Endothelin-1 as dual marker for renal function decline and associated cardiovascular complications in patients with chronic kidney disease.

Abstract

Cardiovascular (CV) complications are the leading cause of death in patients with chronic kidney disease (CKD). Endothelin-1 (ET-1), a potent vasoconstrictor involved in both renal and vascular dysfunction, may represent a promising biomarker for the disease. ET-1 plasma levels were quantified in 692 Spanish CKD patients (stages 1-5) and used to stratify individuals into three clusters (cluster 3 meaning highest concentrations). Associations with CKD progression, CVE, and all-cause mortality were assessed over a mean follow-up of 48.6 ± 27.4 months using linear mixed-effects models and Cox regression analyses adjusted for conventional risk factors. ET-1 levels increased with CKD severity (mean±SD: 1.65 ± 0.71 pg/mL for stages 1-2; 1.82 ± 0.71 pg/mL for stage 3; 2.39 ± 1.08 pg/mL for stages 4-5; p < 0.001). Higher ET-1 levels were independently associated with accelerated eGFR decline over 3 years (β = -12.64, p < 0.001 for cluster 2; and β = -11.71, p = 0.034 for cluster 3). Sixty-nine CVE (10.1 %) were recorded. Participants with higher ET-1 levels had significantly lower CV event-free survival [HR = 2.24 (1.12-4.45), p = 0.022, and HR = 2.50 (1.09-5.73), p = 0.03] for clusters 2 and 3, respectively. ET-1 also predicted all-cause mortality (p < 0.001) although the association lost significance after adjusting for age. Random forest models for CV risk and all-cause mortality including the ET-1 cluster produced C-indices of 0.835 and 0.837, respectively. Elevated ET-1 levels are independently associated with both CKD progression and CV complications. ET-1 may serve as a dual biomarker for renal deterioration and CV risk, potentially improving clinical stratification in CKD management.