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Hyperphosphatemia has been associated with higher mortality risk in CKD 5 patients receiving dialysis. Here, we determined the association between the use of single and combined phosphate- binding agents and survival in 6797 patients of the COSMOS study: a 3-year follow-up, multicenter, open-cohort, observational prospective study carried out in 227 dialysis centers from 20 European countries. Patient phosphate-binding agent prescriptions (time-varying) and the case- mix–adjusted facility percentage of phosphate- binding agent prescriptions (instrumental variable) were used as predictors of the relative all-cause and cardiovascular mortality using Cox proportional hazard regression models. Three different multivariate models that included up to 24 variables were used for adjustments. After multivariate analysis, patients prescribed phosphate-binding agents showed a 29 and 22% lower all-cause and cardiovascular mortality risk, respectively. The survival advantage of phosphate- binding agent prescription remained statistically significant after propensity score matching analysis. A decrease of 8% in the relative risk of mortality was found for every 10% increase in the case-mix–adjusted facility prescription of phosphate-binding agents. All single and combined therapies with phosphate-binding agents, except aluminum salts, showed a beneficial association with survival. The findings made in the present association study need to be confirmed by randomized controlled trials to prove the observed beneficial effect of phosphate-binding agents on mortality.

The clinical course of secondary hyperparathyroidism (sHPT) in patients on hemodialysis is not well described, and the effect of the calcimimetic cinacalcet on disease progression is uncertain.Our objective was to describe 1) the clinical course of sHPT in patients treated with phosphate binders and/or vitamin D sterols and 2) the impact of cinacalcet on the occurrence of severe unremitting HPT, defined by the persistence of markedly elevated PTH concentrations together with hypercalcemia or parathyroidectomy (PTX).This was a randomized, double-blind, placebo-controlled, global, multicenter clinical trial.Of 5755 patients screened with moderate to severe sHPT, 3883 patients on hemodialysis were included in the trial.Outcomes included PTX; severe, unremitting HPT; and use of commercial cinacalcet (a protocol violation).Intervention was cinacalcet (30-180 mg daily) or placebo for up to 64 months.In the 1935 patients randomized to placebo, 278 patients (14%) underwent PTX (median PTH 1872 pg/mL within the previous 12 weeks from surgery). Age, sex, geographic region, co-morbidity, calcium-containing phosphate binder use, and baseline serum calcium, phosphorus, and PTH concentrations were associated with PTX. Commercial cinacalcet was started in 443 (23%) patients (median PTH 1108 pg/mL before treatment began). Severe unremitting HPT developed in 470 patients (24%). In a multivariable Cox model, the relative hazard (comparing patients randomized to cinacalcet versus placebo) of severe unremitting HPT was 0.31 (95% confidence interval = 0.26-0.37). The relative hazard differed little when adjusted by baseline clinical characteristics.Severe unremitting HPT develops frequently in patients on hemodialysis despite conventional therapy, and cinacalcet substantially reduces its occurrence.

Studies of pulsatile arterial hemodynamics have emphasized that the pulsatile component of pulse pressure has two important characteristics: (i) it increases from central to peripheral arteries for a similar value of mean arterial pressure, and (ii) it is dominantly influenced by the amplitude and timing of the backward pressure wave. Although these important aspects of wave reflections have been poorly investigated in the field of hypertension, they may be easily studied noninvasively in humans on the basis of the analysis of the pulse wave contour of carotid and aortic blood pressure. Increased wave reflections returning toward the thoracic aorta during systole may have deleterious consequences on the structure and function of the heart. Some (but not all) antihypertensive drugs may contribute to decrease and/or to delay wave reflections in association with blood pressure reduction.

Background. Chronic kidney disease–mineral and bone disorders (CKD–MBD) are important complications of CKD5D patients that are associated with mortality. Methods. COSMOS is a multicentre, open cohort, prospective, observational 3-year study carried out in haemodialysis patients from 20 European countries during 2005–07. The present article describes the main characteristics of the European dialysis population, the current practice for the prevention, diagnosis and treatment of secondary hyperparathyroidism and the differences across different European regions. Results. The haemodialysis population in Europe is an aged population (mean age 64.8 ± 14.2 years) with a high prevalence of diabetes (29.5%) and cardiovascular disease (76.0%), and 28.7% of patients have been on haemodialysis more than 5 years. Patients from the former Eastern countries are younger (59.3 ± 14.3 versus 66.0 ± 13.9), having a lower proportion of diabetics (24.1 versus 30.7%). There were relevant differences in the frequency of measurement of the main CKD–MBD biochemical parameters [Ca, P and parathyroid hormone (PTH)] and the Eastern countries showed a poorer control of these biochemical parameters (K/DOQI and K/DIGO targets). Overall, 48.0% of the haemodialysis patients received active vitamin D treatment. Calcitriol use doubled that of alfacalcidiol in the Mediterranean countries, whereas the opposite was found in the non-Mediterranean countries. The criteria followed to perform parathyroidectomy were different across Europe. In the Mediterranean countries, the level of serum PTH considered to perform parathyroidectomy was higher than in non-Mediterranean countries; as a result, in the latter, more parathyroidectomies were performed in the year previous to inclusion to COSMOS. Conclusions. The COSMOS baseline results show important differences across Europe in the management of CKD–MBD.

