Treatment of chronic proteinuric kidney disease: what next?

The 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 22 000 publications. These have revealed that ET exerts its activity by binding to 2 types of receptors, namely, ETA and ETB, with the ETA 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 ETA receptor antagonist in rats with renal mass reduction3 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. The interesting article by Dhaun et al6 in the present issue of Hypertension suggests the ETA receptor antagonist as a candidate drug in a multipharmacological strategy to promote renoprotection. They found in an acute study that administration of ETA receptor antagonist BQ123, on top of maximally tolerated treatment with ACEis or ARBs, further reduced blood pressure and proteinuria and increased renal blood flow in patients with stable proteinuric nondiabetic chronic kidney disease. Arterial hypertension is a major determinant of renal disease progression, and lowering the blood pressure has become the main strategy for nephroprotection in patients with chronic kidney disease. In addition to arterial hypertension, increased urinary protein excretion is another important factor associated with the tendency of renal function to decline over time with heavy proteinuria ( 3 g per 24 hours) invariably predicting the progression to end stage kidney disease and cardiovascular events. Proteinuria does not simply reflect glomerular injury, but it is itself harmful.7 The injury of the tubular epithelium and the protein overload of proximal tubular cells as a consequence of the increased glomerular permeability of proteins in the setting of glomerular disease activate intracellular signals that cause increased production of vasoactive, inflammatory mediators and growth factors, including ET-1. These substances are released into the interstitium and promote the local recruitment of inflammatory cells, in turn stimulated to release cytokines/chemokines and growth factors7 and to produce extracellular matrix collagen and fibronectin that are responsible for interstitial fibrosis.7 Studies in patients with chronic kidney disease have shown that, other than their effect on blood pressure, Ang II blockers (by their unique capacity to lower proteinuria and its deleterious consequences) effectively limited the rate of progression of renal disease to end stage kidney disease and reduced cardiovascular risk.8 In this context, the study by Dhaun et al6 found that BQ123, a peptidic ETA receptor antagonist, administered intravenously on top of ACEis or ARBs, reduced proteinuria by 30%. Should studies with the available orally active ETA receptor antagonists after a prolonged treatment period confirm this trend, these results would have major clinical relevance. The effect of BQ123 was related to baseline proteinuria with subjects with a higher level of baseline proteinuria achieving greater reductions in line with previous reports.9 One limitation of the present study is the heterogeneity of patients, as well as therapeutic regimens. Subjects with IgA nephropathy, membranous glomerulopathy, and focal segmental glomerulosclerosis were considered. Although patients with IgA nephropathy have been shown to have a high rate of proteinuria remission and a remarkably good longThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Mario Negri Institute for Pharmacological Research (A.B., G.R.); and the Division of Nephrology and Dialysis (G.R.), Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy. Correspondence to Ariela Benigni, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy. E-mail [email protected] (Hypertension. 2009;54:29-31.) © 2009 American Heart Association, Inc.