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Hemodialysis remains the standard therapy to treat patients affected with end-stage renal disease by removing metabolites accumulated in blood plasma. The efficiency of hemodialysis is mainly monitored by urea clearance, which is routinely checked in clinical laboratory practice. However, there is mounting evidence that the clearance behavior of selected single metabolites is not sufficient to predict long-term outcome of treatment. To address this problem, we evaluated the potential of nuclear magnetic resonance spectroscopy for monitoring hemodialysis efficiency by comprehensive profiling of blood serum metabolites. We carried out a pilot study with a cohort of end-stage chronic kidney disease patients (n = 29), analyzing their serum prior and immediately after hemodialysis. To account for supposed variability in the accumulation of metabolites and efficiency of hemodialysis, patients' blood sera were repeatedly collected over a period of several months. Our results revealed that the metabolic profile in terms of concentrations varied considerably between patients but was comparably constant on the patient's level over the period of 4 months. Interestingly, also the individual clearance of the metabolites was characteristic for each patient. Thus, it is conceivable that the observed patient-dependent clearance patterns reflect to some extent the patients' long-term perspectives. We conclude that nuclear magnetic resonance spectroscopy is an optimal tool to complement traditional clinical methods based on a single variable, providing comprehensive and much more global information, which is crucial for patient evaluation and the development of improved treatments of kidney failure.

Background: Contrast media-induced nephropathy (CIN) is associated with markedly increased morbidity and mortality. Although creatinine is at present routinely used to characterize renal function, many studies and guidelines recommend using the estimated glomerular filtration rate (eGFR) since it was found to be much more accurate. Hypothesis: To assess whether the eGFR or creatinine alone provided a better predictive value for long-term mortality after contrast media-associated renal impairment. Methods: From a prospective trial with 412 patients undergoing heart catheterization, creatinine and eGFR before and after 24 h, 48–72 h, and 30 d after contrast-media exposure were assessed as well as long-term mortality. Results: Univariate Cox regression models identified increases in creatinine after 48 h (hazard rate ratio [HRR] 1.754, 95% confidence interval [CI] 1.134–2.712) and 30 d (HRR 3.157, 95% CI 1.968–5.064) as well as decreases in eGFR after 30 d (HRR 0.962, 95% CI 0.939–0.986) to be significant predictors of long-term mortality. However, by multivariable Cox regression, only increases in creatinine after 48 h (HRR 1.608, 95% CI 1.002–2.581) and after 30 d (HRR 2.685, 95% CI 1.598–4.511) turned out to be significant and independent predictors of mortality. With regard to a possibly critical threshold of creatinine increase, our data confirmed the historically grown increase in creatinine of 0.5 mg/dl or more during the first 48 h as being associated with increased mortality (p = 0.016, log rank test). Conclusions: Serum creatinine, but not eGFR, was predictive for long-term mortality, with a threshold of 0.5 mg/dl or more indicating worse prognosis. Copyright © 2010 Wiley Periodicals, Inc. Supported by an unrestricted research grant from Schering AG, Berlin, Germany.

OBJECTIVE End-stage renal disease (ESRD) is characterized by markedly increased sympathetic outflow that contributes to increased cardiovascular mortality in these patients. The central sympatholytic drug moxonidine (MOX) has been shown to reduce muscle sympathetic nerve activity (MSNA) in initial stages of chronic kidney disease; however, the effects in ESRD are not known. The aim of this study was to test the hypothesis that low-dose MOX causes sustained decreases in sympathetic outflow in ESRD patients. DESIGN AND METHODS Twenty-three ESRD patients (mean age 46.4 +/- 16 years, 14 men, seven women, no diabetic patients) were randomized to a daily treatment of 0.3 mg MOX or placebo (PLA) in addition to pre-existing antihypertensive therapy. At baseline and after 1 and 6 months of treatment, heart rate (HR, ECG), blood pressure (mean arterial pressure, automatic sphygmanometer), calf blood flow (CBF, venous occlusion plethysmography), muscle sympathetic nerve activity (MSNA) (microneurography at the peroneal nerve) were measured. Data are mean +/- SEM. RESULTS MOX acutely decreased MSNA within 2 h after oral intake (from 45 +/- 3.7 to 35 +/- 3.9 bursts/min, P < 0.05). This decrease was sustained over 6 months (MSNA 45 +/- 3.7, 35 +/- 4.6, 33 +/- 4.5 bursts/min at 0, 1 and 6 months, P < 0.05). PLA had no effect. Neither MOX nor PLA resulted in any significant acute or long-term changes in HR, MAP or CBF. CONCLUSIONS In ESRD patients, low-dose MOX produced sustained and substantial reductions in sympathetic outflow without hemodynamically compromising them. We suggest that the inhibition of central sympathetic outflow may improve cardiovascular prognosis in ESRD.

Beschrieben ist der Fall einer 49-jahrigen Patientin mit dualer sekundarer arterieller Hypertonie bei einer Nierenarterienstenose durch externe Kompression bei katecholaminserzernierendem extraadrenalem Phaochromozytom/Paragangliom. Fallstricke in der bildgebenden Diagnostik werden anhand des vorliegenden Bildmaterials – Sonographie, Duplexsonographie, Computertomographie, Angiographie und MIBG-Szintigraphie – erlautert.