Summary Background and Objectives A high body mass index (BMI) is associated with lower mortality in patients undergoing hemodialysis. Short-term weight gains and losses are also related to lower and higher mortality risk, respectively. The implications of weight gain or loss may, however, differ between obese individuals and their nonobese counterparts. Design, Setting, Participants, & Measurements The Current Management of Secondary Hyperparathyroidism: A Multicenter Observational Study (COSMOS) is an observational study including 6797 European hemodialysis patients recruited between February 2005 and July 2007, with prospective data collection every 6 months for 3 years. Time-dependent Cox proportional hazard regressions assessed the effect of BMI and weight changes on mortality. Analyses were performed after patient stratification according to their starting BMI. ResultsAmong 6296 patients with complete data, 1643 died. At study entry, 42% of patients had a normal weight (BMI, 20–25 kg/m2), 11% were underweight, 31% were overweight, and 16% were obese (BMI $30 kg/m2). Weight loss or gain (,1% or .1% of body weight) was strongly associated with higher rates of mortality or survival, respectively. After stratification by BMI categories, this was true in nonobese categories and especially in underweight patients. In obese patients, however, the association between weight loss and mortality was attenuated (hazard ratio, 1.28 [95% confidence interval (CI), 0.74 to 2.14]), and no survival benefi to f gaining weight was seen (hazard ratio, 0.98 [95% CI, 0.59 to 1.62]). ConclusionsAssuming that these weight changes were unintentional, our study brings attention to rapid weight variations as a clinical sign of health monitoring in hemodialysis patients. In addition, a patient’ sB MI modifies the strength of the association between weight changes with mortality. Clin J Am Soc Nephrol 8: 1725–1733, 2013. doi: 10.2215/CJN.10951012

Introduction Il y a peu de donnees sur la prise en charge des troubles du metabolisme mineral et osseux (TMO) de la maladie renale chronique avant le stade de la dialyse en France. Une meilleure connaissance de la prise en charge actuelle pourrait conduire a une amelioration de l’implementation des recommandations internationales (KDIGO). Patients et methodes L’Observatoire national (Sanofi-Genzyme©) dans sa 3e version a inclus une cohorte de patients aux stades 4 et 5 de la MRC dans le but d’examiner les TMO de la MRC et la qualite de leur prise en charge chez des patients suivis par 62 nephrologues repartis dans 20 regions francaises. Les TMO et leurs traitements ont ete etudies en octobre 2011, soit 1 an apres l’inclusion des patients. L’inertie therapeutique est definie comme le pourcentage de patients ayant une anomalie des parametres biologiques refletant les TMO, mais ne recevant pas de traitement adequat. Resultats Au total, 456 patients au stade 4 et 154 au stade 5 ont ete etudies avec un âge moyen de 72,9 ± 14,2 ans et de sexe masculin dans 58 % des cas. Les cibles des KDIGO (stades 4 et 5) n’etaient pas atteintes dans respectivement 80 et 84 % des cas pour la PTH serique, dans 8 et 22 % des cas pour la calcemie et dans 12 et 46 % des cas pour la phosphatemie. Une explication potentielle peut etre l’inertie therapeutique estimee a 45 et 60 % pour l’hyperparathyroidie secondaire (HPTS) et a 45 % pour l’hyperphosphatemie au stade 5. A noter que 55,5 et 57,5 % des patients recevaient de la vitamine D native. Discussion La prise en charge suboptimale des TMO de la MRC provient probablement d’une meconnaissance des cibles biologiques (KDIGO) est des consequences futures des TMO au stade de la dialyse. Conclusion Dans cet Observatoire national, la prise en charge des TMO de la MRC aux stades 4 et 5 apparait suboptimale, surtout pour ce qui concerne l’HPTS qui n’est pas traitee dans pres de 50 % des cas. L’hyperphosphatemie est egalement frequente et insuffisamment controlee au stade 5. Une amelioration de la prise en charge des TMO de la MRC passe par une sensibilisation des nephrologues a l’importance de viser les cibles biologiques et aux moyens d’y arriver.

Increasing numbers of cross-sectional studies on general populations and chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients have reported relationships between cardiovascular calcifications and bone disorders, including osteoporosis, osteopenia and high or low bone activity. The mechanisms underlying this bone-cardiovascular axis and biological links between bone and arterial abnormalities are suggestive of bone-vascular cross-talk. The nature of these links is not well understood and could result from: 1) common factors acting on bone remodeling and arterial calcification; 2) compromised bone blood supply responsible for arteriosclerosis of bone vessels and reduced perfusion; and/or 3) direct action of bone cells (osteoblasts/osteocytes) on vascular biology and structure. Inflammation and accumulation of reactive oxygen species are the principal common pathways linking bone and arterial pathologies.

Background. Secondary hyperparathyroidism (sHPT) and other abnormalities associated with chronic kidney disease– mineral bone disorder can contribute to dystrophic (including vascular) calcification. Dietary modification and variety of medications can be used to attenuate the severity of sHPT. However, it is unknown whether any of these approaches can reduce the high risks of death and cardiovascular disease in patients with end-stage renal disease. Methods. The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial was designed to test the hypothesis that treatment with the calcimimetic agent cinacalcet compared with placebo (on a background of conventional therapy including phosphate binders 1/� vitamin D sterols) reduces the risk of death or non-fatal cardiovascular events (specifically myocardial infarction, unstable angina, heart failure and peripheral arterial disease events) among patients on hemodialysis with sHPT. This report describes baseline characteristics of enrolled subjects with a focus on regional variation. Results. There were 3883 subjects randomized from 22 countries, including the USA, Canada, Australia, three Latin American nations, Russia and 15 European nations. The burden of overt cardiovascular disease at baseline was high (e.g. myocardial infarction 12.4%, heart failure 23.3%). The median plasma parathyroid hormone concentration at baseline was 692 pg/mL (10%, 90% range, 363–1694 pg/ mL). At baseline, 87.2% of subjects were prescribed phosphate binders and 57.5% were prescribed activated vitamin D derivatives. Demographic data, comorbid conditions and baseline laboratory data varied significantly across regions. Conclusions. EVOLVE enrolled 3883 subjects on hemodialysis with moderate to severe sHPT. Inclusion of subjects from multiple global regions with varying degrees of disease severity will enhance the external validity of the trial results.

