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

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: www.clinicaltrials.gov unique identifier: nct00810732. © 2015 the authors. published on behalf of the american heart association,inc.,by wiley blackwell.