Risk factors for metabolic syndrome independently predict arterial stiffness and endothelial dysfunction in patients with chronic kidney disease and minimal comorbidity.

OBJECTIVE: Metabolic syndrome (MS) is common in patients with chronic kidney disease (CKD), but its contribution to arterial stiffness and endothelial dysfunction in CKD is not well defined. We hypothesized that risk factors for MS would independently predict arterial stiffness and endothelial dysfunction in CKD patients. RESEARCH DESIGN AND METHODS: Risk factors for MS, carotid-femoral pulse wave velocity (CF-PWV) and flow-mediated dilation (FMD) as measures of arterial stiffness and endothelial dysfunction, respectively, were assessed in 113 minimally comorbid CKD patients and in 23 matched control subjects. RESULTS: CF-PWV correlated with systolic blood pressure (SBP), waist circumference, and plasma glucose (r(2) = 0.25, 0.09, and 0.09; P < 0.01 for all). FMD correlated with SBP (r(2) = 0.09; P < 0.01) and waist circumference (r(2) = 0.03; P < 0.05). CF-PWV increased progressively (r(2) = 0.07; P < 0.01) with increasing number of risk factors for MS. In multiple linear regression, SBP and waist circumference were independent determinants of CF-PWV, whereas only SBP predicted FMD. CONCLUSIONS: The number of MS risk factors is an important determinant of arterial stiffness in CKD patients irrespective of the degree of renal impairment. Although BP remains the major determinant of arterial stiffness and endothelial dysfunction, waist circumference independently predicts arterial stiffness. MS risk factors, particularly abdominal girth, are potential targets for future interventional studies in patients with CKD.

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.

Renal dysfunction does not affect the peripheral-to-central arterial pressure transfer function.

Arterial generalized transfer functions (GTFs) are increasingly used to estimate central pressure from peripheral measurements. Analysis of derived central waveforms may be valuable in the assessment of patients with chronic kidney disease. The aim of this study was to assess whether the GTF is affected by renal disease. Ninety-four subjects with varying degrees of renal function (Kidney Disease Outcomes Quality Initiative stages 1 to 5; 14 controls) had simultaneous measurements of carotid and radial waveforms made by applanation tonometry. GTFs were calculated by Fourier analysis for each subject group. Derived carotid waveforms were obtained by applying an independently generated GTF to the radial waveform. Glomerular filtration rate inversely correlated with central systolic (R = -0.42; P < 0.001), mean (R = -0.34; P < 0.01) and diastolic (R = --0.27, P < 0.01) blood pressures, as well as central augmentation index (R = -0.30; P< 0.01) and carotid-femoral pulse wave velocity (R = -0.33; P < 0.001). Derived waveforms were not significantly different from measured waveforms in terms of systolic blood pressure, augmentation index, maximum slope, or the delay between the incident and reflected waves, although the derived waveforms slightly underestimated the systolic ejection period (-4.4 ± 0.9 ms; P < 0.001). Overall root-mean-square error was 2.4 ± 0.1 mm Hg. No significant relationship existed between the degree of bias of any derived waveform measure and glomerular filtration rate or chronic kidney disease stage (P > 0.16). No significant differences between chronic kidney disease stages were observed in transfer function gain or phase (P > 0.05). We conclude that the peripheral-to-central GTF is not affected by degree of renal dysfunction and can be used with equivalence in patients with varying degrees of chronic kidney disease.

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 ET(A):ET(B) receptor blockade. As yet, there are no comparative studies in humans that measure biochemical and functional ET(B) blockade achieved by currently licensed ETRAs. We therefore investigated the effects of bosentan, a mixed ETRA, and sitaxsentan, an ET(A) selective ETRA, on plasma ET-1 concentrations and ET(B)-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 ET(A/B) antagonist bosentan, but not the selective ET(A) antagonist sitaxsentan, causes functional ET(B) blockade at clinically relevant doses in healthy human subjects.

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.

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.

Are rare diseases still orphans or happily adopted? The challenges of developing and using orphan medicinal products.

Orphan medicinal products (OMPs) are targeted at the diagnosis, prevention or treatment of rare diseases and have a special status in European law. This status brings incentives for pharmaceutical companies to invest in OMP development. The goal of the legislation is to encourage the development of more treatments for life-threatening rare disorders, but increased availability of OMPs raises important issues surrounding the public funding of very expensive treatments by national health services. In this article we review OMPs and the incentives for their development and discuss the challenges presented by funding these treatments.