Iain M. MacIntyre

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.

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

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.

Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis

Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 +/- 2.7%, 10.0 +/- 3.0 pg/mumol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 +/- 1.4% (P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal.

Endothelin Receptor Antagonism and Renin Inhibition as Treatment Options for Scleroderma Kidney

Scleroderma renal crisis (SRC) is an important complication of scleroderma associated with significant morbidity and mortality. Current treatment of patients with SRC focuses on renin-angiotensin-aldosterone system (RAAS) blockade, ideally using angiotensin-converting enzyme inhibitors. We present a case of SRC in a patient established on maximal tolerable RAAS-blocking treatment. Introduction of a selective endothelin-A receptor antagonist followed by a direct renin inhibitor provided excellent blood pressure control and complete abrogation of heavy proteinuria. This was associated with a decrease in kidney function, with serum creatinine level increasing by approximately 30%. This increase is considered acceptable after the introduction of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, is regarded as an indicator of drug efficacy, and confers longer term renal protection. Both endothelin receptor antagonism and direct renin inhibition offer alternate novel therapies for patients with SRC. Their ability to preserve or improve kidney function is unclear.

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

To the Editor:nnWe 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 DiseaseNovelty and Significance: 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.

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.

Sitaxsentan sodium for pulmonary hypertension.

Sitaxsentan is the first oral endothelin receptor antagonist (ETRA) with high selectivity for the endothelin-A (ET(A)) receptor to be approved for clinical use by regulatory agencies in Europe for the treatment of pulmonary arterial hypertension (PAH). Clinical trials have shown it to be well tolerated and to improve exercise tolerance, functional class and pulmonary hemodynamics in PAH, results which appear to be at least as good as those for the mixed ETRA bosentan. Importantly, compared to bosentan, sitaxsentan has a lower incidence of liver toxicity and no interaction with sildenafil, a drug commonly used in the management of PAH. Furthermore, there is increasing evidence to suggest that ETRAs may play an important role in the future management of a wide variety of other conditions, from hypertension and renal disease to connective tissue disease and cancer. In some of these conditions, ET(A) selectivity may be an advantage.

Ambrisentan and its role in the management of pulmonary arterial hypertension.

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.