Treatment of Chronic Proteinuric Kidney Disease

T he vascular endothelium synthesizes and releases a range of vasodilators and vasoconstrictors that have key roles in the local regulation of vascular tone.Among those, endothelin (ET) was identified in 1988 by Yanagisawa et al, 1 as one of the most potent vasoconstrictors known, and so far, the landmark discovery of ET has led to Ͼ22 000 publications.These have revealed that ET exerts its activity by binding to 2 types of receptors, namely, ET A and ET B , with the ET A mediating the majority of the deleterious effects of ET in the kidney, including vasoconstriction, cell proliferation, and fibrosis.ET is an important physiological regulator of blood pressure through its effects on blood vessels, heart, and kidneys, and the ET system can be overactive in disorders, eg, hypertension, heart failure, and renal disease. 2 Such observations have created much interest among researchers and have prompted pharmaceutical companies to set up high-throughput screens to search for antagonists of ET receptors.The initial observation in 1993 of a renoprotective effect of a selective ET A receptor antagonist in rats with renal mass reduction 3 was further confirmed by a large body of publications that consistently documented the involvement of ET in the process of progressive renal injury in experimental models of nondiabetic and diabetic proteinuric nephropathies. 4 Animal data also suggested that concomitant blockade of the renin-angiotensin system (RAS) and the ET system displayed more renoprotective effects than blockade of either system alone, 5 a synergism based on the interaction of angiotensin II (Ang II) and ET at the molecular level.Results in experimental animals led to great hope that such an approach could ameliorate the treatment of progressive renal diseases in humans.When control of blood pressure and proteinuria cannot be achieved by angiotensin-converting enzyme (ACE) inhibitors (ACEis) and/or Ang II receptor antagonists (ARBs), patients theoretically can benefit from combining one of these drugs with an ET receptor antagonist.However, there have actually been relatively few studies in humans so far.