Arterielle Hypertonie betrifft die Mehrheit aller Patienten nach Nierentransplantation. Die Genese ist multifaktoriell. Hierzu zahlen progressive Transplantatdysfunktion, Schadigung des Gefassystems durch die vorbestehende Niereninsuffizienz und weitere kardiovaskulare Risikofaktoren, Transplantatnierenarterienstenosen, Aktivierung des sympathischen Nervensystems, genetische Pradisposition des Empfangers und vor allem des Spenders sowie Nebenwirkungen von Immunsuppressiva wie Calcineurininhibitoren und Steroiden. Die Hypertonie nach Nierentransplantation beeinflusst nicht nur die kardiovaskulare Prognose der Patienten, sondern bestimmt entscheidend das Transplantatuberleben. Eine langfristig gute Blutdruckkontrolle auf Zielwerte von

Nebivolol (NEB) is a [beta]1-receptor blocker with nitric oxide-dependent vasodilating properties. NEB-induced nitric oxide release is mediated through the estrogen receptor.Here, we tested the hypothesis that NEB decreases endothelial cell stiffness and that these effects can be abolished by both endothelial nitric oxide synthase and estrogen receptor blockade. Human endothelial cells (EAHy-926) were incubated with vehicle, NEB 0.7 nmol/l, metoprolol 200 nmol/l, 17[beta]-estradiol (E2) 15 nmol/l, the estrogen receptor antagonists tamoxifen 100 nmol/l and ICI 182780 (ICI) 100 nmol/l, the nitric oxide synthase inhibitor N[omega]-nitro-L-arginine methyl ester 1 mmol/l and combinations of NEB and E2 with either tamoxifen, ICI or N[omega]-nitro-L-arginine methyl ester as well as metoprolol and ICI. Atomic force microscopy was performed to measure cellular stiffness, cell volume and apical surface. Presence of estrogen receptor protein in EAHy-926 was confirmed by western blot analysis; quantification of ER[alpha] and ER[beta] total RNA was performed by semiquantitative PCR.Both NEB as well as E2 decreased cellular stiffness to a similar extent (NEB: 0.83 +/- 0.03 pN/nm, E2: 0.87 +/- 0.03 pN/nm, vehicle: 2.19 +/- 0.07 pN/nm), whereas metoprolol had no effect on endothelial stiffness (2.07 +/- 0.04 pN/nm, all n = 60, P0.01). The decrease in stiffness occurred as soon as 5 min after starting NEB incubation. The effects are mediated through nongenomic ER[beta] pathways, as ER[alpha] is not translated into measurable protein levels in EAHy-926. Furthermore, NEB increased cell volume by 48 +/- 4% and apical surface by 34 +/- 3%. E2 had comparable effects. Tamoxifen, ICI and N[omega]-nitro-L-arginine methyl ester substantially diminished the effects of NEB and E2.NEB decreases cellular stiffness and causes endothelial cell growth. These effects are nitric oxide-dependent and mediated through nongenomic ER[beta] pathways. The morphological and functional alterations observed in endothelial cells may explain improved endothelial function with NEB treatment.

In patients with severe hypertension a search for a renal cause, particularly for a renal artery stenosis, needs to be undertaken with 24-hour blood pressure measurement, urinary examination, determination of renal function and duplex sonography of the kidneys.--Sympathetic hyperactivity, which is associated with an increased cardiovascular risk, may already be found in an early stage of renal diseases. There is evidence that administration of an ACE inhibitor or an angiotensin receptor antagonist (ARB) may induce a decrease of sympathetic hyperactivity as well as a reduced rate of adverse cardiovascular events in patients in renal failure.--In patients with renal disease and high proteinuria antihypertensive therapy with ACE-inhibitors or ARB delays the progression of chronic renal failure. Combined therapy of ACE-inhibitors plus ARB may reduce proteinuria more than that would be the case with either of these drugs alone. However, there is no evidence that combination of these two drugs improves renal function more than monotherapy.--Renal artery stenosis of > 70% should be treated by dilatation, if there is evidence of fibromuscular dysplasia. Dilatation and/or stent implantation in an atherosclerotic renal artery stenosis of > 70% should be performed if indicated by the patient's clinical state. i.e. severe hypertension has proved to be resistant to triple drug antihypertensive therapy or pulmonary edema has occurred frequently. Preservation of renal function by angioplasty of an atherosclerotic renal artery stenosis remains a challenge. However, exact criteria for such intervention need to be established. But so far there have not been adequate data from controlled prospective trials.

Background Antihypertensive drugs may have differential, pressure-independent effects on hypertension-associated alterations of arterial function. We compared the effects of a 12-week therapy with the AT(1)-receptor antagonist valsartan (Val) versus the beta-blocker metoprolol (Met) on arterial stiffness and endothelial function in mildly hypertensive patients at rest and during generalized sympathetic stimulation. Methods Sixty-eight patients (37 male, 31 female, 46 +/- 6 years) were randomized to Val (80-160 mg/d) or Met (50-100 mg/d). Effects of therapy on endothelial function, brachial and carotid artery distensibility coefficients, pulse wave velocity, carotid intima-media thickness and elastic modulus were assessed at rest and during the cold pressor test. Results Fifty-two patients were available for per protocol analysis. Blood pressure was comparably reduced in both treatment groups. Effects on endothelial function and large artery elastic wall properties did not differ significantly between the two antihypertensive treatment regimens. Trends did not differ significantly between groups for any parameter including carotid intima-media thickness and elastic modulus. Conclusion Short-term treatment with Val and Met had similar effects on large artery functional vessel wall properties in a population of mildly hypertensive patients.

