Supplementary Material for: Iron indices mediate but not modify association of parathyroid hormone with erythropoietin resistance in hemodialysis patients

Introduction: Disordered iron balance and abnormal parathyroid hormone (PTH) concentrations, both prevalent in hemodialysis patients, are risk factors of erythropoietin (EPO) resistance. Few studies have evaluated the correlation between iron indices and PTH and the potential role of iron markers on the association of PTH with EPO resistance in hemodialysis population. Methods: In this cross-sectional study of 71 maintenance hemodialysis patients, iron indices including hepcidin, ferritin, reticulocyte hemoglobin content (CHr) and transferrin saturation (TSAT) were examined. EPO responsiveness was measured as EPO resistance index (ERI). Lowess regression curves were performed to explore the cor-relations of iron indices, PTH and ERI. The association between PTH and ERI was modeled using linear regressions. Potential role of iron indices on this association was examined using stratified analyses and mediation analyses. Results: The average ERI value of 10.3 ± 5.3 IU w−1 kg−1 (g/dL) −1. ERI was linked to PTH, hepcidin, CHr and TSAT (all P<0.05). PTH was associated with ERI levels (β=0.007, 95%CI: 0.002-0.012, P=0.007). Hepcidin and PTH were closely correlated with each other (r = 0.28, P = 0.020). No clinically significant interaction between iron indexes and PTH was identified. Hepcidin appeared to mediate about one-fourth of the total association between PTH and ERI in hemodialysis population (25.71%, P=0.020). Conclusion: Iron indices and PTH levels were related to ERI values. Hepcidin ap-peared to be closely correlated to PTH and partly mediate the association between PTH and ERI in he-modialysis population.

引言：血液透析患者中普遍存在的铁代谢紊乱与甲状旁腺激素（parathyroid hormone, PTH）浓度异常，均为促红细胞生成素（erythropoietin, EPO）抵抗的危险因素。目前鲜有研究针对血液透析人群，探讨铁相关指标与甲状旁腺激素的相关性，以及铁标志物在甲状旁腺激素与促红细胞生成素抵抗关联中发挥的潜在作用。
方法：本研究纳入71例维持性血液透析患者开展横断面研究，检测了包括铁调素（hepcidin）、铁蛋白（ferritin）、网织红细胞血红蛋白含量（reticulocyte hemoglobin content, CHr）及转铁蛋白饱和度（transferrin saturation, TSAT）在内的多项铁相关指标。促红细胞生成素反应性以促红细胞生成素抵抗指数（EPO resistance index, ERI）进行量化。采用Lowess回归曲线分析铁相关指标、甲状旁腺激素与ERI的相关性；通过线性回归模型分析甲状旁腺激素与ERI的关联；并采用分层分析与中介分析，探讨铁相关指标在该关联中的潜在调控作用。
结果：本研究受试者的ERI平均水平为10.3 ± 5.3 IU·周⁻¹·千克⁻¹·(克/分升)⁻¹。ERI与甲状旁腺激素、铁调素、CHr及TSAT均存在显著统计学关联（均P<0.05）。甲状旁腺激素与ERI水平呈显著正相关（β=0.007，95%置信区间：0.002~0.012，P=0.007）。铁调素与甲状旁腺激素之间存在显著相关性（r=0.28，P=0.020）。未发现铁相关指标与甲状旁腺激素存在具有临床意义的交互作用。在血液透析人群中，铁调素可中介甲状旁腺激素与ERI总关联中约四分之一的效应（中介效应占比25.71%，P=0.020）。
结论：铁相关指标与甲状旁腺激素水平均与ERI水平相关。铁调素与甲状旁腺激素密切相关，并可部分中介血液透析人群中甲状旁腺激素与促红细胞生成素抵抗的关联。