Vanessa Melville

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

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. BQ-123 reduced blood pressure (mean arterial pressure: −7±1%; P<0.001 versus placebo) and increased renal blood flow (17±4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (−26±4%; P<0.01 versus placebo) and pulse wave velocity (−5±1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (−38±3% versus 26±11%; P<0.001) and pulse wave velocity (−9±1% versus −3±1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.

Effect of Regular Phosphodiesterase Type 5 Inhibition in Hypertension

There are no published controlled clinical trials of regular phosphodiesterase type 5 inhibitor therapy as a long-term treatment of hypertension. In a randomized, double-blind, 2-way crossover study, 25 otherwise untreated hypertensive subjects were administered 50 mg of sildenafil or matched placebo 3 times daily for 16 days, and the effects on ambulatory blood pressure (BP), clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity, and brachial artery flow-mediated dilatation were assessed. Three subjects were withdrawn because of adverse effects, and the data from the remaining 22 subjects were analyzed. Sildenafil reduced ambulatory BP (mean [SE] change from baseline for average daytime BP: systolic −8 [2] mm Hg versus 2 [2] mm Hg with placebo, P<0.01; diastolic −6 [1] mm Hg versus 0 [1] mm Hg, P<0.01) and clinic BP (change from baseline to 1 hour after drug administration on day 16: systolic −5 [2] mm Hg versus 4 [2] mm Hg, P<0.01; diastolic −5 [1] mm Hg versus 2 [2] mm Hg, P<0.01). Compared with baseline, sildenafil, but not placebo, reduced arterial wave reflection both acutely and after chronic treatment, but the chronic change in arterial wave reflection was not statistically different from the chronic change with placebo. Sildenafil did not affect pulse wave velocity or flow-mediated dilatation. The main adverse effects of sildenafil, which were generally transient and rated as mild or moderate in severity, were dyspepsia, headache, and myalgia. In conclusion, regular sildenafil constitutes effective antihypertensive therapy. Further studies are warranted to evaluate the role of longer-acting phosphodiesterase type 5 inhibitors as antihypertensive agents in clinical practice.

Blood pressure and not uraemia is the major determinant of arterial stiffness and endothelial dysfunction in patients with chronic kidney disease and minimal co-morbidity

INTRODUCTION Patients with chronic kidney disease (CKD) have increased risk of cardiovascular disease to which co-morbidity and associated conventional risk factors contribute. We hypothesised that arterial stiffness (AS) and endothelial dysfunction (ED), as surrogates of cardiovascular risk, would worsen as renal function declined even in patients without co-morbidity and that this would relate to emerging cardiovascular risk factors. METHODS Carotid-femoral pulse wave velocity (PWV), as a measure of AS, and flow-mediated dilatation (FMD) of the brachial artery, as a measure of ED, were assessed in CKD patients without established cardiovascular disease or diabetes mellitus. RESULTS PWV increased linearly as renal function declined (r(2) = 0.08, p < 0.01) whereas FMD was reduced only in patients with advanced kidney disease. In multivariable analysis, blood pressure was the major determinant of PWV and FMD. High-sensitivity C-reactive protein and asymmetric dimethylarginine, and isoprostanes and endothelin-1, were independent predictors of PWV and FMD, respectively. However, renal function did not independently predict either AS or ED. CONCLUSIONS These findings suggest that declining renal function, in the absence of significant co-morbidity, is associated with progressive arterial stiffness, but only patients close to dialysis exhibit endothelial dysfunction. Whilst blood pressure remains the major determinant of PWV and FMD, inflammation, oxidative stress and endothelin-nitric oxide balance contribute to cardiovascular risk, in this non-comorbid cohort.

Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD

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.

Top-down lipidomics of low density lipoprotein reveal altered lipid profiles in advanced chronic kidney disease.

This study compared the molecular lipidomic profile of LDL in patients with nondiabetic advanced renal disease and no evidence of CVD to that of age-matched controls, with the hypothesis that it would reveal proatherogenic lipid alterations. LDL was isolated from 10 normocholesterolemic patients with stage 4/5 renal disease and 10 controls, and lipids were analyzed by accurate mass LC/MS. Top-down lipidomics analysis and manual examination of the data identified 352 lipid species, and automated comparative analysis demonstrated alterations in lipid profile in disease. The total lipid and cholesterol content was unchanged, but levels of triacylglycerides and N-acyltaurines were significantly increased, while phosphatidylcholines, plasmenyl ethanolamines, sulfatides, ceramides, and cholesterol sulfate were significantly decreased in chronic kidney disease (CKD) patients. Chemometric analysis of individual lipid species showed very good discrimination of control and disease sample despite the small cohorts and identified individual unsaturated phospholipids and triglycerides mainly responsible for the discrimination. These findings illustrate the point that although the clinical biochemistry parameters may not appear abnormal, there may be important underlying lipidomic changes that contribute to disease pathology. The lipidomic profile of CKD LDL offers potential for new biomarkers and novel insights into lipid metabolism and cardiovascular risk in this disease.