BACKGROUND: Chronic kidney disease (CKD) is associated with markedly increased in-hospital morbidity and mortality. Its effect on in-hospital costs for the treatment of coronary heart disease (CHD) has not been assessed that, although it is of interest due to the exponential increase in its prevalence. METHODS: Clinical and costing data were retrospectively assessed from 765 consecutive patients who suffered from CHD requiring percutaneous coronary interventions. Based on their estimated glomerular filtration rate (eGFR), patients were classified in accordance with the National Kidney Foundation. Patient-level in-hospital costs for this single hospitalization were thoroughly calculated from precise in-house assessments for the national DRG database. RESULTS: In univariate analysis, the average total in-hospital costs increased with each stage of CKD [euro2926; euro3466; euro4208; euro9687 (stages 4 and 5 combined), P < 0.0001]. Treating patients with CKD stages 4 and 5 utilized markedly more resources than patients with ST-elevation myocardial infarction (euro4916), coronary three-vessel disease (euro4659), severely impaired left ventricular function (euro6072) or diabetes (euro4495). Multivariate analyses identified, even after adjustment for confounding comorbidities, that CKD was a significant and independent predictor of in-hospital costs; with each loss of 1 ml/min in the eGFR, the expenses for this hospitalization increased by euro18 (95% CI euro13-23). CONCLUSIONS: Although the absolute amount of costs may vary between different countries, this work showed, for the first time, that in all stages of CKD, there is a significant increase of in-hospital costs when treating patients with both CHD and CKD.

Vascular actions of steroid hormones have gained increasing importance. Indeed, some steroid hormones favorably influence vascular structure and function, whereas others are detrimental. This review will focus on the endothelial effects of steroid hormones. In the first part, we summarize data from in vivo studies elucidating the regulation of endothelial function by steroid hormones. Accumulating data argue for an improvement of endothelium-derived relaxation and impaired vascular contraction by estradiol, whereas testosterone, progesterone, and aldosterone have contrary effects. In the second part, we present data from novel atomic force microscopy studies performed in living endothelial cells under the influence of steroid hormones. These studies provide insight into structural and functional alterations of endothelial cells characterized by changes in volume, apical surface, and stiffness. We summarize the available evidence that changes in shape of endothelial cells translate into changes of endothelial cell stiffness. Under the influence of estradiol, endothelial cells become spherical with consecutive improvement of elasticity, whereas aldosterone flattens endothelial cell-shape leading to increased stiffness. Both, endothelial cell shape and stiffness are major determinants of endothelial nitric oxide production. These studies emphasize the great potential of atomic force microscopy to investigate the function of living endothelial cells.

Dietary salt plays a major role in the regulation of blood pressure, and the mineralocorticoid hormone aldosterone controls salt homeostasis and extracellular volume. Recent observations suggest that a small increase in plasma sodium concentration may contribute to the pressor response of dietary salt. Because endothelial cells are ( i ) sensitive to aldosterone, ( ii ) in physical contact with plasma sodium, and ( iii ) crucial regulators of vascular tone, we tested whether acute changes in plasma sodium concentration, within the physiological range, can alter the physical properties of endothelial cells. The tip of an atomic force microscope was used as a nanosensor to measure stiffness of living endothelial cells incubated for 3 days in a culture medium containing aldosterone at a physiological concentration (0.45 nM). Endothelial cell stiffness was unaffected by acute changes in sodium concentration per se may affect endothelial function and thus control vascular tone.

A few recent studies suggested that anaemia has a marked impact on the survival of patients with coronary heart disease (CHD). However, all of these analyses did not take into consideration that chronic kidney disease (CKD) plays an important role in erythropoiesis and anaemia. Therefore, we assessed in this study whether anaemia is an independent predictor of mortality or if its impact was confounded by CKD, which is known to have itself a marked impact on outcomes of patients with CHD.In a retrospective cohort study, we analysed 709 patients with symptomatic and significant CHD who underwent percutaneous coronary interventions. Patients were classified as anaemic using the WHO definition; renal function was classified by the estimated glomerular filtration rate (eGFR).In comparison with non-anaemic patients, anaemic patients had a significantly higher in-hospital mortality (4.9 vs 0.5%, P0.001). Moreover, 1-year mortality rates of anaemic patients were significantly higher regardless of whether they had a normal eGFR (22 vs 2.8%, P=0.029), an eGFR of 60-89 ml/min (14 vs 4.2%, P0.001), an eGFR of 30-59 ml/min (21 vs 3.7%, P0.001) or an eGFR30 ml/min (26 vs 0%, NS). When cumulative mortality was analysed by haemoglobin concentrations in steps of 1 g/dl from11.0 g/dl to16.9 g/dl, 1-year mortality rates were 28, 18, 15, 5.5, 3.8, 5.7, 1.5 and 0%, respectively (P0.001, log rank). Even after adjustment for comorbidities by multivariable Cox regression models, haemoglobin remained a significant predictor of long-term mortality (hazard rate ratio 0.77, 95% confidence interval (CI): 0.62-0.82, P0.001) while eGFR was not (hazard rate ratio 1.0, 95% CI: 0.99-1.01).Anaemia was found to be a strong and independent predictor of acute and long-term mortality in patients with symptomatic CHD, regardless of the presence of CKD.

