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Diabetic Nephropathy


Endothelin Receptor Antagonists in Diabetic Nephropathy René R Wenzel,1


Eberhard Ritz2 and Maximilian Q Wenzel3


1. Head, Department of Internal Medicine, Teaching Hospital, Zell am See; 2. Professor Emeritus, Ruperto Carola University Heidelberg; 3. Medical Student, University of Vienna


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: 21 December 2011 Accepted: 16 January 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


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


32


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


therapeutic efficacy of this approach is limited and suboptimal.9


However, the 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 © TOUCH BRIEFINGS 2012


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