Heike Bruck

Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor

AIM This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor. METHODS Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (<30mlmin(-1) ). RESULTS Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONS Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

Avosentan Reduces Albumin Excretion in Diabetics with Macroalbuminuria

Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory, antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER 0.2 to 5.6 mg/min), and BP <180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo, in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean relative UAER (-16.3 to -29.9%) compared with placebo (35.5%). Median relative UAER decreased with all avosentan dosages (-28.7 to -44.8%) compared with placebo (12.1%). Creatinine clearance and BP were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (>/=25 mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%) patients experienced adverse events that led to withdrawal from study medication. In summary, the endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER in patients with diabetic nephropathy and macroalbuminuria.

Relationship between Magnesium and Clinical Biomarkers on Inhibition of Vascular Calcification

Background: Arteriosclerosis and cardiovascular disease are strongly associated with vascular calcification. Hyperphosphatemia is an essential risk factor for increased vascular calcification. End-stage renal disease (ESRD) patients could serve as an in vivo model for accelerated calcification. This study focuses on the most likely protective effects of magnesium ion (Mg2+) on phosphate-induced vascular calcification ex vivo/in vitro. Furthermore, plasma Mg2+ concentrations of ESRD and healthy controls were investigated for association with surrogate parameters of vascular calcification in vivo. Methods: Aortic segments of male Wistar-Kyoto rats were incubated and the phosphate concentration of the medium was elevated. The aortic segments were incubated in the absence and presence of MgCl2; tissue calcification was quantified by different methods. Serum Mg2+ concentrations of patients with chronic kidney disease (CKD stage 5; ESRD) and patients without CKD (controls) were associated with carotid intima media thickness (IMT) and aortic pulse wave velocity (PWV) as surrogate parameter for arteriosclerosis and arterial stiffening. Results: Incubation of aortic segments in the presence of β-glycerophosphate and NaH2PO4 caused an increased tissue Ca2+ deposition compared to control conditions. This increased amount of Ca2+ in the aortic rings was significantly decreased in the presence of Mg2+. In CKD patients, but not in controls, magnesium serum concentration was associated with the IMT of the carotid arteries. In addition, CKD patients with higher magnesium serum concentration had a significantly lower PWV. Discussion and Conclusion: Elevated phosphate concentrations in the culture media induce ex vivo/in vitro medial calcification in intact rat aortic rings in the presence of alkaline phosphatase. Mg2+ ions reduced ex vivo/in vitro vascular calcification despite increased phosphate concentration. This hypothesis is additionally based on the fact that CKD patients with high Mg2 serum levels had significantly lower IMT and PWV values, which may result in a lower risk for cardiovascular events and mortality in these patients. Therefore, Mg2+ supplementation may be an option for treatment and prevention of vascular calcification resulting in a reduction of cardiovascular events in CKD patients.

Human β2-adrenergic receptor gene haplotypes and venodilation in vivo

β2‐Adrenergic receptors (β2‐ARs) are polymorphic. In vitro studies have shown that agonist‐promoted down‐regulation is enhanced for Arg16Gly and blunted for Gln27Glu β2‐AR variants; Thr164Ile β2‐ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether β2‐AR polymorphisms affect β2‐AR‐mediated venodilation in healthy subjects in vivo.

Genotype‐dependent time course of lymphocyte β2‐adrenergic receptor down‐regulation

Volunteers homozygous for Glu27 β2‐adrenergic receptor (β2AR) polymorphism have delayed onset of agonist‐induced desensitization of cardiac β2AR responses.