Effects of Endothelin Receptor Antagonism Relate to the Degree of Renin-Angiotensin System Blockade in Chronic Proteinuric Kidney Disease

To the Editor: We thank Benigni and Remuzzi1 for their informative editorial relating to our study.2 They raise a number of pertinent issues. They comment that it would be interesting to know whether subjects included with focal segmental glomerulosclerosis (FSGS) had idiopathic or secondary disease, because there are currently few treatments available for this condition. We agree that specifically studying FSGS would be of great interest. However, all of the FSGS subjects included in our study had secondary disease. Idiopathic FSGS, more often than secondary, presents with problematic nephrotic syndrome (a specific exclusion for our study), …

Diurnal Variation in Blood Pressure and Arterial Stiffness in Chronic Kidney Disease: The Role of Endothelin-1

Abstract—Hypertension and arterial stiffness are important independent cardiovascular risk factors in chronic kidney disease (CKD) to which endothelin-1 (ET-1) contributes. Loss of nocturnal blood pressure (BP) dipping is associated with CKD progression, but there are no data on 24-hour arterial stiffness variation. We examined the 24-hour variation of BP, arterial stiffness, and the ET system in healthy volunteers and patients with CKD and the effects on these of ET receptor type A receptor antagonism (sitaxentan). There were nocturnal dips in systolic BP and diastolic BP and pulse wave velocity, our measure of arterial stiffness, in 15 controls (systolic BP, −3.2±4.8%, P<0.05; diastolic BP, −6.4±6.2%, P=0.001; pulse wave velocity, −5.8±5.2%, P<0.01) but not in 15 patients with CKD. In CKD, plasma ET-1 increased by 1.2±1.4 pg/mL from midday to midnight compared with healthy volunteers (P<0.05). Urinary ET-1 did not change. In a randomized, double-blind, 3-way crossover study in 27 patients with CKD, 6-week treatment with placebo and nifedipine did not affect nocturnal dips in systolic BP or diastolic BP between baseline and week 6, whereas dipping was increased after 6-week sitaxentan treatment (baseline versus week 6, systolic BP: −7.0±6.2 versus −11.0±7.8 mm Hg, P<0.05; diastolic BP: −6.0±3.6 versus −8.3±5.1 mm Hg, P<0.05). There was no nocturnal dip in pulse pressure at baseline in the 3 phases of the study, whereas sitaxentan was linked to the development of a nocturnal dip in pulse pressure. In CKD, activation of the ET system seems to contribute not only to raised BP but also the loss of BP dipping. The clinical significance of these findings should be explored in future clinical trials. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01770847 and NCT00810732.

Greater Functional ETB Receptor Antagonism With Bosentan Than Sitaxsentan in Healthy Men

Endothelin (ET)-1 is implicated in the development of hypertension and a role for endothelin receptor antagonists (ETRAs) in the management of hypertension is emerging. ETRAs are classified as selective or mixed depending on their degree of ETA:ETB receptor blockade. As yet, there are no comparative studies in humans that measure biochemical and functional ETB blockade achieved by currently licensed ETRAs. We therefore investigated the effects of bosentan, a mixed ETRA, and sitaxsentan, an ETA selective ETRA, on plasma ET-1 concentrations and ETB-mediated vasodilatation to ET-3. In a randomized, double-blind, 3-way crossover study, 10 healthy subjects received 7 days of placebo, bosentan 250 mg, and sitaxsentan 100 mg daily. Plasma ET-1 concentrations were measured at baseline and 3 hours on day 1 and predose on day 7. Subjects also underwent forearm blood flow measurements on day 7 of each period with brachial artery infusion of ET-3 (60 pmol/min for 5 minutes). Bosentan, but not placebo or sitaxsentan, significantly increased plasma ET-1 concentrations at day 7 (+0.70±0.20 pg/mL; P<0.005). Maximal ET-3–mediated vasodilatation was seen at 2 minutes following placebo (30±6%) and sitaxsentan (21±11%); however, this was abolished by bosentan, with a reduction in forearm blood flow of 8±3% (P<0.01 versus placebo and sitaxsentan). Bosentan but not sitaxsentan increases circulating plasma ET-1 levels and abolishes acute ET-3–mediated vasodilatation, confirming that the mixed ETA/B antagonist bosentan, but not the selective ETA antagonist sitaxsentan, causes functional ETB blockade at clinically relevant doses in healthy human subjects.

What is the best method of proteinuria measurement in clinical trials of endothelin receptor antagonists

AIMS 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. MAIN METHODS 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. KEY FINDINGS 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. SIGNIFICANCE 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.

Arterial stiffness &Sri Lankan chronic kidney disease of unknown origin.

Chronic kidney disease (CKD) is common and independently associated with cardiovascular disease (CVD). Arterial stiffness contributes to CVD risk in CKD. In many developing countries a considerable proportion of CKD remains unexplained, termed CKDu. We assessed arterial stiffness in subjects with Sri Lankan CKDu, in matched controls without CKD and in those with defined CKD. Aortic blood pressure (BP), pulse wave velocity (PWV) and augmentation index (AIx) were assessed in 130 subjects (50 with CKDu, 45 with CKD and 35 without CKD) using the validated TensioMed™ Arteriograph monitor. Brachial and aortic BP was lower in controls than in CKDu and CKD subjects but no different between CKDu and CKD. Controls had a lower PWV compared to subjects with CKDu and CKD. Despite equivalent BP and renal dysfunction, CKDu subjects had a lower PWV than those with CKD (8.7 ± 1.5 vs. 9.9 ± 2.2 m/s, p < 0.01). Excluding diabetes accentuated the differences in PWV seen between groups (controls vs. CKDu vs. CKD: 6.7 ± 0.9 vs. 8.7 ± 1.5 vs. 10.4 ± 1.5 m/s, p < 0.001 for all). Sri Lankan CKDu is associated with less arterial stiffening than defined causes of CKD. Whether this translates to lower cardiovascular morbidity and mortality long term is unclear and should be the focus of future studies.