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      Endothelin Blockade in Diabetic Kidney Disease

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          Abstract

          Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin-angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET-1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ET A) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors (ET A and ET B) within the kidney, as well as the ET-1 functions through them. In addition, we summarize the therapeutic benefit of endothelin receptor antagonists in experimental and human studies and the adverse effects that have been described.

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          Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.

          Nazzareno Galiè, Horst Olschewski, Ronald Oudiz … (2008)
          Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P 3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.
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            Avosentan for overt diabetic nephropathy.

            Giancarlo Viberti, Johannes Mann, Susan Kuranoff … (2010)
            In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.
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              The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes.

              Takashi A. Inoue, M Yanagisawa, Shigeo S. Kimura … (1989)
              Article 0 comments Cited 110 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Juan F. Navarro-González: Role: Academic Editor
                Desirée Luis: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): J Clin Med
                Journal ID (iso-abbrev): J Clin Med
                Journal ID (publisher-id): jcm
                Title: Journal of Clinical Medicine
                Publisher: MDPI
                ISSN (Electronic): 2077-0383
                Publication date (Electronic): 25 May 2015
                Publication date Collection: June 2015
                Volume: 4
                Issue: 6
                Pages: 1171-1192
                Affiliations
                [1 ]Department of Nephrology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Institute), 88 Dr. Aiguader Street, Barcelona, 08003, Spain; E-Mails: languiano@ 123456imim.es (L.A.); mriera1@ 123456imim.es (M.R.); JPascualSantos@ 123456parcdesalutmar.cat (J.P.)
                [2 ]Red de Investigación Renal (REDINREN), Instituto Carlos III-FEDER, Madrid 28029, Spain
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: msoler@ 123456parcdesalutmar.cat ; Tel.: +34932483162; Fax: +34932483373.
                Article
                Publisher ID: jcm-04-01171
                DOI: 10.3390/jcm4061171
                PMC ID: 4484993
                PubMed ID: 26239552
                SO-VID: 9b15ea3f-aad9-4522-abb0-99a783469915
                Copyright © © 2015 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 31 March 2015
                Date accepted : 18 May 2015
                Categories
                Subject: Review

                Keywords: diabetic kidney disease (dkd),endothelin-1 (et-1),endothelin a receptor (eta receptor),endothelin b receptor (etb receptor),endothelin receptor antagonists
                Data availability:
                Keywords: diabetic kidney disease (dkd), endothelin-1 (et-1), endothelin a receptor (eta receptor), endothelin b receptor (etb receptor), endothelin receptor antagonists

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