Abstract:

Abstract: Carotid intima media thickness (IMT) is a strong, independent predictor of cardiovascular events in both the general population and among those with end-stage renal disease (ESRD), but it is unknown whether changes in IMT or other ultrasound-measured indicators of atherosclerosis over time provide additional prognostic information. The progression of atherosclerosis with carotid ultrasound was followed in a cohort of 135 ESRD patients, 103 of whom had a repeat ultrasound after 15 mo of follow-up. The number of plaques and the proportion of patients with severe atherosclerosis increased substantially during the follow-up period, but IMT, common carotid artery diameter, common carotid artery wall-to-lumen ratio, and cross-sectional area, did not change. The rate of formation of new plaques was a strong, independent predictor of incident cardiovascular events, even after adjusting for baseline plaque burden and other potential confounders. New plaque formation over time was independently predicted by background plaque burden and serum C-reactive protein (P = 0.004 and P = 0.02, respectively). Changes in IMT and the other ultrasound-measured indicators of atherosclerosis progression did not predict cardiovascular outcomes. Therefore, monitoring IMT over time is unlikely to provide additional prognostic information compared with a single measurement, but longitudinal ultrasound monitoring of plaque formation may be useful for cardiovascular risk stratification in the ESRD population.

Abstract:

Abstract:

Abstract: BACKGROUND: The endogenous inhibitor of nitric oxide (NO) synthase, asymmetric dimethylarginine (ADMA), is a strong cardiovascular (CV) risk marker in patients with chronic renal insufficiency. Statins have pleiotropic effects and are currently considered as potential ADMA-lowering agents. METHODS: We investigated the effect of simvastatin on plasma ADMA levels in 35 patients with chronic kidney disease (CKD) by performing a secondary analysis of a randomized double-blind placebo-controlled trial where patients were randomized to receive simvastatin or placebo for 6 months. RESULTS: Plasma ADMA was higher in CKD patients (0.84 +/- 0.14 micromol/L) than in healthy subjects (0.69 +/- 0.10 micromol/L) (p<0.001). In CKD patients, ADMA at baseline was related directly with triglycerides (r=0.42, p=0.01) and inversely with HDL cholesterol (r=-0.37, p=0.03) and creatinine clearance (p=0.03). As expected, simvastatin caused significant reductions in total cholesterol, LDL cholesterol and triglycerides, as well as in C-reactive protein (CRP; -28%, p=0.001) and IL-6 (-20%, p=0.05) but failed to decrease plasma ADMA both in crude and adjusted analyses. CONCLUSIONS: Simvastatin does not modify plasma ADMA. Because raised ADMA is known to prevent the favorable effect of statins on myocardial blood flow, cointerventions aimed at lowering or antagonizing ADMA may either prompt or potentiate the cardiovascular protective effect of simvastatin.

Abstract:

Abstract: This review discusses various screening approaches for chronic kidney disease that are used in Europe. The criterion for defining chronic kidney disease in the various programs differs but is frequently limited to estimated glomerular filtration rate, thus offering only data on chronic kidney disease stages 3 and higher; however, screening should not be limited to measuring only estimated glomerular filtration rate but should also include a measure of microalbuminuria, because this will offer identification of chronic kidney disease stages 1 and 2. Defining these earlier stages is of importance because the risk for developing end-stage renal disease that is associated with stages 1 and 2 is nearly equal to the risk that is associated with stage 3. Moreover, the risk for cardiovascular events in stages 1 and 2 is equal to that in stage 3. Various reports argue that costs of screening programs in general practitioner or outpatient offices are high and that they are cost-effective only for preventing end-stage renal disease when they are limited to target groups, such as patients with diabetes or hypertension and elderly. The benefits of screening programs, however, should not be evaluated only with respect to the prevention of renal events but should also include the benefits of preventing cardiovascular events. The use of preselection based on either an impaired estimated glomerular filtration rate or on protein-dipstick positivity or elevated albuminuria in a morning urine void has been found effective in various European countries as an alternative for targeted screening.