Tonic activation of the sympathetic nervous system is a major factor contributing to hypertension in patients with chronic renal failure. Besides its role in blood pressure regulation, sympathetic overactivity causes structural and functional alterations of the myocardium and large artery walls. Altogether, these factors contribute substantially to the increased cardiovascular morbidity and mortality in patients with chronic renal disease. Moreover, increased sympathetic outflow in conjunction with increased oxidative stress causes progression of renal disease thereby accelerating the course towards the need of renal replacement therapy. The origin of increased sympathetic outflow in patients with renal disease still has not been fully elucidated. There is sound evidence that signals arising from the diseased kidneys - mediated via renal afferent nerves – cause tonic activation of efferent sympathetic nerve fibres. Renal ischemia with release of adenosine and renal chemoreceptor activation, accumulation of angiotensin II and fibroproliferative scarring with renal mechanoreceptor dysfunction may be involved in the activation of renal afferences. Sympathetic overactivity in renal disease can be diminished by blockers of the renin angiotensin aldosterone system, by adrenoreceptor blockers and by substances inhibiting central sympathetic outflow such as imidazolines. These drugs not only reduce sympathetic nerve activity, they attenuate cardiovascular pathology and they slow the progression of renal disease. A combination of these drugs in patients with chronic renal failure seems promising and warrants randomized large-scale studies.

Aim: In response to aldosterone endothelial cells swell and stiffen. Although amiloride-sensitive sodium and water uptake is known to be involved, the underlying mechanisms are yet unclear. We tested the hypothesis whether the intracellular accumulation of water or organic matter is responsible for the structural and functional alterations. Methods: Atomic force microscopy was used as an imaging tool and a mechanical nanosensor. Cell water, organic cell matter and cell pressure was measured at single cell level in human umbilical vein endothelial cells (HUVEC). Furthermore, we tested by means of a miniature perfusion chamber in vitro the physical robustness to blood flow of the aldosterone-treated endothelium. Results: In response to a three-day treatment with 1 nm aldosterone HUVEC swell. To our surprise, cell water decreased from 82 � 6% to 71 � 5% while intracellular organic matter increased from 18 � 1.8% to 29 � 3.0%. These changes were paralleled by a rise in cell pressure of 114%, measured in living HUVEC in vitro. Blood flow across the endothelium was found significantly altered after aldosterone treatment. Imaging the endothelial monolayer after blood perfusion disclosed large gaps between cells treated with aldosterone. The mineralocorticoid receptor blockers, spironolactone and eplerenone could prevent the aldosterone actions. Conclusion: Mild aldosteronism causes intracellular accumulation of organic matter at the cost of cell water. This makes endothelium stiff and vulnerable to shear stress. The measurements could explain clinical observations that high blood pressure combined with high plasma aldosterone concentration may damage the endothelium of blood vessels.

It has been suggested that the increase in blood pressure observed in transplant patients treated with cyclosporine is mediated by cyclosporine-induced sympathoexcitation. However, the chronic effects of cyclosporine on sympathetic outflow in renal transplant patients have not been investigated. Therefore we studied sympathetic nerve activity and blood pressure before and 6 months after the withdrawal of cyclosporine in renal transplant patients.Twenty-four renal transplant patients with histologically confirmed chronic allograft nephropathy (age 48 +/- 3 years, 60 +/- 10 months after transplantation) were included in the prospective study and randomly assigned to either withdrawal (n = 12) or continuation (n = 12) of cyclosporine. Both groups received mycophenolate mofetil and prednisolone as additional immunosuppressants. At entry and 6 months later blood pressure, muscle sympathetic nerve activity (MSNA), and plasma norepinephrine were measured. To assess the potential influence of the diseased native kidneys, three renal transplant patients who had their native kidneys removed were studied before and after cyclosporine withdrawal.Mean arterial pressure decreased significantly in the cyclosporine-withdrawal group (95 +/- 4 versus 105 +/- 4 mmHg 6 versus 0 months, P0.05) but not in the cyclosporine-continuation group (103 +/- 3 versus 105 +/- 4 mmHg, NS). However, plasma norepinephrine and MSNA did not change significantly in either group (MSNA 43 +/- 4 versus 44 +/- 3 and 38 +/- 5 versus 39 +/- 4 bursts/min in the cyclosporine-withdrawal and cyclosporine-continuation groups, NS). Graft function remained stable in both groups and in transplant patients who had their native kidneys removed MSNA did not decrease after cyclosporine withdrawal.The withdrawal of cyclosporine in renal transplant patients, receiving relatively low doses of cyclosporine, resulted in a substantial decrease in blood pressure. However, MSNA and norepinephrine did not change. This suggests that cyclosporine treatment does not cause chronic sympathetic activation that could explain the cyclosporine-induced blood pressure elevation in renal transplant patients.

