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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.