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Endothelin Receptor Antagonists in Diabetic Nephropathy 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 regulates a number of renal functions11 several different mechanisms.12,13


ET-1 and causes proteinuria by In the kidney, both the endothelin


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


In DN, the ET system is overactive, as indicated by the elevated plasma and urinary ET-1 levels found in patients.16


Increased plasma


ET-1 concentrations found in type 2 diabetes patients correlate with the severity and duration of diabetes.17,18


Importantly, in diabetic


patients with nephropathy, raised levels of ET-1 also correlate with reduced renal function, increased blood pressure and albuminuria.18 Insulin increases renal ET expression, which may be especially relevant in diabetics with insulin resistance in an earlier phase of the disease when higher insulin concentrations occur.19


Role of Endothelin Receptor Antagonists in Experimental Diabetic Nephropathy After the groundbreaking discovery of the endothelial-cell-derived vasopressor agent ET by Yanagisawa et al.,6


inhibitors of the ET


receptor were high on the priority list of the pharmaceutical industry. After various promising experimental trials, clinical studies in various pathologies with an assumed pathophysiological role of ET were conducted.20,21


Several other experimental trials have been published in the past decade, all of which suggest a nephroprotective effect of ET receptor antagonists alone and/or in combination with a blocker of the RAS.15 The question still remains whether such beneficial effects are mainly due and restricted to an antagonism at the level of the ETA. Indeed, stimulation of renal ETB may have beneficial effects via increased NO release and sodium excretion. Antagonists that block both ET receptors (so-called dual ET receptor antagonists) as well as very high doses of ET receptor antagonists with a lower selectivity for the ETA may therefore be disadvantageous. Unfortunately, the role of the ETB in kidney disease is unclear and it may counteract or contribute to renal damage.25


On the other hand, in one specific condition, i.e., pulmonary arterial hypertension, several clinical trials yielded positive results, leading to a well-defined indication for this class of drugs.22


Although several were disappointing, we increasingly learned from these trials – mainly from the side effects. In patients with heart failure, high doses of bosentan and darusentan were investigated. Although pulmonary and systemic haemodynamics were improved, the overall outcome was negative because of increases in morbidity and mortality, mainly due to volu me overload. As a result, the treatment of cardiovascular disease with ET receptor antagonists was abandoned.20,21


Role of Endothelin Receptor Antagonists in Clinical Diabetic Nephropathy


Encouraged by experimental data and by a promising pilot trial, we performed a multicentre study in more than 50 European centres (the SPEED II trial).26


Another attractive target was renal disease. The various renal effects of ET had led to the hypothesis that ET receptor antagonists were presumably renoprotective.16


Learning from the experiences in


pulmonary arterial hypertension, and in contrast to congestive heart failure, many investigators were convinced that renoprotection was provided not by the haemodynamic effects of ET receptor antagonists, but rather by their anti-inflammatory and antiproliferative effects. This led to several studies with the goal of protecting the kidney in diabetic and non-diabetic nephropathies.


Various studies have shown marked beneficial effects of ET receptor antagonists in animal models of diabetes and, although these models are limited in terms of their comparability with the human kidney, they still helped us understand the mechanisms of these beneficial effects.


EUROPEAN ENDOCRINOLOGY


The study population comprised 286 patients with DN (chronic kidney disease [CKD] stage II). The ETA-selective receptor antagonist avosentan was given at doses of 5, 10, 25 and 50 mg on top of RAS blockade (with ACE-inhibitors or ARBs) for 12 weeks and compared with placebo. The trial was supported by Speedel Pharma AG (Basel, Switzerland) and higher doses (i.e., 25 and 50 mg) were favoured, mainly based on haemodynamic effects and animal experiments. The primary endpoint, urinary albumin excretion rate (UAER), was dramatically reduced by up to 45 %. Unfortunately, at the higher doses of avosentan, oedema and fluid retention occurred in up to 26 % of patients. Furthermore, no further antiproteinuric effect could be shown with avosentan doses above 10 mg.26


A Phase III trial (the ASCEND study, ClinicalTrials.gov identifier NCT00120328) was performed, looking at more than 1,300 patients with DN, but with a more advanced stage of kidney disease – i.e., CKD stage IIIb.27


Despite the side effects with higher doses known from our preceding trial, the ASCEND study investigated 25 and 50 mg of avosentan over six months on top of RAS blockade and compared the effects with placebo. Again, there was a marked reduction in UAER of up to 49 %. After a median treatment period of four months, the


33


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


Among a great number of experiments, two experimental studies which had led to the hypothesis of renoprotection by ET blockade will be discussed in more detail here. In the trial by Gagliardini et al.,23 streptozotocin diabetic rats were uninephrectomised and treated with an ACE-inhibitor (lisinopril) and ETA-antagonist (avosentan), or both. Therapy with both lisinopril and avosentan normalised proteinuria, prevented tubulointerstitial damage and induced a regression of glomerular lesions. Interestingly, while only partial renoprotection was achieved by each drug alone, the two drugs, which both reduced proteinuria, affected different renal targets: lisinopril improved pathological glomerular size selectivity to large macromolecules, whereas avosentan ameliorated peritubular capillary architecture and reduced interstitial inflammation and fibrosis.23


In a recently published trial conducted by Zoja et al., Zucker diabetic fatty rats were treated orally with an ACE-inhibitor (ramipril), with an ETA-antagonist (sitaxsentan) or with both.24


In this setting, the


antiproteinuric effects could mainly be attributed to the ACE-inhibitor. However, the ETA-antagonist had important effects on cardiac structure, mitochondrial damage and microvascular architecture, mainly through blocking the effects of VEGF-1.


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