Ein 75-jahriger Patient, der seit 35 Jahren eine Schachtel Zigaretten pro Tag raucht, mit deutlichem Ubergewicht (Body-Mass-Index [BMI] 32 kg/m2), schlecht eingestelltem Hypertonus (Praxisblutdruckwerte um 165/100 mmHg), Hyperurikamie, kombinierten Fettstoffwechselstorungen und einem seit 17 Jahren bekannten Diabetes mellitus 2b (HbA1c 7,2%) wird seit vielen Jahren mit einer antihypertensiven Medikamentenkombination aus einem β-Blocker, Calciumantagonisten, Diuretikum sowie einem zentral wirksamen Antihypertensivum behandelt. Mittlerweile hat sich eine Nierenfunktionsverschlechterung eingestellt, das Serumkreatinin betragt 2,2 mg/dl, und im 24-h-Sammelurin verliert der Patient etwa 1,8 g Eiweis pro Sammelperiode. Vor 1 Jahr war eine Therapie mit einem ACE-Inhibitor abgebrochen worden, da sich unter der Therapie ein Anstieg des Serumkreatinins um 0,3 mg/dl eingestellt hatte. Hoher Blutdruck, die eingeschrankte Nierenfunktion und die weiteren Symptome des metabolischen Syndroms erfordern dringend eine Neukonzeption der blutdrucksenkenden Therapie. Der eingangs geschilderte Patient leidet sicherlich zum einen an einer unzureichenden Blutdruck—und zum anderen an einer sehr schlechten Blutzuckereinstellung. Es finden sich nahezu alle Manifestationen des metabolischen Syndroms, das kardiovaskulare Risikoprofil muss also als sehr hoch eingestuft werden. Trotz relativ weit fortgeschrittener Nierenschadigung sollte bei diesem Beispiel eine strikte Nikotinkarenz konsequent durchgesetzt werden, da sich Nikotinkonsum auch als ein Progressionsfaktor der Niereninsuffizienz herausgestellt hat. Die medikamentose Therapie sollte aufgrund der oben angefuhrten stichhaltigen Argumente unbedingt um einen Hemmstoff des RAAS, z. B. in Form eines ACE-Inhibitors, erganzt werden. Aufgrund der eingeschrankten Nierenfunktion musste die Dosis angepasst werden. Inwieweit eine Kombination aus einem ACE-Hemmer mit einem Angiotensin-Rezeptor-Antagonisten sinnvoll ist, bleibt abzuwarten. Vorteilhaft in der Therapie mit dem ACE-Hemmer ist sicherlich auch seine weitestgehende Stoffwechselneutralitat. Die Kombination mit dem Diuretikum in unserem Beispiel ist sinnvoll, da sich die Wirkprinzipien erganzen. Aufgrund der Nierenfunktionseinschrankung sollten Thiaziddiuretika nicht mehr eingesetzt werden, ein weiterer Abfall der GFR ware hier bestimmt die Folge. Auf den Einsatz des β-Blockers und Calciumantagonisten wird man wahrscheinlich nicht verzichten konnen. Sinnvoll konnte aber durchaus eine 24-h-Blutdruckmessung sein, mit der sich ein Praxishochdruck ausschliesen lasst und die, z. B. durch Fehlen einer nachtlichen Blutdrucksenkung, Hinweise auf eine sekundare Hochdruckursache liefert. In Anbetracht des Risikoprofils des Patienten ware eine Nierenarterienstenose nicht unwahrscheinlich.

Decisions about the management of patients with hypertension should not be based on the level of blood pressure alone but also on the presence of target organ damage. Apart of classical sites of target organ damage - kidney and heart - the assessment of functional and structural alterations of large arteries is of increasing clinical importance. Modern non-invasive procedures allow the assessment of large artery wall properties within the clinical routine. Hypertension associated large artery damage may present as structural and functional alterations. Structural alterations comprise intima-media thickening, plaque formation, stenosis of the artery and formation of aneurysms. Functional alterations comprise endothelial dysfunction and alterations of the mechanical properties of the arterial wall with increasing stiffness and loss of the Windkessel function. Loss of central artery elastic properties will ensue an early reflection of the pulse wave with a resulting increase in central systolic and central diastolic pressure. This causes an increase in left ventricular afterload and a reduction in diastolic perfusion of the myocardium. In the last decade the relevance of large artery structural alterations, endothelial dysfunction and arterial stiffness for the risk of cardiovascular morbidity and mortality in hypertensive patients could be demonstrated convincingly. Measurement of intima-media-thickness therefore is part of the standard evaluation of hypertensive patients. Because of the equal prognostic relevance of functional properties of the arterial wall, assessment of large artery functional alterations is helpful for the risk stratification of hypertensive patients. Modern antihypertensive drugs have favourable effects on arterial wall properties. Therefore, the quantification of large artery wall properties should be part of the management of hypertensive patients.

