To determine whether protein-creatinine ratio (PCR) and albumin-creatinine ratio (ACR) are comparable to 24h urine protein in terms of agreement and repeatability, and therefore whether they are suitable for monitoring and comparing reduction in proteinuria in clinical trials of endothelin receptor antagonists.Using data from a recent study of sitaxentan in 27 patients with proteinuric chronic kidney disease, the assays were compared with reference to their agreement, repeatability, the number of measurements required to obtain accurate results and correlation with reduction in proteinuria at baseline.The median coefficient of variation was lower for PCR than 24h urine protein (25 vs. 28%) but the range was higher (70 vs. 47%). When converted into the same units, mean difference between 24h urine protein and both PCR (0.03 g/day), and ACR (0.10 g/day), was small. However, scatter increased with mean level of proteinuria, such that agreement fell substantially above 1.5 g/day. According to 2-factor within-subjects ANOVA, the assay used was not a significant source of variation (PCR p=0.63, ACR p=0.38). With 3 measurements at each time point, baseline proteinuria correlated equally well with change in proteinuria, and percentage change was detected accurately by all 3 methods.PCR and ACR may well be suitable replacements for 24h urine protein in the clinical trial context due to their similar accuracy and repeatability, greater convenience and lower cost. However, a randomised control trial comparing all 3 assays in a larger and more diverse population is necessary before 24h urine protein can be replaced.
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. Compared with placebo, sitaxsentan reduced 24-hour proteinuria (−0.56±0.20 g/d; P =0.0069), protein:creatinine ratio (−38±15 mg/mmol; P =0.0102), BP (−3.4±1.2 mm Hg; P =0.0069), and pulse wave velocity (−0.64±0.24 m/s; P =0.0052). Nifedipine matched the BP and pulse wave velocity reductions seen with sitaxsentan but did not reduce proteinuria. Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects. Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing proteinuria, BP, and arterial stiffness in optimally treated chronic kidney disease subjects. The antiproteinuric effects of sitaxsentan likely relate to changes in BP and renal hemodynamics.
Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET(A) receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET(A) receptor antagonism may modify risk factors for cardiovascular disease in CKD.
Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade.We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls -4+/-2%, CRF -13+/-2%, P<0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8+/-23.9%, P<0.01 versus placebo) and reduced renal vascular resistance (-44.5+/-11.3%, P<0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls.ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.
Chronic kidney disease (CKD) patients have an increased risk of cardiovascular disease (CVD) contributed to by arterial stiffness (AS). Impairment of the nitric oxide (NO) system leads to AS. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, promotes vasoconstriction. Endothelin-1 (ET-1), a potent endogenous vasoconstrictor, is upregulated in CKD. Hyperuricemia, another feature of CKD, contributes to AS. ETA receptor antagonism is a promising novel therapy for CKD. Its effects on ADMA, the ET system and urate in CKD are unknown. In a randomized double-blind, 3-way crossover study, 27 CKD subjects received 6 weeks treatment with placebo, sitaxentan, an ETA antagonist, and nifedipine 30 mg. ADMA, urate, plasma ET-1 and urine ET-1/creat, as a reflection of renal ET-1 production, were measured at baseline, weeks 3 and 6 of each treatment period alongside the primary endpoints of proteinuria, BP, and AS. Whereas placebo and nifedipine did not affect urate, ADMA, or urine ET-1/creat, sitaxentan reduced all three (baseline vs. week 6 ± SEM – urate: 506 ± 21 vs. 451 ± 22 μmol/l, p<0.01; ADMA: 0.52 ± 0.01 vs. 0.48 ± 0.01 μmol/l, p<0.0001; urine ET-1/creat: 783 ± 84 vs. 613 ± 81ag/mmol, p<0.01). Plasma ET-1 was unaffected by all treatments. Reductions in proteinuria and BP following sitaxentan treatment were associated with change in urine ET-1/creat, and reduction in pulse wave velocity (as a measure of AS) by change in ADMA. In addition to currently recognized effects on proteinuria, BP and AS, ETA antagonism may modify novel CVD risk factors and so have broader cardioprotective effects in CKD. Larger and longer-term trials with these specific endpoints are now warranted.
Ambrisentan is the second selective endothelin-A receptor antagonist to be licensed in Europe, and the first in the United States, for the management of pulmonary arterial hypertension (PAH). It has been shown to be clinically effective in improving exercise tolerance and functional class. Furthermore, ambrisentan is well tolerated and associated with low rates of liver toxicity and minimal interactions with other medicines commonly used to treat PAH. Overall, current data support a role for ambrisentan in the management of PAH. However, the results of longer-term follow-up studies are still required to fully assess efficacy and safety.
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