BACKGROUND We wished to assess the respective roles of the antihypertensive and blood pressure (BP)-independent effects of antihypertensive drugs on arterial hemodynamics and left ventricular hypertrophy (LVH) in end-stage renal disease (ESRD) patients. METHODS AND RESULTS In a double-blind study, 24 ESRD patients with LVH were randomized to 12 months' administration of either the angiotensin-converting enzyme (ACE) inhibitor perindopril (n = 14) or the calcium channel blocker nitrendipine (n = 10). Repeated measurements of the following parameters were performed: BP (mercury sphygmomanometry), left ventricular mass (LVM, echocardiography), cardiac output (aortic cross-section and velocity integral), total peripheral resistance (cardiac output and mean BP), aortic and large-artery compliance (pulse wave velocity, Doppler flowmeter), and arterial wave reflections (augmentation index, applanation tonometry). Radioimmunoassay was used to determine plasma renin activity, aldosterone, and plasma catecholamine levels. Two-way (time-treatment) ANOVA for repeated measures was used for statistical analysis. Perindopril and nitrendipine induced significant and similar decreases in BP, total peripheral resistance (P < .001), aortic and arterial pulse wave velocities (P < .001), and arterial wave reflections (P < .01). At baseline, the two groups had LVH mostly due to increased LV end-diastolic diameter (LVEDD) (perindopril, 54.3 +/- 1.4 and nitrendipine, 54.3 +/ 2.4 mm) with near-normal mean LV wall thickness (perindopril, 11.4 +/- 0.3 and nitrendipine, 11.2 +/- 0.4 mm). A decrease in LVM was observed only in patients receiving perindopril (from 317 +/- 18 to 247 +/- 21 g) (time-treatment interaction, P = .036). Nitrendipine had no significant effect on LVM (314 +/- 29 versus 286 +/- 32 g). The decrease in LVM observed with perindopril was associated with a reduction in LVEDD (49.9 +/- 1.6 versus 54.3 +/- 1.4 mm after 12 months) (time-treatment interaction, P = .04), while the mean LV wall thickness was unchanged (11.4 +/- 0.3 versus 10.5 +/- 0.5 mm). Cardiac alterations were not correlated with changes in BP or with alterations in plasma renin activity or aldosterone or catecholamine levels. CONCLUSIONS In ESRD patients with LVH, ACE inhibition decreases LVM independently of its antihypertensive effect and of associated alterations in arterial hemodynamics. The decrease in LVM was due primarily to a decrease in LV volume, which may have resulted in these patients from chronic volume overload.

Left ventricular hypertrophy is a frequent cardiovascular alteration in end-stage renal disease patients on hemodialysis which is associated with increased morbidity and mortality. Hypertrophy results from chronic flow and pressure overload and from poorly understood neurohumoral alterations. Clinical symptomatology associated with ventricular hypertrophy is related to diastolic dysfunction which characterizes this condition. The symptoms are (1) an unusual sensitivity to volume changes such that hypotension and hemodynamic instability and/or pulmonary edema occur with small volume variations and (2) a high frequency of supraventricular arrhythmias.

In this narrative review, we discuss the dynamics and patho- biology of calcium accumulation in the arterial system and then appraise the validity of vascular calcification as a surro- gate end point in cardiovascular (CV) diseases and in chronic kidney disease (CKD) in particular. Calcification follows in- flammation in human atherosclerosis and therefore most P O L A R V IE W S IN N E P H R O L O G Y © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 352 by C rm ne Z ocali on Feruary 7, 2015 http://ndtrdjournals.org/ D ow nladed from

Epidemiological and clinical studies have shown that damage to large arteries contributes to the high cardiovascular mortality in patients with end-stage renal disease (ESRD). Atherosclerosis is the most frequent cause of arterial damage. Occlusive lesions from atherosclerotic plaques (calcification) decrease the conduit function of arteries and reduce the elasticity of capacitance arteries (stiffening), affecting their dampening function. Arterial calcification and aortic stiffness are independent predictors of cardiovascular risk in the general population, and independent predictors of all-cause and cardiovascular mortality in ESRD patients. Successful treatment to reduce blood pressure (BP) and reverse aortic stiffness has a significant, BP-independent effect on survival in ESRD patients. However, response to such treatment may be limited in patients with microinflammation and raised levels of C-reactive protein.

Prognosis, risk stratification and monitoring the effects of treatment are fundamental elements in the decision-making process when implementing prevention strategies for chronic kidney disease. The use of biomarkers is increasingly proposed as a method to refine risk stratification and guide therapy. In this Review, we present basic concepts regarding the validation of biomarkers and highlight difficulties inherent to the identification of useful new biomarkers in patients on hemodialysis. We focus on prognostic biomarkers that have been consistently linked to survival in this group of patients. To date, no biomarker has had sufficient full-scale testing to qualify as a useful addition to standard prognostic factors or to guide the prescription of specific treatments in this population. Furthermore, little information exists on the relative strength of various biomarkers for their prediction of mortality. A multimarker approach might refine prognosis in patients on hemodialysis, but this concept needs to be properly evaluated in large longitudinal studies and clinical trials. The potential of proteomics for the identification and study of new biomarkers in the pathophysiology of cardiovascular disease in patients with end-stage renal disease is also discussed.