Abstract: Circulating urotensin (UTN) is increased in patients with heart failure and in patients with renal diseases, and UTN antagonism is currently considered as a potential treatment for these conditions. Contrary to this contention, studies in end-stage renal disease suggest that, perhaps because of interference with sympathetic and NO systems, UTN may be cardioprotective. Therefore, we investigated the relationship between circulating UTN and echocardiographic parameters of left ventricular function (midwall fractional shortening), left atrial volume, and myocardial geometry (mean wall thickness and relative wall thickness) in 191 patients with end-stage renal disease. UTN was associated directly (r=0.39; P<0.001) with left ventricular systolic function and inversely with left atrial volume (r=-0.40; P<0.001) and the muscular component of the left ventricular (UTN versus mean wall thickness: r=-0.30, P<0.001; UTN versus relative wall thickness: r=-0.32, P<0.001). Adjustment for a series of 11 risk factors produced a relatively small change in the strength of these relationships. However, further adjustment for plasma norepinephrine or, particularly so, for the endogenous inhibitor of NO synthase asymmetrical dimethyl arginine produced a 33% to 50% decrease in the strength of such associations. Of note, there was a strong UTN-asymmetrical dimethyl arginine interaction in determining midwall fractional shortening (P=0.001) and mean wall thickness (P=0.006). These data support the hypothesis that high UTN is cardioprotective in end-stage renal disease and that interference by UTN with sympathetic activity and NO synthesis represents an intermediate mechanism mediating the favorable echocardiographic profile of patients with high UTN. Additional mechanistic insights may be needed before launching long-term clinical trials with UTN antagonists in patients with end-stage renal disease.

Abstract: BACKGROUND AND METHODS: Endogenous ouabain (EO) is markedly raised in patients with chronic renal failure. As high EO induces myocardial cell hypertrophy in vitro and it is associated with left ventricular hypertrophy (LVH) in essential hypertensives and in patients with heart failure we investigated the relationship between plasma EO and LV mass and geometry in 156 end-stage renal disease (ESRD) patients. EO was measured by a specific radioimmunoassay and by mass spectrometry. RESULTS: On univariate analysis, plasma EO was directly related to LV mass (r = 0.26, P = 0.001) and LV end diastolic volume (r = 0.25, P = 0.002) and these relationships held true in multiple linear regression models including a series of potential confounders. Patients with eccentric LVH (n = 41, i.e. 26%) had the highest plasma levels of EO when compared to patients with other patterns of LV geometry (P = 0.001). Furthermore, plasma EO had diagnostic value for eccentric LVH because the area under the corresponding ROC curve (68%) was significantly greater (P = 0.002) than the threshold of diagnostic indifference. In this analysis, the sensitivity was 91% and the specificity was 36%. The positive predictive value was 33% but EO had a remarkably high negative predictive value (92%) for the exclusion of eccentric hypertrophy. CONCLUSIONS: In ESRD patients, plasma EO is independently associated with LV mass, LV volume and eccentric LVH. The results of this study are compatible with the hypothesis that EO is involved in alterations of LV mass in ESRD.

Abstract: OBJECTIVE: Type 2 diabetes and essential hypertension are major risk factors for cardiovascular diseases. Endothelial dysfunction is an early step in the development of atherosclerosis and has been demonstrated in hypertensive and diabetic patients. RESEARCH DESIGN AND METHODS: We designed this study to determine whether forearm endothelial dysfunction is an independent predictor of type 2 diabetes in patients with essential hypertension. We enrolled 400 white never-treated hypertensive outpatients, free of type 2 diabetes at the time of the first evaluation. Endothelium-dependent vasodilation was investigated by intra-arterial infusion of acetylcholine. Insulin resistance was estimated by homeostasis model assessment. RESULTS: During the follow-up (4.5 +/- 1.6 years), 44 patients developed type 2 diabetes. The event rate was 2.4 events/100 patient-years. In a multivariate Cox regression analysis, the peak percentage increase in acetylcholine-stimulated forearm blood flow (hazard ratio [HR] 0.77 [95% CI 0.61-0.99]; P = 0.04) and C-reactive protein (1.16 [1.03-1.32]; P = 0.01) resulted in the only independent predictors of type 2 diabetes. CONCLUSIONS: An impaired vasodilatory response to acetylcholine predicts development of type 2 diabetes in patients with essential hypertension. Present data also extend recent findings regarding a possible inflammatory pathogenesis of type 2 diabetes and suggest a new approach in treatment of essential hypertension.

Abstract:

Abstract: Urotensin II (UTN), a cyclic vasoactive peptide expressed in multiple organs, had higher plasma levels that was previously shown to predict longer survival in dialysis patients. We sought to determine if this association exists in earlier stages of chronic kidney disease (CKD) by studying a cohort of 122 incident clinically stable pre-dialysis patients. Linear models were used to determine associations of UTN with baseline characteristics such as renal function and traditional and nontraditional cardiovascular risk factors. We used Cox regression analysis to model time-to-death as a function of UTN and the same variables for adjustment including a time-varying covariate that indicated progression to end-stage renal disease. No correlation was found between baseline glomerular filtration rate and plasma UTN. In adjusted analysis, UTN correlated directly with serum albumin and, inversely, with history of previous coronary events. During a mean follow-up of 41 months, 43 patients died - 29 from cardiovascular events. After adjusting for potential confounding factors, increased UTN predicted lower risk of death from all-cause and cardiovascular causes. In patients with moderate-to-severe CKD, plasma UTN was found to be an inverse predictor of overall and cardiovascular mortality.

