Supplementary Material for: Fibroblast growth factor 23, endogenous erythropoietin, erythropoiesis-stimulating agents, and erythropoietin resistance in hemodialysis patients

Introduction. Recent experimental studies have reported that fibroblast growth factor 23 (FGF23) inhibits erythropoiesis by suppressing erythropoietin (EPO) production and downregulating the EPO receptor. Conversely, either endogenous or exogenous EPO has been shown to stimulate FGF23 production. However, little is known about the relationships between FGF23, erythropoiesis-stimulating agent (ESA) treatment, ESA resistance, and endogenous EPO in hemodialysis patients. Methods. We analyzed cross-sectional data from a cohort of 654 maintenance hemodialysis patients. We examined the associations of intact or C-terminal FGF23 with ESA treatment, ESA resistance index (ERI), hemoglobin, C-reactive protein, and endogenous EPO levels using linear regression models. EPO was measured only in patients not receiving ESAs. Results. A total of 458 patients (70%) were treated with ESAs. The median EPO concentration in non-ESA users was 7.8 (interquartile range, 5.3-14.4) mIU/mL. The median levels of intact and C-terminal FGF23 were 1598 (interquartile range, 548-4586) pg/mL and 38.7 (interquartile range, 14.0-127.6) pmol/L, respectively, in non-ESA users and 1955 (interquartile range, 573-5264) pg/mL and 41.4 (interquartile range, 13.9-116.8) pmol/L, respectively, in ESA users. After adjustment for potential confounders, higher ESA dose was associated with higher FGF23 levels measured by both intact and C-terminal assays. Higher C-terminal FGF23 was also associated with higher ERI, lower hemoglobin, and higher endogenous EPO, but no such associations were observed for intact FGF23 levels. Conclusions. Both intact and C-terminal FGF23 showed similar associations with ESA dose, but they showed different patterns of association with other parameters related to anemia. Further research is needed to elucidate the mechanisms underlying these different associations.引言。近期多项实验研究表明，成纤维细胞生长因子23（fibroblast growth factor 23, FGF23）可通过抑制促红细胞生成素（erythropoietin, EPO）的产生并下调促红细胞生成素受体，从而抑制红细胞生成。反之，内源性或外源性促红细胞生成素均已被证实可促进成纤维细胞生长因子23的生成。然而，目前对于血液透析患者体内成纤维细胞生长因子23、促红细胞生成素类药物（erythropoiesis-stimulating agent, ESA）治疗、促红细胞生成素抵抗以及内源性促红细胞生成素之间的关联仍知之甚少。方法。本研究对654例维持性血液透析患者的队列横断面数据进行了分析。采用线性回归模型，探讨完整型或C端型成纤维细胞生长因子23与促红细胞生成素类药物治疗、促红细胞生成素抵抗指数（ESA resistance index, ERI）、血红蛋白、C反应蛋白以及内源性促红细胞生成素水平之间的关联。仅对未接受促红细胞生成素类药物治疗的患者检测了促红细胞生成素水平。结果。共计458例患者（占比70%）接受了促红细胞生成素类药物治疗。未使用促红细胞生成素类药物的患者中，促红细胞生成素浓度的中位数为7.8 mIU/mL（四分位间距：5.3~14.4）。未使用促红细胞生成素类药物的患者中，完整型成纤维细胞生长因子23的中位数水平为1598 pg/mL（四分位间距：548~4586），C端型成纤维细胞生长因子23的中位数水平为38.7 pmol/L（四分位间距：14.0~127.6）；而在使用促红细胞生成素类药物的患者中，二者的中位数水平分别为1955 pg/mL（四分位间距：573~5264）与41.4 pmol/L（四分位间距：13.9~116.8）。在校正潜在混杂因素后，更高的促红细胞生成素类药物剂量与通过完整型检测法、C端型检测法测得的更高成纤维细胞生长因子23水平均呈显著相关。更高的C端型成纤维细胞生长因子23水平还与更高的促红细胞生成素抵抗指数、更低的血红蛋白水平以及更高的内源性促红细胞生成素水平相关，但未观察到完整型成纤维细胞生长因子23水平存在此类关联。结论。完整型与C端型成纤维细胞生长因子23均与促红细胞生成素类药物剂量呈现相似的关联模式，但二者与贫血相关其他参数的关联模式却存在差异。未来仍需开展进一步研究以阐明这些不同关联背后的分子机制。