Clinical Medicine Reviews in Vascular Health

Endothelin (ET) is an important modulator of renal function through its binding to ETA and ETB receptors in renal tissue. Various renal cells have the ability to synthesize and release endothelin-1 and elevated plasma and urinary endothelin levels have been measured in patients with chronic kidney diseases. Within the last 5 year, several studies have demonstrated that ET plays a role in the pathogenesis and progression of chronic kidney diseases and associated cardiovascular diseases. With this increasing evidence, several ET receptor antagonists have been developed, some of them being specifically investigated for their ability to provide renal protection in diabetic nephropathy. For this indication, a selective blockade of ETA receptors appears to be the preferred approach. Thus, recent clinical phase II and phase III studies have shown that ETA receptor blockers such as avosentan are able to lower proteinuria significantly in type 2 diabetic patients even on top of a full treatment with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, today, the clinical benefits of ET receptor antagonists appear to be limited by the development of fluid retention and peripheral edema which have been reported to occur with all antagonists, but more so with non-selective ET antagonists. Fluid retention, like headache, nausea and nasal congestion probably represent class side-effects. Nevertheless, provided a good equilibrium can be obtained between their clinical benefits and their tolerability profile, ET receptor blockers remain promising for the management of patients with chronic kidney diseases.