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.