Extracellular volume excess is an important factor in the pathogenesis of arterial hypertension, and control of volume status by ultrafiltration and achievement of dry weight is considered as an essential therapeutical approach. In the present issue of the Journal of Nephrology, Curatola and coworkers present challenging data indicating that ultrafiltration intensification improves hypertension control but increases the risks for cardiovascular events, with peripheral arteriopathy as the principal complication. This is another challenge for determination of dry weight on the basis of blood pressure (BP) measurement. The reference BP is brachial blood pressure. Brachial blood pressure is lower than limb BP. In normal conditions, lower-limb BP (ankle blood pressure) is higher than brachial BP, and the so-called ankle-brachial systolic pressure index is between 0.9 and 1.3. An ankle-brachial index

Objectif Evaluer l’association entre PTH basse et mortalite des patients incidents en hemodialyse chronique. Patients et methodes Cohorte prospective multicentrique de 2164 patients incidents en hemodialyse a M0 en octobre 2010 et suivie jusqu’a M24 en octobre 2012. Classification des patients selon leur statut PTH a M0 et/ou M12 selon les seuils des K/DIGO. La mortalite toute cause, la mortalite cardiovasculaire (CV) et non CV entre M12 et M24 ont ete evaluees pour chaque statut PTH par analyses de Cox ajustees, les facteurs de variabilite de la PTH entre M0 et M12 par une regression logistique multivariee. Resultats Une diminution de la PTH vers un statut PTH basse a M12 etait independamment et fortement associee a la mortalite CV entre M12 et M24 (RR 2,01 ; IC : 1,2–3,37 ; p = 0,009). Parmi les patients ayant une PTH haute ou normale a M0, les facteurs a M6 de la diminution de la PTH vers un statut PTH basse a M12 etaient l’hypoalbuminemie (OR : 0,96 ; IC 95 % : 0,93–0,99 ; p = 0,01), un dialysat enrichi en calcium (1,75 mmol/L) (OR : 2,02 ; OC : 1,37–2,99 ; p Discussion et conclusion Les patients presentant une baisse de la PTH conduisant au statut PTH basse un an apres l’initiation de l’hemodialyse sont a haut risque de deces CV a court terme. Un dialysat enrichi en calcium est associe a cette baisse et son maintien dans cette situation est un facteur majeur de mortalite CV l’annee suivante. Son utilisation devrait etre restreinte en hemodialyse chronique.

Arterial pressure is a cyclic phenomenon characterized by a pressure wave oscillating around the mean blood pressure, from diastolic to systolic blood pressure, defining the pulse pressure. Aortic input impedance is a measure of the opposition of the circulation to an oscillatory flow input (stroke volume generated by heart work). Aortic input impedance integrates factors opposing LV ejection, such as peripheral resistance, viscoelastic properties and dimensions of the large central arteries, and the intensity and timing of the pressure wave reflections, associated with the opposition to LV ejection influenced by inertial forces. The two most frequently used methods of arterial stiffness are measurement of PWV and central (aortic or common carotid artery) pulse wave analysis, recorded directly at the carotid artery or indirectly in the ascending aorta from radial artery pressure curve. The arterial system is heterogenous and characterized by the existence of a stiffness gradient with progressive stiffness increase (PWV) from ascending aorta and large elastic proximal arteries to the peripheral muscular conduit arteries. Analysis of aortic or carotid pressure waveform and amplitude concerns the effect of reflected waves on pressure shape and amplitude, estimated in absolute terms, augmented pressure in millimetre of mercury, or, in relative terms, 'augmentation index' (Aix in percentage of pulse pressure). Finally, if the aortic PWV has the highest predictive value for prognosis, the aortic or central artery pressure waveform should be recorded and analysed in parallel with the measure of PWV to allow a deeper analysis of arterial haemodynamics.

Background. Although many studies have recently addressed the mineral and bone disorder of chronic kidney disease (CKD-MBD), only limited information is available for elderly dialysis patients. Methods. We prospectively collected serum phosphorus, calcium, parathyroid hormone (PTH), 25(OH) vitamin D, albumin, C-reactive protein, protein intake and CKD-MBD treatments in 9169 maintenance haemodialysis patients in France in June 2008. We then compared biological and treatment patterns in 3403 patients aged 75 or over to their younger counterparts. Results. Elderly patients exhibited lower serum phosphorus and parathyroid hormone concentrations (-8 and -18%, respectively) but slightly higher corrected serum calcium levels (+2%) compared to patients aged below 75 years. Elderly patients had higher mean C-reactive protein, lower serum albumin levels and reduced protein intake. Calcium and non-calcium phosphate binders as well as cinacalcet usage and dosage were significantly reduced in elderly patients, with a trend towards lower active vitamin D derivatives usage. Elderly patients were better controlled according to the Kidney Disease Outcome Quality Initiative (K/DOQI) targets compared to patients aged below 75. Conclusion. In this large 2008 cohort of elderly haemodialysis patients, it appears easier to control serum parameters of CKD-MBD as compared to younger dialysis patients. A better control of serum phosphorus was observed, with less phosphate binder and reduced cinacalcet dosage.

Aims: Carotid-femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results: We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion: The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.

BACKGROUND: In hypertension, structural changes in the cardiovascular system affect not only small arteries and the heart but also the large arteries, particularly in elderly people. It has been suggested that structural alterations to the small arteries are responsible for the elevation in mean arterial pressure seen in hypertension, as a result of increased vascular resistance. However, the amplitude of pressure oscillation (pulse pressure) is influenced by other haemodynamic mechanisms that involve large arteries including a decrease in compliance and an increase in wave reflection. EFFECTS OF STRUCTURAL ALTERATIONS TO LARGE ARTERIES ON BLOOD PRESSURE: Structural alterations to the large arteries may, in hypertensive subjects, be responsible for an increase in the amplitude of pressure oscillation, leading to a disproportionate increase in systolic over diastolic blood pressure because of arterial (not arteriolar) changes. These findings not only contribute to a better understanding of the relationship between vascular structure and blood pressure levels but also to a better interpretation of hypertensive complications, particularly those related to the heart and large vessels. APPLICATION TO TREATMENT: The reversal of structural arterial changes may become a goal in long-term antihypertensive treatment. Angiotensin converting enzyme (ACE) inhibitors in particular can reverse structural arterial changes, increase arterial compliance and produce a more pronounced decrease in systolic than in diastolic blood pressure.

