Supplementary Material for: Endothelin-1 and cardio-kidney events among patients with CKD, diabetes, and anemia

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor and is implicated in the pathogenesis of proteinuria and progressive chronic kidney disease (CKD). With the development of ET-1 receptor antagonists, there is interest in whether higher ET-1 concentrations are associated with a greater risk of adverse cardio-kidney events among high-risk patients, e.g., those with established chronic kidney disease (CKD) and type 2 diabetes (T2DM). Methods: Endothelin-1 concentrations were measured in a random subset of TREAT (n=997 (25%) of the original 4,038 patients with CKD, T2DM, and anemia) using an automated ELISA assay on the Ella analyzer (ProteinSimple). We used unadjusted and adjusted Cox regression models to explore the association of baseline serum ET-1 (log-transformed and quartiles) with kidney events (composite of kidney failure or doubling of serum creatinine), heart failure, and cardiovascular and all-cause death. Results: At baseline, mean age was 67 10 years and 56% were female. The mean eGFR was 34 11 mL/min/1.73 m2; median urine protein/creatinine ratio was 0.4 [0.1, 1.7] g/g; median ET-1 was 2.4 [1.9, 3.0] pg/mL. During a median follow-up of 2.4 years, there were 225 kidney events, 99 heart failure (HF) events, 124 cardiovascular deaths, and 188 all-cause deaths. Each log-unit higher ET1 was associated with a higher adjusted risk of the kidney composite (HR 1.61; 95%CI 1.08, 2.39), HF (HR 2.61; 95%CI 1.42, 4.81), but not with cardiovascular death (HR 1.06; 95%CI 0.65, 1.75) or all-cause death (HR 1.33; 95%CI 0.86, 2.04). Compared with the lowest quartile, categorical analyses suggested a higher risk of kidney events (HR 1.69; 95%CI 1.08, 2.64), HF events (HR 2.35; 95%CI 1.16, 4.80), and all-cause death (HR 1.81; 95%CI 1.09, 3.00) for the highest quartile of ET-1. Conclusions: Among patients with established CKD, T2DM, and anemia, higher baseline ET-1 was associated with a higher subsequent risk of kidney outcomes, HF events, and all-cause death. Whether higher ET-1 predicts responsiveness to ET-receptor antagonism warrants further investigation.

背景：内皮素-1（Endothelin-1, ET-1）是一种强效血管收缩剂，与蛋白尿及进展性慢性肾脏病（chronic kidney disease, CKD）的发病机制密切相关。随着内皮素-1受体拮抗剂的研发，学界开始关注高危患者（例如已确诊慢性肾脏病（CKD）合并2型糖尿病（type 2 diabetes, T2DM）中，更高的ET-1浓度是否与更高的不良心肾事件风险相关。
方法：本研究采用Ella分析仪（ProteinSimple公司）的自动化酶联免疫吸附试验（enzyme-linked immunosorbent assay, ELISA），对TREAT试验的随机亚组患者（原队列中共4038名CKD、T2DM合并贫血的患者中的997名（占比25%）进行了血清ET-1浓度检测。本研究采用未校正与校正的Cox回归模型，探讨基线血清ET-1（经对数转换并按四分位数分组）与肾脏复合终点（肾衰竭或血清肌酐翻倍）、心力衰竭事件、心血管死亡及全因死亡的关联。
结果：基线时，受试者平均年龄为67±10岁，其中56%为女性；平均估算肾小球滤过率（estimated glomerular filtration rate, eGFR）为34±11 mL/min/1.73 m²；尿蛋白/肌酐比值中位数为0.4 [四分位距0.1, 1.7] g/g；血清ET-1中位数为2.4 [四分位距1.9, 3.0] pg/mL。中位随访2.4年期间，共发生225例肾脏事件、99例心力衰竭（HF）事件、124例心血管死亡及188例全因死亡。每升高1个对数单位的ET-1水平与校正后的肾脏复合终点风险升高相关（风险比（hazard ratio, HR）1.61；95%置信区间（confidence interval, CI）1.08, 2.39）、心力衰竭风险升高（HR 2.61；95%CI 1.42, 4.81），但与心血管死亡（HR 1.06；95%CI 0.65, 1.75）或全因死亡（HR 1.33；95%CI 0.86, 2.04）无显著关联。与最低四分位数组相比，分类分析显示，ET-1最高四分位数组的肾脏事件风险（HR 1.69；95%CI 1.08, 2.64）、心力衰竭事件风险（HR 2.35；95%CI 1.16, 4.80）及全因死亡风险（HR 1.81；95%CI 1.09, 3.00）均显著升高。
结论：在已确诊CKD、T2DM合并贫血的患者中，基线更高的ET-1水平与后续更高的肾脏结局、心力衰竭事件及全因死亡风险相关。更高的ET-1水平能否预测内皮素-1受体拮抗剂的治疗反应性，仍需进一步开展研究。