Lorenzo Malatino

Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study

BACKGROUND The plasma concentration of asymmetrical dimethylarginine (ADMA), an inhibitor of nitric-oxide synthase, which has been linked to endothelial dysfunction and atherosclerosis in the general population, is raised in patients with end-stage renal disease and could contribute to the high cardiovascular risk in patients with chronic renal failure. We investigated the relation between cardiovascular risk factors and plasma ADMA concentration in a cohort of haemodialysis patients (n=225), and tested the predictive power of ADMA for mortality and cardiovascular outcomes. METHODS Patients had standard dialysis three times a week. We accurately recorded cardiovascular events over a mean follow-up of 33.4 months (SD 14.6); these events were reviewed by a panel of physicians. We identified correlates of plasma ADMA by univariate and multivariate analyses. FINDINGS On univariate analysis, ADMA concentration in plasma was directly related to concentrations of fibrinogen and L-arginine in plasma, duration of dialysis treatment, and serum cholesterol concentration, and was inversely related to serum albumin concentration. On multivariate analysis, only plasma fibrinogen (p=0.0001) and serum albumin (p=0.04) concentrations were independently related to plasma ADMA concentration (multiple r=0.44, p=0.0001). 83 patients died, 53 (64%) by cardiovascular causes. In a Coxs proportional-hazards model, plasma ADMA ranked as the second factor predicting overall mortality (hazard ratio 1.26, 95% Cl 1.11-1.41, p=0.0001) and cardiovascular events (1.17, 1.04-1.33, p=0.008). INTERPRETATION In haemodialysis patients, plasma ADMA is a strong and independent predictor of overall mortality and cardiovascular outcome. These findings lend support to the hypothesis that accumulation of ADMA is an important risk factor for cardiovascular disease in chronic renal failure.

Inflammation is associated with carotid atherosclerosis in dialysis patients

Objective To investigate the relationship between inflammatory processes and atherosclerosis in uraemic patients on chronic dialysis. Design A cross-sectional study in 138 dialysis patients (92 on haemodialysis and 46 on continuous ambulatory peritoneal dialysis). Methods Serum C-reactive protein (CRP), IgG anti-Chlamydia pneumoniae antibodies, lipoprotein (a), fibrinogen and plasma homocysteine as well as the intima–media thickness and the number of atherosclerotic plaques of the carotid arteries (by Echo-Colour-Doppler) were measured in each patient. Results One hundred and eight patients had at least one plaque and 26 had more than six plaques. Serum CRP was above the upper limit of the normal range (5 mg/l) in 85 of 138 patients (62%). IgG anti-Chlamydia pneumoniae antibodies were detectable in 64% of patients (high level in 24%, intermediate in 33% and low in 7%) and undetectable in the remaining 36% of patients. In a multiple regression model age (β = 0.35), serum CRP (β = 0.23), plasma homocysteine (β = 0.19), duration of dialysis (β = 0.19) and pulse pressure (β = 0.18) were independent predictors of intima–media thickness (R = 0.54, P < 0.0001). Similarly, age (β = 0.33), serum CRP (β = 0.29), plasma homocysteine (β = 0.20) and serum albumin (β = −0.18) were independent correlates of the number of atherosclerotic plaques (R = 0.55, P < 0.0001). Furthermore, in smokers, the interaction serum CRP–IgG anti–Chlamydia pneumoniae antibodies was the stronger independent predictor (β = 0.43, P = 0.0001) of the number of atherosclerotic plaques while no such relationship (P = 0.73) was found in non-smokers. Conclusions In patients on chronic dialysis treatment CRP is independently associated to carotid atherosclerosis and appears at least in part to be explained by IgG anti-Chlamydia pneumoniae antibodies level. These data lend support to the hypothesis that inflammation plays a role in the pathogenesis of atherosclerosis in these patients.

Circulating Natriuretic Peptide Concentrations in Patients With End-Stage Renal Disease: Role of Brain Natriuretic Peptide as a Biomarker for Ventricular Remodeling

OBJECTIVES To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality. PATIENTS AND METHODS One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI). RESULTS Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002). CONCLUSIONS Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.

