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      Endothelin and Endothelin Antagonists in Chronic Kidney Disease

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      Author(s): 1 , 2
      Publication date (Electronic):
      Journal: Kidney international

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          Abstract

          The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, while clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and non-diabetic CKD patients even on top of maximal renin angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.

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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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            Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.

            Ashutosh Mahajan, Jan Simoni, Simon Sheather … (2010)
            In most patients with hypertensive nephropathy and low glomerular filtration rate (GFR), the kidney function progressively declines despite the adequate control of the hypertension with angiotensin-converting enzyme inhibition. Previously we found that 2 years of oral sodium citrate slowed GFR decline in patients whose estimated GFR (eGFR) was very low (mean 33 ml/min). This treatment also slowed GFR decline in an animal model of surgically reduced nephron mass. Here, we tested if daily oral sodium bicarbonate slowed GFR decline in patients with hypertensive nephropathy with reduced but relatively preserved eGFR (mean 75 ml/min) in a 5-year, prospective, randomized, placebo-controlled, and blinded interventional study. Patients matched for age, ethnicity, albuminuria, and eGFR received daily placebo or equimolar sodium chloride or bicarbonate while maintaining antihypertensive regimens (including angiotensin-converting enzyme inhibition) aiming for their recommended blood pressure targets. After 5 years, the rate of eGFR decline, estimated using plasma cystatin C, was slower and eGFR was higher in patients given sodium bicarbonate than in those given placebo or sodium chloride. Thus, our study shows that in hypertensive nephropathy, daily sodium bicarbonate is an effective kidney protective adjunct to blood pressure control along with angiotensin-converting enzyme inhibition.
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              Regulation of blood pressure and salt homeostasis by endothelin.

              Donald Kohan, Marcelo Rossi, Edward W. Inscho … (2010)
              Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0323470
                Journal ID (pubmed-jr-id): 5428
                Journal ID (nlm-ta): Kidney Int
                Journal ID (iso-abbrev): Kidney Int.
                Title: Kidney international
                ISSN (Print): 0085-2538
                ISSN (Electronic): 1523-1755
                Publication date Nihms-submitted: 15 May 2014
                Publication date (Electronic): 07 May 2014
                Publication date (Print): November 2014
                Publication date PMC-release: 01 May 2015
                Volume: 86
                Issue: 5
                Pages: 896-904
                Affiliations
                [1 ]Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT
                [2 ]Molecular Internal Medicine, University of Zürich, 8057 Zürich, Switzerland
                Author notes
                Address for correspondence: Donald E. Kohan, M.D., Ph.D., Division of Nephrology, University of Utah Health Sciences Center, 1900 East, 30 North, Salt Lake City, UT 84132 23, Tel: +1 801 581 2726, Fax: +1 801 581 4343, donald.kohan@ 123456hsc.utah.edu or Matthias Barton, M.D., Molecular Internal Medicine, University of Zurich, LTK Y44 G22, Winterthurerstrasse 190, CH 8057 Zurich, Switzerland, Tel: +41 77 439 554, Fax: +41 44 635 6975, barton@ 123456access.uzh.ch
                Article
                Manuscript ID: NIHMS581486
                DOI: 10.1038/ki.2014.143
                PMC ID: 4216619
                PubMed ID: 24805108
                SO-VID: 46db3b08-5e70-41b8-b202-6fc5e5e60897
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                Subject: Article

                ScienceOpen disciplines: Nephrology
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                ScienceOpen disciplines: Nephrology

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