1. The forearm venous pressure-volume relationship was studied in 14 young men with borderline hypertension and in 16 control subjects of the same age and sex. Strain-gauge plethysmography was used to evaluate volume changes after slow increases and decreases in distention, in order to estimate the amplitude of the hysteresis curve. 2. Compared with normotensive control subjects, subjects with borderline hypertension had significantly higher values of blood pressure, heart rate and forearm blood flow. 3. Baseline forearm venous tone was slightly, but not significantly, increased in borderline hypertensive subjects (21.35 ± 6.53 versus 18.75 ± 5.95 mmHg ml−1 100 ml−1) and was significantly enhanced after a cold pressor test. The increase was no higher in the borderline hypertensive subjects than in the normotensive control subjects. 4. The area of the hysteresis curve was significantly decreased (7.58 ± 3.58 versus 10.34 ± 5.67 arbitrary units; P = 0.0092) as was the extent of isotonic relaxation (creep) (0.28 ± 0.11 versus 0.39 ± 0.22 ml/100 ml; P = 0.0098) in borderline hypertensive subjects compared with control subjects. Both parameters were unaffected by the cold pressor test. 5. The study suggests that the viscous component of the venous wall is altered in young patients with borderline hypertension, indicating intrinsic changes in vascular segments which are not exposed to increased intraluminal pressure.

Forearm hemodynamics using pulsed Doppler flowmeter measurements were studied in 60 hemodynamics men (30 nonobese and 30 obese) and in 45 hypertensive women (15 nonobese and 30 obese subjects). Age and blood pressure of nonobese and obese patients were identical in men as well as in women. Blood flow, expressed in milliliters/minute or corrected for body surface area, was significantly higher in obese hypertensive patients. When blood flow was expressed per unit liter of forearm volume, the difference was no longer present. The increased blood flow in milliliters/minute in obese hypertensive patients was due to an increased blood velocity, while arterial diameter was similar in nonobese and obese hypertensive patients. Forearm vascular resistance, expressed either in absolute values or in normalized values was significantly higher in nonobese than in obese hypertensive patients. When men and women with similar body weight and mean arterial pressure were compared, women were characterized by lower values of arterial diameter, body surface area and forearm volume, whereas vascular resistance in absolute value or corrected for body surface area was higher. This increase was no longer present when vascular resistance was normalized for forearm volume. This study provides evidence that body composition and body mass index evolve as determinants of arterial blood velocity whereas the gender of the patient seems to influence the arterial diameter.

The relationship between the presence of arterial calcinosis and the antihypertensive response to calcium blockers was studied in 40 hypertensive patients with end-stage renal failure (ESRF) on chronic hemodialysis, before and during 16 weeks after administration of nitrendipine in monotherapy. In a double-blind, placebo-randomized study, nitrendipine reduced systolic blood pressure regardless of the presence or absence of arterial calcifications. The antihypertensive effects were significantly more pronounced in subjects with aortic calcium deposits in comparison with patients without clinical signs of arteriosclerosis (p

Purpose of review To review the most recent publications concerning the pathophysiology and clinical impact of arterial stiffening in patients with chronic kidney disease and those with end-stage renal disease. Recent findings The results of recent studies confirmed that arterial stiffening is independently associated with decreased glomerular filtration rate and increased decline in parallel kidney function, and is predictive of kidney disease progression and the patient's cardiovascular outcome. Arterial stiffening is of multifactorial origin, including arterial calcifications, systemic inflammation, malnutrition, vitamin deficiencies, endothelial dysfunction, and bone activity. Summary Arterial stiffness and intensity of wave reflections are considered the principal determinants of systolic blood and pulse pressures, and their measurements are increasingly used to assess cardiovascular risk. Aortic stiffness has independent predictive value for all-cause and cardiovascular mortality in general populations and in patients with end-stage renal disease. Arterial stiffening in patients with chronic kidney disease and those with end-stage renal disease is of multifactorial origin with extensive arterial calcifications representing a major covariate. Carotid–femoral pulse wave velocity is a direct measure of aortic stiffness and is the ‘gold standard’ for its evaluation in clinical and epidemiological studies.

An inverse relationship between arterial calcifications and bone activity has been documented in patients with ESRD. Calcium overload is associated with arterial calcification, which is associated with arterial stiffening. Whether bone activity interacts with calcium load, aortic stiffness, or arterial calcification is unknown. This study assessed the impact of bone activity on the relationships between the dosage of calcium-containing phosphate binders and aortic stiffness (measured by pulse wave velocity) or abdominal aorta calcification score. Aortic stiffness and calcification were both positively associated with calcium load and negatively associated with bone activity. A significant interaction was found between dosage of calcium-containing phosphate binders and bone activity such that calcium load had a significantly greater influence on aortic calcifications and stiffening in the presence of adynamic bone disease. Independent of any other factor, including dosage of calcium-containing phosphate binders, adynamic bone was associated with greater aortic stiffening, suggesting cross-talk between the bone and arterial walls.

Cardiovascular disease is a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Macrovascular disease develops rapidly in ESRD patients and is responsible for the high incidence of left ventricular hypertrophy, ischemic heart disease, cerebrovascular accidents, and peripheral artery diseases. Occlusive lesions due to atheromatous plaques frequently cause these complications; however, atherosclerosis represents only one form of structural response to metabolic and hemodynamic alterations interfering with the "natural" process of aging. The spectrum of arterial alterations in ESRD is broader, including large artery remodeling, changes in viscoelastic properties, and stiffening of arterial walls. Nonatheromatous remodeling principally changes the dampening function of arteries, characterized by stiffening of arterial walls and with deleterious effects on the left ventricle and coronary perfusion. The origin of arterial stiffening in ESRD patients is multifactorial, with extensive arterial calcifications as an important covariate.