Alterations in the metabolism of calcium and magnesium have been implicated in the pathogenesis of primary hypertension. Calcium influx across the external cellular membrane in smooth muscle cells and cardiomyocytes plays a crucial role in the control of cellular excitation contraction and impulse propagation. Intracellular calcium and magnesium concentrations are controlled by reversible binding to specific calcium-binding proteins. The calcium and magnesium flux across the external membrane is regulated by a calcium pump (calcium-magnesium-ATPase), calcium channels, and binding to the membrane. In cell membranes and in lymphocytes of essential hypertensives our group showed increased calcium and a decreased magnesium and increased calcium/magnesium ratio in hypertensive cells. In this context, in aortic smooth muscle cells from 13 spontaneously hypertensive rats (SHR) of the Munster strain (systolic blood pressure 188.4 +/- 9.8 mm Hg) and 13 normotensive rats (NT, systolic blood pressure 118.5 +/- 7.2 mm Hg) aged 9 months, the intracellular calcium and magnesium contents were measured under nearly in vivo conditions by electron probe microanalysis. Measurements were performed in aortic cryosections 3 microm thick; the calcium content was 124.7 +/- 4.5 mmol/kg dry weight in SHR versus 110.3 +/- 4.1 mmol/kg dry weight in NT (mean +/- SD, P

Whether withdrawal of calcineurin inhibitors has a beneficial effect on disturbed endothelial function and large artery distensibility in renal transplant recipients is not clear. We studied the effects of cyclosporine A (CsA) withdrawal on arterial compliance and endothelium-dependent flow-mediated vasodilatation (FMD) in a prospective, randomized trial; 24 renal transplant recipients receiving mycophenolate mofetil were randomized to withdrawal (n=12) or continuation of CsA (n=12). At baseline and after 6 months, carotid and brachial artery distensibility coefficients and brachial FMD were measured. Brachial distensibility coefficients increased in both groups (withdrawal: 11.1+/-1-14.9+/-2 10(-3)/kPa, continuation: 10.7+/-1-15.2+/-3 10(-3)/kPa, P

Quantitative ultrasound (QUS) is a new and non-invasive method to assess skeletal status after kidney transplantation. We evaluated the potential use of this novel method in renal allograft recipients and studied the accuracy compared to normal controls. Thirty patients (NTP, age 47.5 ± 13.0 years) were studied 4.8 ± 3.2 years after kidney transplantation. Twenty-five healthy control persons (CON) were matched for age and sex. The left and right os calcis were studied by QUS, and speed of sound (SOS) and broadband ultrasound attenuation (BUA) were measured. Bone stiffness (BS) was calculated from these parameter and corrected for age (CBS). Differences between right and left os calcis were compared to CON to assess the side variability (mean ± SD); BS was 75 ± 25% compared to young adults, age-corrected CBS was decreased in NTP with 86 ± 25% of normal, indicating a 2-fold increased risk of fracture. SOS was 1,525 ± 47.7 m/s, BUA was 105 ± 22 dB/MHz. Mean difference between right and left os calcis was significantly higher in NTP than in CON (7.2 ± 7.1% vs. 2.1 ± 2.1%, p < 0.01). Limits of agreement of the measurements (MW of differences ± 2 SD) according to a Bland-Altmann type statistic were 16.9% and 20.7%. There was no correlation between CBS and age, cumulative steroid dose, parathyroid hormone concentrations or time after transplantation. In addition, 19 patients (49 ± 3 years, graft function: 1.8 ± 0.2 and 2.0 ± 0.2 mg%) were investigated in a 2-year follow-up study. The measures of bone stiffness at months 0 and 24 were well correlated (r < 0.9, p < 0.001), however, bone stiffness did not change significantly with time. There was a significant correlation between bone stiffness and serum calcium values (0.49, p < 0.015). Our data show altered bone structure expressed by low bone stiffness values measured by quantitative ultrasound in kidney transplant patients. However, because of relatively high interfeet variance of QUS, we suggest measurement of both os calcis to minimize measurement error after transplantation. In addition, we conclude from the data of this follow-up study that despite continued low-dose steroid treatment (< 10 mg prednisolone/day), renal transplant recipients are not subject to accelerated osteoporosis. Bone stiffness did not significantly decrease over 2 years in the present study. However, bone stiffness baseline and 2 years later were found to be decreased compared to healthy controls, a finding that is in accordance with previous data demonstrating an increased fracture rate in allograft recipients.

BACKGROUND Endothelial function of large arteries is impaired in chronic haemodialysis patients and oxidative stress due to the dialysis procedure has been suggested as a causal factor. However, it is not clear whether different types of dialysis membranes affect endothelial function differently. Therefore we determined endothelium-dependent, flow-mediated dilatation (FMD) of the brachial artery as well as markers of oxidative stress immediately before and after haemodialysis (HD) with either a cellulosic cuprophane or a synthetic polysulphone dialyser in a blinded, randomized, cross-over study. METHODS Twelve haemodialysis patients (age 55+/-3 years, time on dialysis 20+/-2 months, mean fluid change -1782+/-21 ml, systolic/diastolic blood pressure 139/75 mmHg) were included. Using a multi-gate-pulsed Doppler system (echo-tracking device) brachial artery FMD and nitroglycerine-induced, endothelium-independent vasodilatation (NMD) were measured. Patients were randomized to HD with either a polysulphone or a cuprophane membrane and were crossed over to the other filter. Investigators were blinded to the type of membrane used. Serum concentrations of oxidized LDL (oxLDL) and alpha-tocopherol as markers of oxidative stress were measured before and after each dialysis session. RESULTS Data are given as mean+/-SEM. Treatment with polysulphone filter HD did not significantly affect FMD (baseline 9.3+/-2.0% vs after HD 9.6+/-1.8%). After dialysis with a cuprophane membrane FMD decreased from 9.4+/-2.1 to 7.4+/-1.8% (P