The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in chronic kidney disease

Cognitive impairment is a frequent finding in patients with chronic kidney disease (CKD). We examined cognitive performance in a prospective study of 119 patients with CKD stages 3-5 (including dialysis) and 54 control patients of the same age without CKD but with similar vascular risk profiles. Analysis included a comprehensive test battery evaluating memory, information processing speed, executive function, language, and visuoconstructive function, in addition to depression and anxiety. Thirty percent of patients with CKD had cognitive deficits (one or more s.d. below control patient performance). Cognitive deficits (T-value related to published norm values) were mild but significantly decreased to 48.8 in patients with stage 3-5 CKD not requiring hemodialysis and 47.2 in patients with stage 5D disease requiring hemodialysis, compared with 51.5 in control patients. Linear regressions among patients with CKD (forced entry strategy) showed that age (β=-0.50 per s.d.), HbA1c (β=-0.18 per s.d.), and fibrinogen (β=-0.18 per s.d.) predicted cognitive performance. Interestingly, HbA1c discriminated cognition in all age groups, while fibrinogen differentiated cognition particularly in patients over 70 years of age. Thus, our cross-sectional study suggests the severity of cognitive impairment in CKD is mild. As such, longitudinal studies are required to further characterize the role of cognitive deficits in CKD.

The nitric oxide synthase inhibitor L-nmma potentiates noradrenaline-induced vasoconstriction: effects of the alpha2-receptor antagonist yohimbine

Objective Alpha2-adrenoceptors can be found both on vascular smooth muscle cells and on the endothelium, where they exert opposing effects on vascular tone. In vitro, the stimulation of α2-adrenoceptors on endothelial cells leads to the release of vasodilating substances like nitric oxide (NO) and prostanoids. Little is known of this mechanism in vivo. Design and methods We investigated the effects of the NO-synthase inhibitor L-NMMA (10−6 mol) and the α2-adrenoceptor antagonist yohimbine (YO, 10−10−10−6 mol) on noradrenaline (NA, 10−12−10−8 mol)-induced vasoconstriction in the forearm skin microcirculation of 16 healthy volunteers using double injection technique and laser Doppler flowmetry. Results are expressed in perfusion units (PU) as differences from baseline and control in mean ± SEM; the area under the time–response-curve was calculated (AUC). Results NA (10−8–10−12 mol) caused a marked, dose-dependent reduction in blood flow (mean effect − 745 ± 84 AUC PU;P < 0.001 versus saline). NA-induced vasoconstriction was enhanced by L-NMMA (mean effect − 916 ± 72 AUC PU;P< 0.001 versus NA). YO (10−6–10−10 mol) induced a significant, dose-dependent vasodilation (mean effect + 446 ± 110 AUC PU;P < 0.05 versus control); high doses of YO (10−6 mol) inhibited NA constriction (P < 0.001 versus NA), whereas lower doses of YO (10−8/10−10 mol) had no effect or even increased NA-induced constriction. In the presence of L-NMMA, YO (10−8 and 10−10 mol) further potentiated NA-induced vasoconstriction (mean effect − 1165 ± 108 AUC PU; NS versus NA). Conclusion These data demonstrate, that in humans in vivo, endogenous NO attenuates noradrenergic constriction. The effects of YO suggest that endothelial α2-adrenoceptors are involved in the release of NO and other vasodilating substances. Furthermore, there is an additive NO-independent vasodilation, which can be unmasked by L-NMMA.

Identification of the Vasoconstriction-Inhibiting Factor (VIF), a Potent Endogenous Cofactor of Angiotensin II Acting on the Angiotensin II Type 2 Receptor