We studied the influence of parathyroid gland activity on cardiovascular response to dihydropyridines (nicardipine (NIC), 80 mg/day for 4 weeks) in 20 hypertensive patients with end-stage renal failure (ESRF). Before the treatment hyperparathyroidism (HPTH) was estimated on the basis of serum parathormone (PTH), and bone histomorphometry (osteoclastic resorption surfaces (ORS), and number of osteoclasts (NO]. NIC induced a significant decrease in systolic (SAP) and diastolic (DAP) arterial blood pressure, but did not significantly change the heart rate (HR) or the SAP X HR (myocardial oxygen consumption estimate). Changes in SAP and DAP were correlated to baseline serum PTH (P less than .001), to ORS (P less than .01) and to NO (P less than .01). Furthermore, a significant decrease in blood pressure was observed only in patients with histological signs of hyperparathyroidism (ORS greater than 1%). In this subset of patients NIC induced a significant decrease in SAP X HR (P less than .02) which was correlated to PTH and histomorphometric indexes of HPTH (P less than .01). The results of the present study show that blood pressure response to dihydropyridines in ESRF is associated with parathyroid activity as judged from serum PTH and bone histomorphometry.

The load of the heart in hypertension is related not only to increased peripheral vascular resistance but also to decreased aortic compliance. From non-invasive clinical studies involving determinations of pulse wave velocity and systolic-diastolic variations of aortic arch diameter, it can be shown that decreased aortic compliance is strongly related to increased cardiac mass. The correlation is observed even after adjustment for the level of blood pressure. It is suggested that decreased aortic compliance in hypertension causes a disproportionate increase in systolic pressure and end-systolic stress, thus contributing to promote cardiac hypertrophy with possible consequences for epidemiology, clinical investigation and treatment.

Aortic and large artery compliance in end-stage renal failure. Pulse wave velocity (PWV) was measured in the aorta, right leg and arm of 90 control subjects (CS) and 92 hemodialysis patients (HD) of the same age and mean arterial pressure (MAP). Blood chemistry, including blood lipids, and echographic dimensions of the aorta, were measured in all subjects. Presence of aortic calcification was evaluated by abdominal X-ray and echography. Whereas femoral and brachial PWV were only slightly increased in HD (P < 0.05), the aortic PWV was significantly elevated (1113 ± 319 cm/sec) in comparison with CS (965 ± 216 cm/sec; P = 0.0016). Aortic diameters were larger in HD, both at the root of aorta (32.7 ± 4 vs. 28.2 ± 2.8mm; P < 0.0001) and aortic bifurcation (16.9 ± 3.1 vs. 14.6 ± 2.2mm; P < 0.0001). Although the MAP was similar in HD (109.9 ± 19.3mm Hg) and CS (110.2 ± 17.2mm Hg), the pulse pressure was significantly increased in HD patients (76.6 ± 23.7 vs. 63.9 ± 22mm Hg; P = 0.007). In the two populations, aortic PWV was found to increase with age (P < 0.0001) and MAP (P < 0.0001). The presence of aortic calcification showed only a borderline relationship with the increase in aortic PWV (P = 0.050 in CS and P = 0.069 in HD). As change in PWV is directly related to change in distensibility, and the aortic diameters were increased in HD, these results indicate that aortic wall compliance is decreased in HD, resulting in an increase in the pulsatile component of arterial pressure. Alteration of pulsatile arterial dynamics contributes to an increase in left ventricular load and is significantly related to the left ventricular hypertrophy which is frequently observed in these patients (P < 0.001).

Summary Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD). The risk of CVD disease in these patients appears to be far greater than in the general population and even after the stratification for age, gender, race and the presence or absence of diabetes, cardiovascular mortality in dialysis patients is about 10 to 20 times higher than in the general population. As a diagnostic categorie, CVD includes two principal conditions, i.e., cardiac complications stricto sensu , and vascular complications. These two complications are interrelated and arterial alterations can be the primary reason for the development of cardiac complications. Macrovascular disease develops rapidly in ESRD patients and is responsible for the high incidence of congestive heart failure, left ventricular hypertrophy (LVH), ischemic heart disease, sudden death, cerebrovascular accidents and peripheral artery diseases. Although the most frequent cause of these complications is occlusive lesions due to atheromatous plaques, many complications arise in ESRD patients in the absence of clinically significant atherosclerotic disease. Atherosclerosis, disease characterized by the presence of plaques, represents only one form of structural response to metabolic and hemodynamic alterations which interfere with the “natural” process of aging. The spectrum of arterial alterations in ESRD is broader, including large artery remodeling and changes in viscoelastic properties of arterial walls. The consequences of these alterations are different from those attibuted to plaques. While atheromatous lesions alter principally the conduit function of arteries and perfusion of tissue and organs downstream the lesions, non-atheromatous remodelling result principally in changes in dampening function of arteries, characterized by stiffening of arterial walls and with deleterious effects on the left ventricle and coronary perfusion. Arterial stiffening in ESRD patients is multifactorial at origin with extensive arterial calcifications as an important covariate.

Arterial disease in CKD patients is characterized by extensive calcification. Evidence has accumulated pointing to the active and regulated nature of the calcification process. Elevated phosphate and calcium may stimulate sodium- dependent phosphate cotransport involving osteoblast-like changes in cellular gene expression. AC is responsible for stiffening of the arteries with increased left ventricular afterload and abnormal coronary perfusion as the principal clinical consequences.