BACKGROUND Parathyroid hormone (PTH) has specific effects on function, migration and proliferation of human leukocytes. These effects may contribute to accelerated atherosclerosis and impaired immune response observed in patients with renal insufficiency. Recently, a new G protein-coupled receptor with substantial implications for vascular function--the PTH2 receptor (PTH2-R)--has been identified, however, expression and distribution in humans and a possible regulation has not yet been studied. We therefore investigated the expression of the PTH2 receptor on human leukocytes in healthy subjects and in patients with hyperparathyroidism. METHODS PTH2 receptor expression was quantified by flow cytometry (FACS) analysis on monocytes, lymphocytes and granulocytes that were isolated from peripheral blood (hypotonic density gradient centrifugation) and by immunohistochemistry using a specific alpha-PTH2-R antibody produced in rabbit. Results of 22 patients with hyperparathyroidism (12 renal allograft recipients, 10 hemodialysis patients, mean age 43 +/- 8 years) were compared to 22 age and sex-matched healthy controls. RESULTS Mean relative antigen density of the PTH2 receptor and percentage of positive cells in healthy subjects was 19 +/- 5 and 90 +/- 6% on granulocytes, 5 +/- 2 and 55 +/- 19% on monocytes, and 24 +/- 7 and 21 +/- 7% on lymphocytes. In patients with hyperparathyroidism, mean antigen density was significantly lower on granulocytes and monocytes (17 +/- 4% and 3 +/- 1%, p < 0.01, respectively). The percentage of positive cells and mean expression on lymphocytes was not significantly different. A significant and inverse correlation was found between plasma PTH concentrations and the mean PTH2 receptor expression on granulocytes (r = -0.41, p < 0.05). CONCLUSIONS The PTH2 receptor is expressed on human granulocytes and--to a lesser degree--on monocytes and lymphocytes. In patients with hyperparathyroidism the PTH2 receptor is down-regulated as function of plasma PTH levels.

In patients after renal transplantation functional arterial vessel wall properties are impaired. Whether 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have a sustained effect on endothelial function and arterial distensibility in patients after renal transplantation is not clear. The authors studied the effects of a long-term therapy with fluvastatin on large artery distensibility and flow-mediated vasodilation (FMD) in hypercholesterolemic patients after renal transplantation in a prospective, blinded, and randomized trial.Twenty-six patients who had undergone renal transplantation were assigned randomly to either fluvastatin, 40 mg/d (n = 13) or placebo (n = 13) and underwent follow-up for 3 years. At baseline and after 6, 12, and 36 months of treatment, carotid and brachial artery distensibility, endothelium-dependent FMD, and nitroglycerine-induced vasodilation (NMD) of the brachial artery were measured by a echo-tracking device.A significant decrease in total and low-density cholesterol was observed after 6, 12, and 36 months in patients treated with fluvastatin but not in the placebo group. FMD increased with fluvastatin from 4.6 +/- 2% to 12.4 +/- 2% after 12 months; this improvement was sustained with 13.4 +/- 3% after 36 months (P0.05). However, placebo did not alter FMD (P0.001 for trend difference between groups by analysis of covariance). Endothelium-independent NMD was similar in both groups at baseline and during therapy. Neither carotid nor brachial artery distensibility coefficients were altered by either treatment.HMG-CoA reductase inhibitor therapy over 3 years results in a significant and sustained improvement of endothelial function in hypercholesterolemic patients after renal transplantation. However, this is not accompanied by a beneficial effect on impaired large artery distensibility even after long-term therapy with fluvastatin.

Leptin contributes to the regulation of thermogenesis. In rodents, sympathetic nerve activity efferent to interscapular brown adipose tissue (IBAT-SNA) is involved. On the basis of the hypotheses that 1) leptin acutely potentiates hypothermia-induced increases in IBAT-SNA; 2) this action of leptin is specific to IBAT-SNA, i.e., it does not occur with renal sympathetic nerve activity (R-SNA); and 3) this effect of leptin depends on intact and functional leptin receptors, we measured IBAT-SNA and R-SNA in anesthetized lean and diet-induced obese Sprague-Dawley and in obese Zucker rats, randomly assigned to low-dose leptin or vehicle. Before the start of leptin or vehicle and 5 min, 90 min, and 180 min after, hypothermia (30° C) was induced. Compared with vehicle, leptin did not significantly alter baseline R-SNA or IBAT-SNA. In lean Sprague-Dawley rats, hypothermia-induced increases in IBAT-SNA were significantly augmented by leptin but not by vehicle. In obese Sprague-Dawley rats, leptin did not potentiate hypothermia-induced increases in IBAT-SNA. In Zucker rats, IBAT-SNA did not increase with hypothermia and leptin was not able to induce sympathoactivation with cooling. Changes in R-SNA during hypothermia were not significantly modified by leptin in either group. Thus, low-dose leptin, although not altering baseline SNA, acutely enhances hypothermia-induced sympathetic outflow to IBAT in lean rats. This effect is specific for thermogenic SNA because leptin does not significantly alter the response of R-SNA to hypothermia. The effect depends on intact and functional leptin receptors because it occurs neither in rats with a leptin receptor defect nor in rats with acquired leptin resistance.