Abstract: As confounding obscures the 'real' effect of an exposure on outcome, investigators performing etiological studies do their utmost best to prevent or control confounding. Unfortunately, in this process, errors are frequently made. This paper explains that to be a potential confounder, a variable needs to satisfy all three of the following criteria: (1) it must have an association with the disease, that is, it should be a risk factor for the disease; (2) it must be associated with the exposure, that is, it must be unequally distributed between exposure groups; and (3) it must not be an effect of the exposure; this also means that it may not be part of the causal pathway. In addition, a number of different techniques are described that may be applied to prevent or control for confounding: randomization, restriction, matching, and stratification. Finally, a number of examples outline commonly made errors, most of which result from 'overadjustment' for variables that do not satisfy the criteria for potential confounders. Such an example of an error frequently occurring in the literature is the incorrect adjustment for blood pressure while studying the relationship between body mass index and the development of end-stage renal disease. Such errors will introduce new bias instead of preventing it.

Abstract: BACKGROUND: Recent studies have indicated that the implementation of international guidelines for the management of renal patients is suboptimal in Italy. The Italian Society of Nephrology (SIN) decided to undertake a multicentre study to obtain a clear picture of clinical policies on chronic kidney disease (CKD) in Italy. METHODS: A 76-item structured questionnaire, designed to evaluate the organization of clinical care, was administered to the director of each participating centre, within the context of a large observational trial in 100 Italian nephrology centres, collecting information on newly diagnosed CKD patients (K/DOQI stage 3-5) on conservative treatment. This paper reports the questionnaire results related to management of anaemia and bone metabolism disorders; assessment of renal function; creation of a vascular access for dialysis and referral of patients to a nephrologist. RESULTS: Clinical policies at the centre level deviated from guideline recommendations in 70% (timing of vascular access creation) to 25% (assessment of iron deficiency) of centres. Assessment of renal function differed from the recommended approach in 30% of centres; clinical policies related to anaemia and bone disease did not coincide with guideline standards in 50 and 40% of centres, respectively. Directors of renal unit estimates indicate that the creation of a vascular access occurs very late in 38% of patients and that referral to a nephrologist is late in approximately 40% of cases. CONCLUSION: This survey in Italy highlights important deviations of clinical policies at the centre level from guideline recommendations.

Abstract: The quality of a clinical study depends on internal and external factors. Studies have internal validity when, random error apart, reported differences between exposed and unexposed individuals can be attributed only to the exposure under investigation. Internal validity may be affected by bias, that is, by any systematic error that occurs in the design or in the conduction of a clinical research. Here we focus on two major categories of bias: selection bias and information bias. We describe three types of selection biases (incidence-prevalence bias, loss-to-follow-up bias, and publication bias) and a series of information biases (i.e. misclassification bias--recall bias, interviewer bias, observer bias, and regression dilution bias--and lead-time bias).

Abstract:

Abstract: In previous articles of this series, we focused on relative risks and odds ratios as measures of effect to assess the relationship between exposure to risk factors and clinical outcomes and on control for confounding. In randomized clinical trials, the random allocation of patients is hoped to produce groups similar with respect to risk factors. In observational studies, exposed and unexposed individuals may differ not only for the presence of the risk factor being tested but also for a series of other factors that are potentially related to the study outcome, thus making 'confounding' very likely. One of the most important uses of multivariate modeling is precisely that 'of controlling for confounding' to let emerge the effect of the risk factor of interest on the study outcome. In this paper, we will discuss linear regression analysis for the examination of continuous outcome data and logistic regression analysis for the study of categorical outcome data. Furthermore, we focus on the most important application of multiple linear and logistic regression analyses.

Abstract:

Abstract:

Abstract: How much does the survival of one group differ from the survival of another group? How do differences in age in these two groups affect such a comparison? To obtain a quantity to compare the survival of different patient groups and to account for confounding effects, a multiple regression technique for survival data is needed. Cox regression is perhaps the most popular regression technique for survival analysis. This paper explains how Cox regression works, what the proportionality assumption means and how to interpret the results of univariate and multiple Cox regression models.

Abstract: What is this patient's prognosis regarding graft rejection? Do patients using a particular drug live longer than those not using it? How does this co-morbidity affect access to transplantation? To answer this type of questions one needs to perform survival analysis. This paper focuses on the Kaplan-Meier method, the most popular method used for survival analysis. It makes it possible to calculate the incidence rate of events like recovery of renal function, myocardial infarction or death by using information from all subjects at risk for these events. It explains how the method works, how survival probabilities are calculated, survival data can be summarized and survival in groups can be compared using the logrank test for hypothesis testing. In addition, it provides some guidance regarding the presentation of survival plots. Finally, it discusses the limitations of the Kaplan-Meier method and refers to other methods that better serve additional purposes.