Shear stress is a major determinant of endothelial apoptosis, but its role in the in vivo release of shed membrane microparticles by endothelial cells remains unknown. Thus, we sought to evaluate the possible relationship between circulating endothelial microparticle levels and laminar shear stress in end-stage renal disease patients with high cardiovascular risk, whose levels of endothelial microparticles are elevated. In 34 hemodialyzed patients, we analyzed the relationships between brachial artery and aortic shear stress and circulating microparticles levels. Only endothelial microparticles were inversely correlated with laminar shear stress values ( P

In ESRD, arterial function is abnormal, characterized by decreased capacitive function (arterial stiffening) and reduced conduit function, shown by diminished flow-mediated dilation (FMD). The pathophysiology of these abnormalities is not clear, and this cross-sectional study analyzed possible relationships among arterial alterations and cardiovascular risk factors, including mineral metabolism parameters, such as serum parathormone, and vitamin D "nutritional" and "hormonal" status by measuring serum 25-hydroxyvitamin D [25(OH)D(3)] and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels. Aortic stiffness (pulse wave velocity), brachial artery (BA) distensibility (echotracking; n = 42), BA FMD (hand-warming; n = 37), and arterial calcification scores (echography and plain x-rays) were measured in 52 stable and uncomplicated patients who were on hemodialysis. 25(OH)D(3) and 1,25(OH)(2)D(3) serum levels were low and weakly correlated (r = 0.365, P < 0.05). After adjustment for BP and age, multivariate analyses indicated that 25(OH)D(3) and 1,25(OH)(2)D(3) were negatively correlated with aortic pulse wave velocity (P < 0.001) and positively correlated with BA distensibility (P < 0.01) and FMD (P < 0.001). Arterial calcification scores were not independently associated with 25(OH)D(3) and 1,25(OH)(2)D(3) serum concentrations. These results suggest that nutritional vitamin D deficiency and low 1,25(OH)(2)D(3) could be associated with arteriosclerosis and endothelial dysfunction in patients who have ESRD and are on hemodialysis.

Purpose of review Cardiovascular disease is a major factor in the high mortality of patients with end-stage renal disease, and this population is particularly appropriate to analyse the impact of cardiovascular risk markers on outcome. Recent findings Cardiovascular risk markers in end-stage renal disease include age, left ventricular mass, carotid intima–media thickness, blood pressure and aortic stiffness (pulse wave velocity). Aortic pulse wave velocity has been shown to be an independent predictor of cardiovascular mortality in patients with end-stage renal disease and the general population. Aortic pulse wave velocity has the highest sensitivity and specificity as a predictor of cardiovascular death in end-stage renal disease patients. Pulse wave velocity is an integrated index of vascular function and structure, and is a major determinant of systolic hypertension, thereby increasing left ventricular afterload, left ventricular hypertrophy and left ventricular oxygen consumption. Decreased diastolic blood pressure, another consequence of arterial stiffening, is associated with decreased coronary perfusion contributing to ischaemic heart disease and evolution of adaptive into maladaptive left ventricular hypertrophy. Summary Aortic stiffness measurements could serve as an important tool in identifying end-stage renal disease patients at higher risk of cardiovascular disease. The ability to identify these patients would lead to better risk stratification and earlier and more cost-effective preventive therapy.

The aorta is the principal capacitive element of the arterial tree and its increased stiffness, determined by measurement of aortic pulse wave velocity (PWV), is a strong independent predictor of cardiovascular mortality in the general population and end-stage renal disease (ESRD) patients. Whether stiffness of ESRD patients' peripheral arteries has the same prognostic value has never been investigated. A cohort of 305 ESRD patients was followed for 7049 months (meanSD). Ninety-six deaths of cardiovascular origin occurred. At entry into the study, together with standard clinical and biochemical analyses, patients' aortic, brachial artery, and femorotibial PWV were determined. Based on Kaplan-Meier survival curve analyses and Cox proportional hazards analyses, adjusted for age, pulse pressure, and clinical data, aortic PWV was a significant and independent predictor of outcome. Neither brachial artery nor femotibial artery stiffness was able to predict cardiovascular outcome. Receiver operating characteristic curve analysis of aortic PWV indicated the cutoff value of 10.75 m/s, with 84% sensitivity, 73% specificity, 87% negative predictive value, and 72% positive predictive value. These results provide evidence that, in ESRD, increased stiffness of capacitive arteries, like the aorta, is an independent strong predictor of cardiovascular mortality, whereas stiffness of peripheral conduit arteries had no prognostic value. (Hypertension. 2005;45:592-596.)

Reducing systolic blood pressure (BP) is of major benefit to patients with isolated systolic hypertension, but lowering normal diastolic BP may be harmful in terms of cardiovascular risk. Effects of different drugs on systolic BP, diastolic BP, and pulse pressure are therefore of interest.The NatriliX SR versus CandEsartan and amLodipine in the reduction of systoLic blood prEssure in hyperteNsive patienTs study (X-CELLENT) was a randomized, double-blind, placebo-controlled study comparing the effects of three drugs on these BP components. Patients with systolic-diastolic or isolated systolic hypertension (n = 1758) received indapamide (1.5 mg) sustained release (SR), candesartan (8 mg), amlodipine (5 mg), or placebo once daily for 12 weeks.Compared to placebo all active treatments reduced all BP components significantly (P.001). For the patients with isolated systolic hypertension (n = 388), the three treatments significantly reduced systolic BP, but only indapamide SR did not change diastolic BP and thus reduced pulse pressure significantly relative to placebo (P = .005). In an ancillary study using ambulatory BP monitoring (n = 576), all three treatments significantly reduced BP components during 24 h relative to placebo. Changes in systolic BP and pulse pressure were similar with the three treatments, but the reduction in diastolic BP was significantly smaller, and therefore more favorable, with indapamide SR compared with candesartan (P = .039). In patients with isolated systolic hypertension (n = 106), indapamide SR reduced 24-h systolic BP significantly more than amlodipine (P = .037), and only indapamide SR reduced 24-h pulse pressure significantly relative to placebo (P = .03). All three drugs were well tolerated.This distinctive BP-lowering profile of indapamide SR seems highly beneficial when compared to the either of candesartan or amlodipine.