OBJECTIVE Arterial distensibility is reduced in end-stage renal failure and also after renal transplantation. The aim of the present study was to test the hypothesis that reduced carotid artery distensibility is a predictor of cardiovascular disease in patients after renal transplantation. SUBJECTS AND METHODS Sixty-eight asymptomatic renal transplant recipients were studied between March 1990 and December 1992, 3-6 months after transplantation. The mean duration of follow-up was 95 +/- 2 months (mean +/- SEM). At entry, vessel wall movements of the common carotid artery were recorded using a pulsed multigate Doppler system; blood pressure was measured by sphygmomanometry. RESULTS Nineteen cardiovascular events (CVE) occurred during follow-up, leading to death in six cases. The distensibility coefficient of the common carotid artery was significantly lower in patients with CVE than in those without CVE (12.2 +/- 1.0 10-3/kPa versus 16.8 +/- 0.7 10-3/kPa, P < 0.005). Logistic regression analysis showed that the occurrence of cardiovascular disease during follow-up was related to carotid artery distensibility (P < 0.05), independent of sex, age, smoking habits, carotid artery end-diastolic diameter, systolic and diastolic blood pressure levels, heart rate, serum creatinine, cholesterol and haemoglobin levels. Patients with a distensibility coefficient above the age-adjusted mean had a significantly longer interval free of cardiovascular disease than patients with a distensibility coefficient below the age-adjusted mean (P < 0.01). CONCLUSIONS The distensibility of the common carotid artery is an independent predictor of cardiovascular disease in renal transplant recipients.

Aims To compare the effects of two long-acting calcium antagonists of different types on cardiovascular stress responses in hypertension. Methods One-hundred and forty-five patients with mild to moderate hypertension and a mean (± s.e.mean) age of 51 ± 0.9 years received for 8 weeks the phenylalkylamine verapamil sustained release (240 mg) and the dihydropyridine amlodipine (5 mg) in a double-blind cross-over design, both after 4 weeks of placebo. Blood pressure, heart rate and plasma noradrenaline were monitored during 3 min of sustained isometric handgrip and 2 min of cold pressor. Results Blood pressure was equally reduced by both drugs. After 3 min handgrip, systolic blood pressure, heart rate and rate-pressure product were lower with verapamil compared with amlodipine. Verapamil attenuated the increases in systolic blood pressure (25 ± 2 vs 30 ± 2 mmHg, difference 4.6, 95% CI (1.0, 8.1), P

Die Bedeutung der arteriellen Hypertonie bei der Entwicklung zerebrovaskularer bzw. kardiovaskularer Erkrankungen ist evident. Ebenso evident ist die Verminderung des Risikos dieser Erkrankungen durch die Senkung des Blutdrucks an sich. Noch offen ist dagegen die Frage, welche Substanzgruppen zur antihypertensiven Therapie besondere Vorteile bei den unterschiedlichen Risikogruppen, wie etwa Patienten mit Diabetes mellitus, bieten. Die vorliegende Ubersicht beschreibt die Ergebnisse einer Reihe von grosen Interventionsstudien, die zur Beantwortung dieser Frage beitragen sollen. Daruber hinaus wird aufgezeigt, welche Therapieempfehlungen sich aus diesen Ergebnissen ableiten lassen.

Background. Disturbances of functional properties of large arteries contribute to increased cardiovascular morbidity and mortality in patients with end-stage renal disease. However, it is not clear whether haemodialysis per se acutely affects mechanical vessel wall properties or endothelial function. Methods. Twenty-five chronic haemodialysis patients (mean ± standard error of the mean (SEM): age 52 ± 5 years; time on dialysis 63 ± 7 months; blood pressure 132 ± 4/72 ± 2 mmHg) were studied before and immediately after a haemodialysis (HD) session using a polysulphone dialyser (ultrafiltration 1460 ± 54 ml), as well as on the following day. Blood pressure was measured with an automatic sphygmomanometer and applanation tonometry. End-diastolic diameter and distension of the brachial and carotid arteries were measured by Doppler frequency analysis of vessel wall movements in M-mode using a multigate pulsed Doppler system and aortic pulse wave velocity (PWV) by an automatic device (Complior®). Endothelial function was determined as brachial artery flow-mediated dilation (FMD) and compared with endothelium-independent t nitroglycerine-induced dilation (NMD). Results. FMD was 7.9 ± 1.8% in patients before HD and did not change significantly after HD or in the dialysis-free intervall (6.7 ± 2.1 and 7.1 ± 2.0%, respectively; NS). The same was true for NMD and PWV (12.6 ± 0.8 m/s before HD, 12.8 ± 0.8 m/s after HD, and 11.9 ± 0.7 m/s on the HD-free day). Carotid distensibility coefficients decreased significantly during HD (from 18.1 ± 1.9 × 10 -3 /kPa to 16.7 ± 2.2 × 10 3 /kPa, P