Blood Pressure–Independent Reduction in Proteinuria and Arterial Stiffness After Acute Endothelin-A Receptor Antagonism in Chronic Kidney Disease

Abstract

Abstract-Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. Key Words: endothelin Ⅲ blood pressure Ⅲ arterial stiffness Ⅲ proteinuria Ⅲ chronic kidney disease C hronic kidney disease (CKD) is common, affecting 6% to 11% of the population in the developed world. 1 Hypertension is a frequent finding in patients with CKD, 2 and its prevalence increases as CKD progresses. 3 Despite treatment with multiple antihypertensive agents, the majority of CKD patients fail to reach target blood pressure (BP). 4 Proteinuria is a common feature of CKD and is independently associated with an adverse renal outcome. 5 Current treatments for proteinuria focus on BP reduction, 5 ideally using angiotensin-converting enzyme (ACE) inhibitors 6 and angiotensin receptor blockers, 7 both of which are thought to reduce proteinuria to a greater extent than accounted for by BPlowering alone. 5 Nevertheless, many CKD patients have significant residual proteinuria despite optimal treatment. 8 CKD is also strongly associated with incident cardiovascular disease (CVD). 9 Hypertension 10 and proteinuria 11 make an important contribution to CVD risk in CKD, as do arterial stiffness 12 and endothelial dysfunction. 13 Thus, there remains an unmet need for newer treatments in CKD that will not only lower BP and proteinuria beyond the levels achieved with standard therapies but will also have favorable effects on arterial stiffness and endothelial dysfunction and so offer longer term cardiovascular and renal protection.Endothelin (ET) 1 is the most potent endogenous vasoconstrictor produced within the vasculature. It is implicated in both the development and progression of CKD. 14 The effects of ET-1 are mediated via 2 receptors, the ET A and ET B receptors, with the major pathological effects in CKD being ET A receptor mediated. 14 However, there are currently few human studies. 15,16 ET-1 also contributes to arterial stiffness 17 and endothelial dysfunction 18 in patients with CVD; however, there are no similar studies in CKD patients.Our group has shown previously that selective ET A receptor antagonism, but not mixed ET A/B antagonism, reduces BP, increases renal blood flow, and reduces the effective filtration fraction in patients with CKD. 15 However, this was a s...

Selective Endothelin-A Receptor Antagonism Reduces Proteinuria, Blood Pressure, and Arterial Stiffness in Chronic Proteinuric Kidney Disease

“…[27][28][29] Furthermore, we have shown recently that acute ET A receptor antagonism can reduce proteinuria by an additional Ϸ30% on top of that achieved with optimal treatment with inhibitors of the renin-angiotensin system in subjects with proteinuric CKD. 14 The current study suggests that these effects are maintained longer term and are of a similar magnitude. Interestingly, the size and time course of this effect are similar to those seen with blockers of the renin-angiotensin system.…”

“…The planned sample size (an approximate target of 30 subjects to be enrolled in the main study) was based primarily on logistical and clinical considerations. However, data from a previous study 14 using an ET A receptor antagonist administered to 22 subjects in a crossover design reported a reduction in proteinuria of up to Ϫ496 g/min with a SE of 141 g/min. This is Ϸ0.7 g/d with an SD of 0.9 g/d.…”

“…These followed our standard protocol and are described fully elsewhere. 14,15 Plasma ET-1 Plasma ET-1 was measured at baseline, week 3, and week 6 of each treatment period. After extraction, 25 ET-1 was determined by radioimmunoassay.…”

“…13 ET-1 also contributes to arterial stiffness in patients with CKD. 14 The effects of ET-1 are mediated via 2 receptors, the ET A and ET B receptors, with the major pathological effects in CKD being ET A receptor mediated. 13 However, there are currently few human studies in CKD.…”

Arterial stiffness, vascular calcification and bone metabolism in chronic kidney disease

“…Short-term administration of endothelin-receptor antagonist in non-diabetic CKD reduces proteinuria and arterial stiffness independently of blood-pressure lowering [20] , data which suggest beneficial effects in the treatment of the vascular complications of CKD in the near future.…”