Background— The renin-angiotensin system and especially the angiotensin peptides play a central role in blood pressure regulation. Here, we hypothesize that an as-yet unknown peptide is involved in the action of angiotensin II modulating the vasoregulatory effects as a cofactor. Methods and Results— The peptide with vasodilatory properties was isolated from adrenal glands chromatographically. The effects of this peptide were evaluated in vitro and in vivo, and the receptor affinity was analyzed. The plasma concentration in humans was quantified in patients with chronic kidney disease, patients with heart failure, and healthy control subjects. The amino acid sequence of the peptide from bovine adrenal glands was HSSYEDELSEVL EKPNDQAE PKEVTEEVSSKDAAE, which is a degradation product of chromogranin A. The sequence of the peptide isolated from human plasma was HSGFEDELSEVLENQSSQAELKEAVEEPSSKDVME. Both peptides diminished significantly the vasoconstrictive effect of angiotensin II in vitro. Therefore, we named the peptide vasoconstriction-inhibiting factor (VIF). The vasoregulatory effects of VIF are mediated by the angiotensin II type 2 receptor. VIF impairs angiotensin II–induced phosphorylation of the p38 mitogen-activated protein kinase pathway but not of extracellular-regulated kinase 1/2. The vasodilatory effects were confirmed in vivo. The plasma concentration was significantly increased in renal patients and patients with heart failure. Conclusions— VIF is a vasoregulatory peptide that modulates the vasoconstrictive effects of angiotensin II by acting on the angiotensin II type 2 receptor. It is likely that the increase in VIF may serve as a counterregulatory effect to defend against hypertension. The identification of this target may help us to understand the pathophysiology of renal and heart failure and may form a basis for the development of new strategies for the prevention and treatment of cardiovascular disease.

Identification of the "Vasoconstriction Inhibiting Factor" (VIF), a Potent Endogenous Cofactor of Angiotensin II Acting on the AT2 Receptor

Background— The renin-angiotensin system and especially the angiotensin peptides play a central role in blood pressure regulation. Here, we hypothesize that an as-yet unknown peptide is involved in the action of angiotensin II modulating the vasoregulatory effects as a cofactor. Methods and Results— The peptide with vasodilatory properties was isolated from adrenal glands chromatographically. The effects of this peptide were evaluated in vitro and in vivo, and the receptor affinity was analyzed. The plasma concentration in humans was quantified in patients with chronic kidney disease, patients with heart failure, and healthy control subjects. The amino acid sequence of the peptide from bovine adrenal glands was HSSYEDELSEVL EKPNDQAE PKEVTEEVSSKDAAE, which is a degradation product of chromogranin A. The sequence of the peptide isolated from human plasma was HSGFEDELSEVLENQSSQAELKEAVEEPSSKDVME. Both peptides diminished significantly the vasoconstrictive effect of angiotensin II in vitro. Therefore, we named the peptide vasoconstriction-inhibiting factor (VIF). The vasoregulatory effects of VIF are mediated by the angiotensin II type 2 receptor. VIF impairs angiotensin II–induced phosphorylation of the p38 mitogen-activated protein kinase pathway but not of extracellular-regulated kinase 1/2. The vasodilatory effects were confirmed in vivo. The plasma concentration was significantly increased in renal patients and patients with heart failure. Conclusions— VIF is a vasoregulatory peptide that modulates the vasoconstrictive effects of angiotensin II by acting on the angiotensin II type 2 receptor. It is likely that the increase in VIF may serve as a counterregulatory effect to defend against hypertension. The identification of this target may help us to understand the pathophysiology of renal and heart failure and may form a basis for the development of new strategies for the prevention and treatment of cardiovascular disease.

Cognitive impairment in chronic kidney disease: clinical findings, risk factors and consequences for patient care.

Cognitive deficits have a high prevalence in elderly patients with chronic kidney disease (CKD). The clinical picture consists of cognitive slowing, executive, memory and language deficits, and is attributed to cerebral white matter disease and clinically often silent brain infarcts. In the meantime, robust evidence exists that low estimated glomerular filtration rate, a measure of CKD severity, predisposes to cognitive deficits, cerebral white matter lesions, and ischemic brain infarcts in addition to demographic factors, vascular risk factors and diseases which also contribute to CKD-related cognitive deficits. In terminal CKD, cerebral blood flow is compromized during hemodialysis sessions, resulting in oxygen desaturation, cognitive deterioration and—in the longer run—brain atrophy. Kidney transplantation improves cognitive deficits in terminal CKD. At all stages, vascular risk factors and associated diseases should stringently be treated according to therapeutic guidelines.