Endothelin Receptor Antagonists in Diabetic Nephropathy

René R Wenzel, Eberhard Ritz, Maximilian Q Wenzel
European Endocrinology, 2012;8(1):32-5

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and affects an estimated 150 million people worldwide. Despite optimal treatment, including glycaemic control and antihypertensive therapy (e.g., renin–angiotensin–aldosterone system [RAS] blockade), the disease progresses. A ‘late escape’ phenomenon has been described, where proteinuria reappears despite continued RAS blockade. The endothelin (ET) system is strongly involved in the pathophysiology of the disease and contributes to vasoconstriction, inflammation and proliferation. ET antagonists are promising drugs that potently slow down disease progression in animal models and have beneficial effects on cardiac structure, mitochondrial damage and microvascular architecture. However, the available ET antagonists, at least in higher doses, may also inhibit tubular endothelin receptors subtype B, which promote sodium and water excretion. The three clinical trials with avosentan and atrasentan published so far show the unique nephroprotective effects of these drugs, with a reduction of up to 45 % in albuminuria. However, fluid retention, oedema and, in higher stages of chronic kidney disease, heart failure limit their use. The reason may be that we have been using too high doses of these ET antagonists so far and they are inhibiting tubular sodium and water excretion. Thus, we will need to learn more about the role of ET and its antagonists in the tubular and collecting duct system, and on how to use these potent drugs in DN. ET antagonists are among the most promising molecules for the treatment of nephropathies. We should definitely not abandon these drugs because of the initial drawbacks in the first clinical trials.

Keywords: Endothelin antagonist, diabetic nephropathy, albuminuria, avosentan, atrasentan, renal failure, nephroprotection
Disclosure: René R Wenzel has received consultancy fees from Takeda, Menarini, Speedel Pharma, Actelion, Abbott and Novartis. Eberhard Ritz has received consultancy fees from Abbott, Daiichi Sankyo, Boehringer Ingelheim and Hexal. Maximilian Q Wenzel has no conflicts of interest to declare.
Received: December 21, 2011 Accepted January 16, 2012 Citation European Endocrinology, 2012;8(1):32-5
Correspondence: René R Wenzel, Head, Department of Internal Medicine, Teaching Hospital of the Paracelsus University Salzburg, Paracelsusstr. 8, A-5700 Zell am See,Austria. E: rene@rrwenzel.at
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Diabetic nephropathy (DN) was discovered by the British physician Clifford Wilson (1906–1997) and the German-born American physician Paul Kimmelstiel (1900–1970). Their first publication reporting the disease came out in 1936.1 Overt nephropathy secondary to glomerular disease usually occurs 15–25 years after the diagnosis of diabetes. In the past, it affected 25–35 % of type 1 diabetic patients under the age of 30 years, but the prognosis of these patients has recently improved.2 The main issue today is type 2 diabetes. Approximately 2 % of type 2 diabetic patients develop both macroalbuminuria and end-stage kidney disease.3 Nephropathy in type 2 diabetes has become the most common cause of chronic kidney failure and end-stage kidney disease in the world. Approximately 50 % of patients admitted for renal replacement therapy have type 2 diabetes. The progressive increase seen in the past has stabilised in recent years at this high level. The basic problem is the high prevalence of type 2 diabetes in the developed world. The International Diabetes Federation predicts an 75 % increase in the worldwide incidence of diabetes. This would mean that, by 2025, 324 million people would be diabetic. Thus, the expected number of DN cases is huge.

Optimal treatment of diabetes, especially glycaemic and blood pressure control, have markedly improved renal prognosis in the past decade. Any antihypertensive therapy reduces renal damage and delays the decline of glomerular filtration rate (GFR).4 Due to the progressive nature of DN, treating the disease is challenging. Current first-line therapies include lowering of blood pressure plus blockade of the renin–angiotensin–aldosterone system (RAS) with angiotensin converting enzyme (ACE)-inhibitors and/or angiotensin receptor blockers (ARBs). These treatments reduce proteinuria and delay the time to end-stage renal disease (ESRD) in patients with type 1 and type 2 diabetic nephropathy.4–8 However, the therapeutic efficacy of this approach is limited and suboptimal.9 Of particular concern is the phenomenon of ‘late escape’, i.e., the recurrence of proteinuria despite continued RAS blockade.5 But the most pressing problems are the incomplete reduction of proteinuria and the failure to completely block GFR loss, warranting additional interventional strategies. In this context, an activated endothelin (ET) system may contribute to the progression of DN.5

Role of the Endothelin System in Diabetic Nephropathy
ET was first described in 1988 by Yanagisawa et al. and is the most potent vasoconstrictor known.6 However, several other effects of ET have been discovered, including the stimulation of vascular and myocardial growth and inflammation.7, 8 The initial stages of DN involve subtle morphologic changes in the renal glomeruli, with progression to microalbuminuria, macroalbuminuria and, ultimately, ESRD.9

The ET system plays an important role in the pathophysiology, not only of cardiovascular disease but also of renal disease.8,10 ET-1 regulates a number of renal functions11 and causes proteinuria by several different mechanisms.12,13 In the kidney, both the endothelin receptors subtype A (ETAs) and the endothelin receptors subtype B (ETBs) are present but differ in their their place and function: the ETA is mainly present in the renal vasculature, whereas the ETB predominates in the tubule-interstitium, the endothelium and the mesangium.14 ET-1 promotes growth and inflammation at the level of the kidney and regulates sodium and water retention as well as acid secretion (see below). It is interesting to note that mesangial cells can rapidly release ET-1 in response to injuries including hypoxia, hypertension and high glucose concentrations.15

