyzed 6,544 community-dwelling subjects (age 53 ± 12 years; 50% males) who participated in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study-a prospective population-based cohort study, of which we used the second survey (2001-2003)-and follow-up was performed for a median of 8 years. We measured circulating parameters of iron status, EPO levels, and plasma total FGF23 levels. Our primary outcome was all-cause mortality. In multivariable linear regression analyses, ferritin (ß = -0.43), transferrin saturation (TSAT) (ß = -0.17), hepcidin (ß = -0.36), soluble transferrin receptor (sTfR; ß = 0.33), and EPO (ß = 0.28) were associated with FGF23 level, independent of potential confounders. During median (interquartile range [IQR]) follow-up of 8.2 (7.7-8.8) years, 379 (6%) subjects died. In multivariable Cox regression analyses, lower levels of TSAT (hazard ratio [HR] per 1 standard deviation [SD], 0.84; 95% confidence interval [CI], 0.75-0.95; P = 0.004) and higher levels of sTfR (HR, 1.15; 95% CI 1.03-1.28; P = 0.01), EPO (HR, 1.17; 95% CI 1.05-1.29; P = 0.004), and FGF23 (HR, 1.20; 95% CI 1.10-1.32; P < 0.001) were each significantly associated with an increased risk of death, independent of potential confounders. Adjustment for FGF23 levels markedly attenuated the associations of TSAT (HR, 0.89; 95% CI 0.78-1.01; P = 0.06), sTfR (HR, 1.08; 95% CI 0.96-1.20; P = 0.19), and EPO (HR, 1.10; 95% CI 0.99-1.22; P = 0.08) with mortality. FGF23 remained associated with mortality (HR, 1.15; 95% CI 1.04-1.27; P = 0.008) after adjustment for TSAT, sTfR, and EPO levels. Mediation analysis indicated that FGF23 explained 31% of the association between TSAT and mortality; similarly, FGF23 explained 32% of the association between sTfR and mortality and 48% of the association between EPO and mortality (indirect effect P < 0.05 for all analyses). The main limitations of this study were the observational study design and the absence of data on intact FGF23 (iFGF23), precluding us from discerning whether the current results are attributable to an increase in iFGF23 or in C-terminal FGF23 fragments. CONCLUSIONS AND RELEVANCE:In this study, we found that functional iron deficiency and higher EPO levels were each associated with an increased risk of death in the general population. Our findings suggest that FGF23 could be involved in the association between functional iron deficiency and increased EPO levels and death. Investigation of strategies aimed at correcting iron deficiency and reducing FGF23 levels is warranted.

译文

背景: 慢性肾脏疾病 (CKD) 患者的最新数据表明,铁缺乏和更高的促红细胞生成素循环水平刺激骨细胞来源的表达和伴随的分裂, 磷酸调节激素成纤维细胞生长因子 23 (FGF23),早逝的危险因素。迄今为止,一般人群中铁缺乏和高促红细胞生成素水平的临床意义以及 FGF23 的潜在下游作用尚不清楚。因此,我们的目的是确定在一个社区居住的受试者队列中,铁缺乏和较高的 EPO 水平与死亡率之间的关系,以及 FGF23 的潜在中介作用。方法和结果: 我们分析了 6,544 名社区居住的受试者 (年龄 53 ± 12 岁; 50% 名男性),他们参与了肾脏和血管终末期疾病的预防研究 -- 一项基于人群的前瞻性队列研究,我们使用了第二次调查 (2001-2003) -- 并进行了平均 8 年的随访。我们测量了铁状态、 EPO 水平和血浆总 FGF23 水平的循环参数。我们的主要结果是全因死亡率。在多变量线性回归分析中,铁蛋白 (ß =-0.43),转铁蛋白饱和度 (TSAT) (ß =-0.17),hepcidin (ß =-0.36),可溶性转铁蛋白受体 (sTfR; ß = 0.33),和 EPO (ß = 0.28) 与 FGF23 水平相关,独立于潜在的混杂因素。在 8.2 (7.7-8.8) 年的中位数 (四分位区间 [IQR]) 随访期间,379 (6%) 名受试者死亡。在多变量 Cox 回归分析中,较低水平的 TSAT (风险比 [HR] 每 1 标准偏差 [SD],0.84; 95% 置信区间 [CI],0.75-0.95; P = 0.004) 和更高水平的 sTfR (HR,1.15; 95% CI 1.03-1.28; P = 0.01),EPO (HR,1.17; 95% CI 1.05-1.29; P = 0.004),和 FGF23 (HR,1.20; 95% CI 1.10-1.32; P <0.001) 每一个都与死亡风险增加显著相关,独立于潜在的混杂因素。FGF23 水平的调整显著减弱了 TSAT (HR,0.89; 95% CI 0.78-1.01; P = 0.06),sTfR (HR,1.08; 95% CI 0.96-1.20; P = 0.19),以及促红细胞生成素 (HR,1.10; 95% CI 0.99-1.22; P = 0.08) 与死亡率。调整 TSAT 、 sTfR 和 EPO 水平后,FGF23 仍然与死亡率相关 (HR,1.15; 95% CI 1.04-1.27; P = 0.008)。调解分析表明 FGF23 解释了 31% 的 TSAT 和死亡率之间的联系; 同样, FGF23 解释了 sTfR 和死亡率之间 32% 的关联,以及促红细胞生成素和死亡率之间 48% 的关联 (所有分析的间接效应 P <0.05)。这项研究的主要局限性是观察性研究设计和完整的 FGF23 (iFGF23) 数据的缺失, 排除我们辨别当前结果是归因于 iFGF23 或 C 端 FGF23 片段的增加。结论和相关性: 在这项研究中,我们发现功能性铁缺乏和更高的促红细胞生成素水平都与普通人群死亡风险的增加有关。我们的研究结果表明,FGF23 可能参与功能性铁缺乏和促红细胞生成素水平升高与死亡之间的关联。研究旨在纠正铁缺乏和降低 FGF23 水平的策略是有必要的。

Erythropoietin (EPO)

肾内泌尿 蛋白激素 基础研究专业名词
概述  :  

红细胞生成素,或称促红细胞生成素,是一种由肾脏产生的糖蛋白激素。人类促红细胞生成素分子量为34 kDa,有4个糖基化位点。EPO通过与靶细胞上特异性的EPO受体(EPO-R)结合发挥生物效应。 传统认识中,EPO是一种作用于骨髓造血细胞,促进红系祖细胞增生、分化和成熟的内分泌激素,对机体供氧状况发挥重要的调控作用。随着近年来研究不断深入,对于EPO的认识产生了一次革命性的飞跃,EPO还可表现出非促红细胞生成作用。最近的研究认为EPO是一种由缺氧

Erythropoietin   英 /ɪ,rɪθrə(ʊ)pɒɪ'etɪn/   美 /ɪ,rɪθropɔɪ'itɪn/

释    义   n. (促)红细胞生成素

例    句   This invention relates to a solution preparation of recombinant human erythropoietin.本发明涉及一种重组人红细胞生成素的溶液制备方法。

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