Prognostic Value of Echocardiographic Indicators of Left Ventricular Systolic Function in Asymptomatic Dialysis Patients

Patients with end-stage renal disease (ESRD) are at high risk for heart failure, but the prevalence and the prognostic value of asymptomatic systolic dysfunction in these patients are unknown. In this prospective cohort study, the authors have therefore assessed by echocardiography the prevalence and the prognostic value of systolic function as estimated by ejection fraction (EF), fractional shortening at endocardial level (endoFS), and at midwall (mwFS), in a cohort of 254 asymptomatic dialysis patients. Systolic dysfunction had a prevalence rate of 26% by endoFS and of 48% by mwFS. During the follow-up period, 125 patients had one or more fatal and nonfatal CV events. On multivariate COX regression analysis, the three LV systolic function indicators were independently associated with incident fatal and nonfatal CV events, and there were no differences in the predictive power of these indicators (P > 0.30). The prediction power of LV function indicators was largely independent of traditional and novel risk factors in ESRD such as C-reactive protein and asymmetric dimethyl arginine (ADMA). ADMA was significantly related with LV function indicators as well as with mortality and incident CV events, but these links were much reduced (P = NS) in models including LV function indicators. Of note, the risk of CV events was minimal in patients with normal LV mass and function, intermediate in patients with either LVH or systolic dysfunction, and maximal in patients displaying both alterations. The study of myocardial contractility by echocardiography provides prognostic information independently of LV mass and other risk factors in ESRD. Risk stratification by simple systolic function parameters may prove useful in secondary prevention strategies in these patients.

Norepinephrine and Concentric Hypertrophy in Patients With End-Stage Renal Disease

We have recently observed that in patients with end-stage renal disease (ESRD) raised plasma norepinephrine (NE) is an independent predictor of incident cardiovascular events but that its prognostic power is reduced when this sympathetic marker is tested in statistical models including also left ventricular mass. Because left ventricular hypertrophy (LVH) may be a mechanism whereby NE contributes to the high rate of cardiovascular events in ESRD, we examined the relationship between plasma NE and echocardiographic parameters of left ventricle mass in a large group of ESRD patients. Mean wall thickness (MWT) was higher in patients in the third NE tertile than in the other 2 tertiles (P =0.001), and such an increase was paralleled by a rise in relative wall thickness (RWT) (P =0.006). Concentric LVH was more prevalent in patients in the third NE tertile (46%) than in the second (38%) and first (25%) NE tertiles. Multivariate regression analysis confirmed that the association of plasma NE with the muscular component of left ventricle (MWT) and with RWT was independent (P ≤0.001) of other cardiovascular risk factors, and in these models, plasma NE ranked as the second correlate of MWT and RWT. Similarly, multiple logistic regression analysis showed that the association of plasma NE with concentric LVH was strong and again independent of other risk factors (P =0.003). Plasma NE is associated to concentric LVH in ESRD patients. These observations constitute a sound basis for testing the effect of anti-adrenergic drugs on left ventricle mass and on cardiovascular outcomes in patients with ESRD.

Prediction of left ventricular geometry by clinic, pre-dialysis and 24-h ambulatory BP monitoring in hemodialysis patients

OBJECTIVE Arterial hypertension is an established risk factor for left ventricular hypertrophy (LVH) in the uremic population. However, whether 24-h monitoring is a better predictor of LVH than clinic blood pressure and routine pre-dialysis measurements in these patients is still undefined. METHODS This problem was studied in 64 nondiabetic hemodialysis patients without heart failure. The echocardiographic study as well as the clinic and 24-h ambulatory blood pressure (BP) measurements were performed during the day off-dialysis. Pre-dialysis arterial pressure was calculated as the average value of the 12 routine recordings taken during the month preceding the study. RESULTS In multivariate models, including also sex, body mass index, hematocrit and serum cholesterol, pre-dialysis systolic, diastolic and pulse pressures were the only independent BP determinants of heart geometry. Twenty-four hour ambulatory BP monitoring (ABPM) did add significant (but weak) information to the prediction of left ventricular internal dimension, i.e. it increased by 9% (P = 0.01) the variance already explained by pre-dialysis diastolic BP and other significant covariates. However, 24-h ABPM did not add any significant and independent explanatory information to the corresponding pre-dialysis measurements for the posterior wall and interventricular septum measurements, and for left ventricular mass (-0.6 to +3.9%; average +1.1%). CONCLUSIONS In dialysis patients, pre-dialysis BP is at least as strong a predictor of left ventricular mass as 24-h ambulatory monitoring. Thus, the average of 12 routine pre-dialysis measurements may be used to predict heart geometry in dialysis patients without any loss of information in comparison with 24-h ambulatory monitoring.

