Plasma pro-endothelin-1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism

J Am Heart Assoc. 2015 Mar 23;4(3):e001624. doi: 10.1161/JAHA.114.001624.


Background: Endothelin 1 (ET-1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET-1 peptides, endothelin-like domain peptide (ELDP) and C-terminal pro-ET-1 (CT-proET-1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists.

Methods and results: We assessed plasma and urine ELDP and plasma CT-proET-1 in CKD patients with minimal comorbidity. Next, in a randomized double-blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT-proET-1 increased with CKD stage (both P<0.0001), correlating inversely with estimated glomerular filtration rate (both P<0.0001). Following intervention, placebo and nifedipine did not affect plasma and urine ELDP or plasma CT-proET-1. Sitaxentan increased both plasma ELDP and CT-proET-1 (baseline versus week 6±SEM: ELDP, 11.8±0.5 versus 13.4±0.6 fmol/mL; CT-proET-1, 20.5±1.2 versus 23.3±1.5 fmol/mL; both P<0.0001). Plasma ET-1 was unaffected by any treatment. Following sitaxentan, plasma ELDP and CT-proET-1 correlated negatively with 24-hour urinary sodium excretion.

Conclusions: ELDP and CT-proET-1 increase in CKD and thus are potentially useful biomarkers of renal injury. Increases in response to endothelin A antagonism may reflect EDN1 upregulation, which may partly explain fluid retention with these agents.

Clinical trial registration: URL: Unique identifier: NCT00810732.

Keywords: CKD; antagonists; endothelin; fluid retention.

Publication types

  • Observational Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / blood
  • Biomarkers / urine
  • Blood Pressure / drug effects
  • Calcium Channel Blockers / adverse effects
  • Calcium Channel Blockers / therapeutic use
  • Cross-Over Studies
  • Double-Blind Method
  • Endothelin A Receptor Antagonists / therapeutic use*
  • Endothelin-1 / blood*
  • Endothelin-1 / urine
  • Female
  • Humans
  • Isoxazoles / adverse effects
  • Isoxazoles / therapeutic use*
  • Male
  • Middle Aged
  • Nifedipine / therapeutic use
  • Protein Precursors / blood*
  • Protein Precursors / urine
  • Proteinuria / blood
  • Proteinuria / drug therapy
  • Receptor, Endothelin A / drug effects*
  • Receptor, Endothelin A / metabolism
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / diagnosis
  • Renal Insufficiency, Chronic / drug therapy*
  • Renal Insufficiency, Chronic / physiopathology
  • Scotland
  • Thiophenes / adverse effects
  • Thiophenes / therapeutic use*
  • Time Factors
  • Treatment Outcome
  • Up-Regulation
  • Vascular Stiffness / drug effects


  • Biomarkers
  • Calcium Channel Blockers
  • Endothelin A Receptor Antagonists
  • Endothelin-1
  • Isoxazoles
  • Protein Precursors
  • Receptor, Endothelin A
  • Thiophenes
  • proendothelin 1
  • Nifedipine
  • sitaxsentan

Associated data