References:
  1. Kimmelstiel P, Wilson C, Benign and malignant hypertension and nephrosclerosis: a clinical and pathological study, Am J Pathol, 1936;12:45–82.3
  2. Orchard TJ, Dorman JS, Maser RE, et al., Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II, Diabetes, 1990;39:1116–24.
  3. Adler AI, Stevens RJ, Manley SE, et al., Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64), Kidney Int, 2003;63:225–32.
  4. Wenzel RR, Renal protection in hypertensive patients: selection of antihypertensive therapy, Drugs, 2005;65(Suppl. 2):29–39.
  5. Wühl E, Trivelli A, Picca S, et al., Strict blood-pressure control and progression of renal failure in children, New Eng J Med, 2009;361:1639–50.
  6. Yanagisawa M, Kurihara H, Kimura S, et al., A novel potent vasoconstrictor peptide produced by vascular endothelial cells, Nature, 1988;332:411–5.
  7. Wenzel RR, Zbinden S, Noll G, et al., Endothelin-1 induces vasodilation in human skin by nociceptor fibres and release of nitric oxide, Br J Clin Pharmacol, 1998;45:441–6.
  8. Wenzel RR, Czyborra P, Lüscher T, Philipp T, Endothelin incardiovascular control: the role of endothelin antagonists, Curr Hypertens Rep, 1999;1:79–87.
  9. Adler AI, Managing diabetes: what to do about cardiovascular disease, Diabetes Res Clin Pract, 2003;61(Suppl. 1):S3–8.
  10. Wenzel RR, Role of angiotensin-1-receptor blockers in cardiorenal disease, Current Drug Therapy, 2006;1:47–54.
  11. Rubanyi GM, Polokoff MA, Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology, Pharmacol Rev, 1994;46:325–415.
  12. Chen S, Evans T, Deng D, et al., Hyperhexosemia induced functional and structural changes in the kidneys: role of endothelins, Nephron, 2002;90:86–94.
  13. Sorokin A, Kohan DE, Physiology and pathology of endothelin-1 in renal mesangium, Am J Physiol Renal Physiol, 2003;285:F579–89.
  14. Rebibou JM, He CJ, Delarue F, et al., Functional endothelin 1 receptors on human glomerular podocytes and mesangial cells, Nephrol Dial Transplant, 1992;7:288–92.
  15. Benz K, Amann K, Endothelin in diabetic renal disease, Contrib Nephrol, 2011;172:139–48.
  16. Wenzel RR, Czyborra P, Luscher T, Philipp T, Endothelin in cardiovascular control: the role of endothelin antagonists, Curr Hypertens Rep, 1999;1:79–87.
  17. Letizia C, Iannaccone A, Cerci S, et al., Circulating endothelin-1 in non-insulin-dependent diabetic patients with retinopathy, Horm Metab Res, 1997;29:247–51.
  18. Peppa-Patrikiou M, Dracopoulou M, Dacou-Voutetakis C, Urinary endothelin in adolescents and young adults with insulin-dependent diabetes mellitus: relation to urinary albumin, blood pressure, and other factors, Metabolism, 1998;47:1408–12.
  19. Hargrove GM, Dufresne J, Whiteside C, et al., Diabetes mellitus increases endothelin-1 gene transcription in rat kidney, Kidney Int, 2000;58:1534–45.
  20. Packer M, McMurray J, Massie BM, et al., Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study, J Card Fail, 2005;11:12–20.
  21. Kelland NF, Webb DJ, Clinical trials of endothelin antagonists in heart failure: a question of dose? Exp Biol Med (Maywood), 2006;231:696–9.
  22. Barst RJ, Gibbs JS, Ghofrani HA, et al., Updated evidencebased treatment algorithm in pulmonary arterial hypertension, J Am Coll Cardiol, 2009;54:S78–84.
  23. Gagliardini E, Corna D, Zoja C, et al., Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes, Am J Physiol Renal Physiol, 2009;297:F1448–56.
  24. Zoja C, Cattaneo S, Fiordaliso F, et al., Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes, Am J Physiol Renal Physiol, 2011;301:F1114–23.
  25. Ritz E, Wenzel R, Endothelin receptor antagonists in proteinuric renal disease: every rose has its thorn, J Am Soc Nephrol, 2010;21:392–4.
  26. Wenzel RR, Littke T, Kuranoff S, et al., SPP301 (Avosentan) Endothelin Antagonist Evaluation in Diabetic Nephropathy Study Investigators, Avosentan reduces albumin excretion in diabetics with macroalbuminuria, J Am Soc Nephrol, 2009;20:655–64.
  27. Mann JF, Green D, Jamerson K, et al., ASCEND Study Group, Avosentan for overt diabetic nephropathy, J Am Soc Nephrol, 2010;21:527–35.
  28. Kohan DE, Pritchett Y, Molitch M, et al., Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy, J Am Soc Nephrol, 2011;22:763–72.
  29. Kohan DE, Rossi NF, Inscho EW, Pollock DM, Regulation of blood pressure and salt homeostasis by endothelin, Physiol Rev, 2011;91(1):1–77.
  30. Smolander J, Vogt B, Maillard M, et al., Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects, Clin Pharmacol Ther, 2009;85:628–34.
  31. Ritz E, Wenzel RR, Endothelin antagonist as add-on treatment for proteinuria in diabetic nephropathy: is there light at the end of the tunnel? J Am Soc Nephrol, 2011;22:593–5.
  32. Moreau P, Takase H, Kung CF, et al., Blood pressure and vascular effects of endothelin blockade in chronic nitric oxide-deficient hypertension, Hypertension, 1997;29:763–9.
  33. Weber MA, Black H, Bakris G, et al., A selective endothelinreceptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial, Lancet, 2009;374:1423–31.
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