Supplementary Material for: Change in Hemoglobin Trajectory and Darbepoetin Dose Approaching End-Stage Renal Disease: Data from the Trial to Reduce Cardiovascular Events with Aranesp Therapy Trial

Background: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). Methods: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD. Results: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI –1.26 to –1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 μg/L and 20%, respectively. Conclusions: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1–2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP.

背景：慢性肾脏病相关性贫血的发病机制呈多因素性，涵盖促红细胞生成素（erythropoietin, EPO）生成减少、铁缺乏、炎症反应及EPO抵抗。为深入明晰上述指标的变化轨迹，本研究对阿瑞司普（Aranesp）治疗降低心血管事件试验（Trial to Reduce cardiovascular Events with Aranesp Therapy, TREAT）中受试者的血红蛋白（hemoglobin, Hb）、铁蛋白、转铁蛋白饱和度、C反应蛋白（C-reactive protein, CRP）及达依泊汀给药剂量的时间趋势进行了描述。
方法：本研究对TREAT试验的4038名受试者开展事后分析。采用混合效应线性回归模型，明确终末期肾脏病（end-stage renal disease, ESRD）发生前目标指标的变化轨迹；借助似然比检验，对比发生与未发生ESRD受试者的生物标志物水平总体差异及轨迹差异。
结果：无论治疗分组如何，发生ESRD的受试者在确诊前1年内，其Hb水平均出现急剧下降；在ESRD确诊/随访结束时，发生ESRD受试者的Hb平均水平较未发生者低1.15 g/dL（95%置信区间：-1.26 ~ -1.04）。与此同时，受试者的平均达依泊汀给药剂量及CRP浓度均呈升高趋势，而血清铁蛋白与转铁蛋白饱和度分别高于140 μg/L及20%。
结论：本研究的分析结果为TREAT试验受试者在ESRD临近阶段时，Hb水平、达依泊汀给药剂量及相关指标的动态变化提供了描述性见解。Hb水平可在ESRD发生前1~2年即出现下降，且无铁缺乏的生化证据；尽管给予递增剂量的达依泊汀，最急剧的Hb下降仍发生于ESRD确诊前的数月内，且这一变化与CRP水平升高同步出现。