Avosentan Reduces Albumin Excretion in Diabetics with Macroalbuminuria

Wenzel, René R.; Littke, Thomas; Kuranoff, Susan; Jürgens, Christiane; Bruck, Heike; Ritz, Eberhard; Philipp, Thomas; Mitchell, Anna

doi:10.1681/asn.2008050482

Cited by 218 publications

(171 citation statements)

References 36 publications

(38 reference statements)

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“…13 In a recent study, the ET receptor antagonist avosentan reduced macroalbuminuria in subjects with diabetic nephropathy in the absence of a change in BP. 16 In the current study, our active control nifedipine matched the fall in BP seen with sitaxsentan, but despite this, sitaxsentan reduced proteinuria to a greater degree. Furthermore, for the reduction in BP seen with sitaxsentan (Ϸ4 mm Hg) a less impressive fall in proteinuria than the observed at Ϸ30% would be expected.…”

Section: Discussionmentioning

confidence: 45%

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

et al. 2011

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Abstract-Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments.Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period.

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Section: Discussionmentioning

confidence: 45%

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

et al. 2011

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“…10 In the dose ranging, 12-week study of albuminuria reduction, treatment-emergent edema occurred in all of the avosentan treatment groups (5, 10, 25, and 50 mg) in a dose-related manner (9 to 24% incidence) that was significantly greater than in the placebo group (4%). 17 In the larger hard endpoint trial, 45 and 46% of subjects in the avosentan 25-and 50-mg groups, Figure 5. The effect of atrasentan on change in UACR from baseline to final visit is independent of edema occurrence during treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical relevance of fluid retention with the use of ET A R antagonists in patients with diabetes and CKD became apparent in recent studies that examined the effect of avosentan on albuminuria lowering 17 and on CKD progression. 10 In the dose ranging, 12-week study of albuminuria reduction, treatment-emergent edema occurred in all of the avosentan treatment groups (5, 10, 25, and 50 mg) in a dose-related manner (9 to 24% incidence) that was significantly greater than in the placebo group (4%).…”

Section: Discussionmentioning

confidence: 99%

Addition of Atrasentan to Renin-Angiotensin System Blockade Reduces Albuminuria in Diabetic Nephropathy

Kohan

Pritchett

Molitch

et al. 2011

Journal of the American Society of Nephrology

209

184

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Although endothelin-receptor antagonists reduce albuminuria in diabetic nephropathy, fluid retention limits their use. Here, we examined the effect of atrasentan, a selective endothelin A receptor (ET A R) antagonist, on albuminuria in a randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy already receiving stable doses of renin-angiotensin system (RAS) inhibitors. We randomly assigned 89 subjects with eGFR Ͼ20 ml/min per 1.73 m 2 and a urinary albumin-to-creatinine ratio (UACR) of 100 to 3000 mg/g to placebo or atrasentan (0.25, 0.75, or 1.75 mg daily) for 8 weeks. Compared with placebo, atrasentan significantly reduced UACR only in the 0.75-and 1.75-mg groups (P ϭ 0.001 and P ϭ 0.011, respectively). Compared with the 11% reduction in the geometric mean of the UACR from baseline to final observation in the placebo group during the study, the geometric mean of UACR decreased by 21, 42, and 35% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups (P ϭ 0.291, P ϭ 0.023, and P ϭ 0.073, respectively). In the placebo group, 17% of subjects achieved Ն40% reduction in UACR from baseline compared with 30, 50, and 38% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups, respectively (P ϭ 0.029 for 0.75 mg versus placebo). Peripheral edema occurred in 9% of subjects receiving placebo and in 14, 18, and 46% of those receiving 0.25, 0.5, and 1.75 mg atrasentan, respectively (P ϭ 0.007 for 1.75 mg versus placebo). In summary, atrasentan, at the doses tested, is generally safe and effective in reducing residual albuminuria and may ultimately improve renal outcomes in patients with type 2 diabetic nephropathy. 22: 763-772, 201122: 763-772, . doi: 10.1681 Diabetic nephropathy (DN) continues to be the most common cause of ESRD, despite attempts at rigorous control of hyperglycemia and hypertension. 1,2 The addition of renin-angiotensin system (RAS) inhibitors to reduce the deleterious effects of excessive renal angiotensin receptor activation has been the only kidney-specific therapy developed for DN during the past 10 years. Although treatment with RAS inhibitors shows reductions in albuminuria in association with delays in chronic kidney disease (CKD) progression, 3,4 there remains a significant unmet need to develop therapies that completely prevent progression to ESRD or even induce regression of glomerular pathology. 5 The endothelin (ET) system is chronically activated in patients with diabetes and in preclinical models as evidenced by elevated circulating levels of endothelin-1 (ET-1), 6 enhanced kidney ET-1 concentrations, 7 and increased renal and systemic endothelin A receptor (ET A R) activa- J Am Soc Nephrol

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“…81 In addition, chronic treatment with the mixed ET A/B receptor antagonist, avosentan, and the selective ET A receptor antagonist, atrasentan, in addition to standard angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment, substantially decreased albumin excretion in patients with diabetic nephropathy. 82,83 The positive effects of ET A receptor antagonism in CKD are attributed to reduced ET-1-mediated effects and to restoration of the NO system, an effect thought to be mediated at least in part through endothelial cell ET B receptor activation leading to an upregulation of eNOS. This effect may also be amplified through a possible synergistic relationship that exists between ET A receptor antagonists and angiotensin-converting enzyme inhibitors.…”

Section: Endothelin Antagonismmentioning

confidence: 99%

Potential Therapeutic Role of Phosphodiesterase Type 5 Inhibition in Hypertension and Chronic Kidney Disease

Brown

Dhaun²,

Goddard³

et al. 2014

Hypertension

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Avosentan Reduces Albumin Excretion in Diabetics with Macroalbuminuria

Cited by 218 publications

References 36 publications

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

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

Addition of Atrasentan to Renin-Angiotensin System Blockade Reduces Albuminuria in Diabetic Nephropathy

Potential Therapeutic Role of Phosphodiesterase Type 5 Inhibition in Hypertension and Chronic Kidney Disease

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