Analysis of the Relationship between Norepinephrine and Asymmetric Dimethyl Arginine Levels among Patients with End-Stage Renal Disease

High sympathetic activity and alterations in nitric oxide synthesis attributable to accumulation of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have recently been identified as potential causal mechanisms for the high cardiovascular mortality rates among patients with ESRD. The link between these risk factors has not been studied. Therefore, the relationship between plasma norepinephrine (NE) and ADMA levels was examined in a large cohort of hemodialysis patients (n = 224), and whether these factors interacted in predicting all-cause mortality and new cardiovascular event rates among those patients was investigated. Plasma ADMA levels were strongly associated with plasma NE levels (P < 0.001) and to a lesser extent with heart rate (P < 0.01). In multivariate analyses, the ADMA-NE correlation was observed to be independent of age, gender, serum albumin levels, arterial pressure and antihypertensive treatment, duration of dialysis treatment, diabetes mellitus, and other risk factors. NE was an independent significant predictor of both death and cardiovascular events in Cox models not including ADMA. However, when ADMA was introduced into those models, NE became a largely nonsignificant predictor of those outcomes, whereas plasma ADMA levels emerged as a highly significant predictor of both death (P < 0.001) and cardiovascular events (P < 0.001). These findings suggest that ADMA is an intervening factor in the causal pathway leading to those outcomes. Plasma NE and ADMA concentrations are strongly related among patients with ESRD. These two factors are likely to be involved in the same causal pathway leading to death and cardiovascular events among those patients.

Left atrial volume in end-stage renal disease: a prospective cohort study.

Background End-stage renal disease (ESRD) is a high-risk condition and left ventricular hypertrophy (LVH) is the strongest risk factor in this population. Objective and methods Since the prognostic value of left atrial (LA) size in ESRD is still unknown, we performed a prospective cohort study aimed at testing the prognostic value of LA volume in a cohort of 249 ESRD patients. Results Both un-indexed and indexed LA volume (LAV) was significantly higher in dialysis patients than in healthy subjects (P < 0.001). On multivariate analysis only left ventricular mass index (LVMI), LV ejection fraction (LVEF), ratio of early (E) to late atrial (A) mitral Doppler peak flow velocity (E/A ratio) and antihypertensive treatment maintained an independent association with LAV. During the follow-up 113 patients died. LAV added significant prognostic power to a multivariate Cox model of all-cause death and the model based on height2.7 provided the best data fit. Notably, this index maintained an independent predictive value for death (P = 0.03) also when LVMI and LVEF were jointly forced into the Coxs model. Neither crude nor body surface area (BSA)-adjusted LAV had an independent association with death when tested in the Cox model including LVMI and LVEF. Conclusions In patients with ESRD, LAV indexed for height2.7 displays prognostic value beyond and above that provided by LV mass and function.

Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure.

Abstract. Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Rapisarda F, Fatuzzo P, Seminara G, Stancanelli B, Nicocia G, Buemi M (Institute of Biomedicine, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Cal; University of Catania; and University of Messina, Italy). Fibrinogen, mortality and incident cardiovascular complications in end‐stage renal failure. J Intern Med 2003; 254: 132–139.

Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients

BACKGROUND Endothelial dysfunction as assessed by asymmetric dimethylarginine (ADMA) and inflammation has been consistently linked to atherosclerosis, death, and cardiovascular (CV) events in ESRD patients. Inflammation amplifies the effect of ADMA on the severity of atherosclerosis in ESRD patients, but it is still unknown whether inflammation and ADMA interact in the high risk of death and CV events in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a cohort of 225 hemodialysis patients, we investigated the interaction between inflammatory biomarkers (C-reactive protein and IL-6) and ADMA as predictors of death and CV events over an extended follow-up (13 years). RESULTS During follow-up, 160 patients died, and 123 had CV events. With crude and multiple Cox regression analyses, an interaction was found between inflammation biomarkers and ADMA for explaining death and CV events in ESRD patients. The adjusted hazard ratios (HRs) for death (HR, 2.18; 95% confidence interval [CI], 1.34 to 3.54) and CV outcomes (HR, 2.59; 95% CI, 1.47 to 4.55) of patients with C-reactive protein and ADMA above the median were higher than expected in the absence of interaction under the additive model (1.15 and 1.97, respectively) and significantly higher than in patients with only one biomarker above the median. Data analyses carried out by stratifying patients according to IL-6 provided similar results. CONCLUSIONS These data support the hypothesis that inflammation amplifies the risk of death and CV events associated with high ADMA levels in ESRD. These analyses further emphasize the need for intervention studies to attenuate inflammation and high ADMA levels in this population.