The ill effects of hypertension are usually attributed to a reduction in the caliber or the number of arterioles, resulting in an increase in total peripheral resistance (TPR). This definition does not take into account the fact that BP is a cyclic phenomenon with systolic and diastolic BP being the limits of these oscillations. The appropriate term to define the arterial factor(s) opposing LV ejection is aortic input impedance which depends on TPR, arterial distensibility (D), and wave reflections (WR). D defines the capacitive properties of arterial stiffness, whose role is to dampen pressure and flow oscillations and to transform pulsatile flow and pressure in arteries into a steady flow and pressure in peripheral tissues. Stiffness is the reciprocal value of D. These parameters are BP dependent, and arteries become stiffer at high pressure. In to D which provides information about theelasticityof artery as a hollow structure, the elastic incremental modulus (Einc) characterizes the properties of the arterial wall biomaterials, independently of vessel geometry. As an alternative, arterial D can be evaluated by measuring the pulse wave velocity (PWV) which increases with the stiffening of arteries. Arterial stiffening increases left ventricular (LV) afterload and alters the coronary perfusion. With increased PWV, the WR impacts on the aorta during systole, increasing systolic pressures and myocardial oxygen consumption, and decreasing diastolic BP and coronary flow. The arterial stiffness is altered primarily in association with increased collagen content and alterations of extracellular matrix (arteriosclerosis) as classically observed during aging or in arterial hypertension. The arterial stiffening estimated by changes in aortic PWV and intensity of WR are independent predictors of survival in end stage renal disease (ESRD) and general population. Improvement of arterial stiffening could be obtained by antihypertensive treatmen as observed with the calcium-channel blocker and ACE inhibitors. ACE inhibitors increased AC and reduced WR, and it has been shown that reversibility of aortic stiffening and use of ACE inhbitors had favorable independent effect on survival in hypertensive patients with advanced renal disease.

The task of dialysis therapy is, amongst other things, to remo ve excess potassium (K+) from the body. The need to achieve an adequate K+ removal with the risk of cardiac arrhythmias due to sudden intra-extracellular K+ gradient advises the distribution of the removal throughout the dialysis session instead of just in the first half. The aim of the study was to investigate the electrical behavior of two different K+ removal rates on myocardial cells (risk of arrhythmia and ECG alterations). Constant acetate-free biofiltration (AFB) and profiled K+ (decreasing during the treatment) AFB (AFBK) were used in a patient sample to understand, first of all, the effect on premature ventricular contraction (PVC) and on repolarization indices [QT dispersion (QTd) and principal component analysis (PCA)]. The study was divided into two phases: phase 1 was a pilot study to evaluate K+ kinetics and to test the effect on the electrophysiological response of the two procedures. The second phase was set up as an extended cross-over multicenter trial in patient subsets prone to arrhythmias during dialysis. Phase 1: PVC increased during both AFB and AFBK but less in the latter in the middle of dialysis (298 in AFB vs. 200 in AFBK). The PVC/h in a subset of arrhythmic patients was 404 ± 145 in AFB and 309 ± 116 in AFBK (p = 0.0028). QT interval (QTc) prolongation was less pronounced in AFBK than in AFB. Phase 2: The PVC again increased in both AFB and AFBK but less in the latter mid-way through dialysis (79 ± 19 AFB vs. 53 ± 13 AFBK). Moreover, in the most arrhythmic patients the benefit accruing from the smooth K+ removal rate was more pronounced (103 ± 19 in AFB vs. 78 ± 13 in AFBK). Conclusion: It is not the K+ dialysis removal alone that can be destabilizing from an electrophysiological standpoint, but rather its removal dynamics. This is all the more evident in patients with arrhythmias who benefit from the K+ profiling during their dialysis treatment.

Recent prospective epidemiologic studies have directed attention to systolic blood pressure (SBP) as a better guide than diastolic blood pressure (DBP) to evaluate cardiovascular and all mortality, and recent data have underlined the importance of pulse pressure (PP) as an independent cardiovascular (CV) risk factors(5-7) in individuals more than 50 years of age. Furthermore, it has been shown that drug treatment of hypertension frequently results in adequate control of DBP, whereas control of SBP is achieved to a significantly smaller extent. Such studies have focused attention on the factors that determine the level of SBP and PP. Systolic blood pressure results from the interaction of three principal factors: 1) characteristics of left ventricular ejection (stroke volume); 2) cushioning (dampening) function of the large arteries (arterial stiffness); and 3) propagative and reflective properties of the arterial tree (intensity of wave reflections and timing of incident and reflected pressure waves). Considering the different mechanisms associated with increased SBP, individualized therapeutic approaches will require knowledge of the patient's unique profile of arterial stiffness and wave reflection characteristics.

Arterial calcification (AC) is a common complication of end-stage renal disease (ESRD). The mechanisms responsible are complex, including disturbances of mineral metabolism and active expression of various mineral-regulating proteins. An inverse relationship between AC and bone density has been documented in uremic patients. In the study presented here, which included 58 patients with ESRD on hemodialysis (HD), bone-histomorphometry characteristics were compared with the AC scores (0 to 4) determined according to the number of arterial sites with calcifications. Patients with AC scores of 0 (no calcifications), or 1 or 2 (mild calcifications) had similar serum parathyroid hormone levels and bone histomorphometry, with larger osteoclast resorption, higher osteoclast numbers, and larger osteoblastic and double tertracycline-labeled surfaces. In contrast, patients with high AC scores (3 and 4) were characterized by lower serum parathyroid hormone, low osteoclast numbers and osteoblastic surfaces, smaller or absent double tetracycline-labeled surfaces, and high percentages of aluminum-stained surfaces. According to multivariate analysis, AC score was positively associated with age (P < 0.0001), daily dose of calcium-containing phosphate binders (P = 0.009), and bone aluminum-stained surfaces (P = 0.037), and an inverse correlation was observed with osteoblastic surfaces (P = 0.001). A high AC score is associated with bone histomorphometry suggestive of low bone activity and adynamic bone disease. These findings suggest that therapeutic interventions associated with excessive lowering of parathyroid activity (parathyroidectomy, excessive calcium or aluminum load) favor lower bone turnover and adynamic bone disease, which could influence the development and progression of AC.