title: Plasma pro-endothelin-1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism.
abstract: 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.
  
  
  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.
  
  
  BACKGROUND
  URL: www.clinicalTrials.gov Unique identifier: NCT00810732.
authors: BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.) Department of Renal Medicine, Royal Infirmary of Edinburgh, UK (N.D., J.G.).
authors: Neeraj
authors: N
authors: Dhaun
authors: William Harvey Research Institute, Barts & the London School of Medicine, Queen Mary University of London, UK (J.Y., E.G.W., R.C.).
authors: Jale
authors: J
authors: Yuzugulen
authors: BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.).
authors: Robert A
authors: RA
authors: Kimmitt
authors: William Harvey Research Institute, Barts & the London School of Medicine, Queen Mary University of London, UK (J.Y., E.G.W., R.C.).
authors: Elizabeth G
authors: EG
authors: Wood
authors: BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.).
authors: Pajaree
authors: P
authors: Chariyavilaskul
authors: BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.).
authors: Iain M
authors: IM
authors: MacIntyre
authors: Department of Renal Medicine, Royal Infirmary of Edinburgh, UK (N.D., J.G.).
authors: Jane
authors: J
authors: Goddard
authors: BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.).
authors: David J
authors: DJ
authors: Webb
authors: William Harvey Research Institute, Barts & the London School of Medicine, Queen Mary University of London, UK (J.Y., E.G.W., R.C.).
authors: Roger
authors: R
authors: Corder
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000097:blood* / Q000652:urine; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009543:Nifedipine / Q000627:therapeutic use; D011498:Protein Precursors / Q000097:blood* / Q000652:urine; D011507:Proteinuria / Q000097:blood / Q000188:drug therapy; D044022:Receptor, Endothelin A / Q000187:drug effects* / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D012606:Scotland; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D059289:Vascular Stiffness / Q000187:drug effects
chemical_list: D015415:Biomarkers; D002121:Calcium Channel Blockers; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D013876:Thiophenes; C093240:proendothelin 1; D009543:Nifedipine; C106276:sitaxsentan
keywords: CKD; antagonists; endothelin; fluid retention