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Randomized Controlled Trial
. 2015 Mar 23;4(3):e001624.
doi: 10.1161/JAHA.114.001624.

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

Neeraj Dhaun  1 , Jale Yuzugulen  2 , Robert A Kimmitt  3 , Elizabeth G Wood  2 , Pajaree Chariyavilaskul  3 , Iain M MacIntyre  3 , Jane Goddard  4 , David J Webb  3 , Roger Corder  2
Affiliations
Randomized Controlled Trial

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

Neeraj Dhaun et al. J Am Heart Assoc. .

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.

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.

Keywords: CKD; antagonists; endothelin; fluid retention.

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Figures

Figure 1.
Figure 1.
Schematic outline of the amino acid structure of preproET‐1 indicating the peptides generated by post‐translational processing. Positions of ELDP (preproET‐1[93–166]) and CT‐proET‐1 (preproET‐1[169–212]) are shown. ET‐1 is produced from big ET‐1 by endothelin‐converting enzyme. CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide; ET‐1, endothelin 1; preproET‐1, prepro‐endothelin‐1.
Figure 2.
Figure 2.
Plasma ELDP (A) and CT‐proET‐1 (C) by stage of CKD and relationship between plasma ELPD (B) and CT‐proET‐1 (D) and eGFR. *P<0.001, **P<0.0001 compared with non‐CKD control subjects (stage 0). For correlation between plasma ELDP and eGFR, r=0.51, P<0.0001. For correlation between plasma CT‐proET‐1 and eGFR, r=0.54, P<0.0001. CKD indicates chronic kidney disease; CT‐proET‐1, C‐terminal pro‐endothelin‐1; eGFR, estimated glomerular filtration rate; ELDP, endothelin‐like domain peptide.
Figure 3.
Figure 3.
Urine ELDP by stage of CKD (A) and relationship between urine ELPD and eGFR (B). CKD indicates chronic kidney disease; eGFR, estimated glomerular filtration rate; ELDP, endothelin‐like domain peptide.
Figure 4.
Figure 4.
Correlation of plasma ELDP with CT‐proET‐1 (r=0.63, P<0.0001). CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide.
Figure 5.
Figure 5.
Percentage change from baseline in plasma ELDP (A) and plasma CT‐proET‐1 (B) following 3 and 6 weeks of treatment with placebo (open bar), sitaxentan (dark grey bar), and nifedipine (light grey bar) (mean±SEM, *P<0.0001 for sitaxentan at 3 or 6 weeks vs baseline). CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide.
Figure 6.
Figure 6.
Relationships between plasma ELDP (A) and plasma CT‐proET‐1 (B) and urine sodium excretion following 6 weeks of treatment with sitaxentan. CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide.
Figure 7.
Figure 7.
Relationships between plasma ELDP and plasma CT‐proET‐1 and urine sodium excretion following 6 weeks treatment with placebo (A and B) and nifedipine (C and D). CT‐proET‐1 indicates C‐terminal pro‐endothelin‐1; ELDP, endothelin‐like domain peptide.
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