Abstract: In traditional Kaplan-Meier or Cox regression analysis, usually a risk factor measured at baseline is related to mortality thereafter. During follow-up, however, things may change: either the effect of a fixed baseline risk factor may vary over time, resulting in a weakening or strengthening of associations over time, or the risk factor itself may vary over time. In this paper, short-term versus long-term effects (so-called time-dependent effects) of a fixed baseline risk factor are addressed. An example is presented showing that underweight is a strong risk factor for mortality in dialysis patients, especially in the short run. In contrast, overweight is a risk factor for mortality, which is stronger in the long run than in the short run. In addition, the analysis of how time-varying risk factors (so-called time-dependent risk factors) are related to mortality is demonstrated by paying attention to the pitfall of adjusting for sequelae. The proper analysis of effects over time should be driven by a clear research question. Both kinds of research questions, that is those of time-dependent effects as well those of time-dependent risk factors, can be analyzed with time-dependent Cox regression analysis. It will be shown that using time-dependent risk factors usually implies focusing on short-term effects only.Kidney International advance online publication, 16 July 2008; doi:10.1038/ki.2008.328.

Abstract: Etiological research aims to investigate the causal relationship between putative risk factors (or determinants) and a given disease or other outcome. In contrast, prognostic research aims to predict the probability of a given clinical outcome and in this perspective the pathophysiology of the disease is not an issue. Multivariate modeling is a fundamental tool both to infer causality and to investigate prognostic factors in epidemiological research. The analytical approaches to etiological and prognostic studies are strictly dependent on the research question and imply knowledge of the main statistical procedures for model building and data interpretation. In this paper we describe the application of multivariate statistical modeling in etiological and prognostic research. We will mainly focus on the differences in model building and data interpretation between these two areas of epidemiologic research.Kidney International advance online publication, 20 August 2008; doi:10.1038/ki.2008.416.

Abstract: OBJECTIVES: Vascular endothelial growth factor induces nitric oxide-dependent angiogenic effects and participates in the inflammatory response. This cytokine is over-expressed in the myocardium in experimental models of pressure overload and renal mass ablation, and vascular endothelial growth factor is increased in end-stage renal disease. We investigated the relationship between vascular endothelial growth factor, left ventricular function (by midwall fractional shortening) and mortality in a prospective cohort study in 228 hemodialysis patients. RESULTS: Serum vascular endothelial growth factor concentration was associated directly with interleukin-6 and tumor necrosis factor-alpha (P < 0.01) and inversely with albumin (P = 0.007) but was independent of the endogenous inhibitor of nitric oxide synthesis, asymmetric dimethylarginine. Vascular endothelial growth factor was inversely related with midwall fractional shortening (P = 0.002) and predicted mortality (P = 0.02). In multivariate analyses testing the involvement of this angiogenic cytokine in left ventricular dysfunction and death, these links remained substantially unmodified after adjustment for Framingham risk factors, risk factors peculiar to end-stage renal disease (Hb, Ca, P) and previous cardiovascular complications. However, these links became weaker and not significant when biomarkers of inflammation and asymmetric dimethylarginine were sequentially introduced into the multivariate models. In crude and adjusted analyses, left ventricular function was lowest in patients who displayed both high vascular endothelial growth factor and high asymmetric dimethylarginine, intermediate in patients with either high vascular endothelial growth factor or high asymmetric dimethylarginine and highest in those with low asymmetric dimethylarginine and low vascular endothelial growth factor (P = 0.001). CONCLUSION: Vascular endothelial growth factor is associated with left ventricular systolic dysfunction and mortality in hemodialysis patients. Vascular endothelial growth factor appears to be in the pathway whereby inflammation and nitric oxide inhibition lead to cardiomyopathy and death in hemodialysis patients.

Abstract: BACKGROUND: Although the association of renal artery stenosis with coronary artery disease is well established, the best cutoff of diseased coronary vessels predicting atherosclerotic narrowing of renal artery remains still undefined. METHODS: In 109 consecutive patients (78/31 M/F) submitted to elective coronary angiography because of effort angina, renal angiography was also performed in the same session. We considered only renal artery stenosis > or =60% to be of clinical relevance. RESULTS: Coronary artery stenosis was present in 87 patients (80%), while significant narrowing of renal arteries was found in 42 patients (39%). On univariate analysis, the odds ratio (OR) of renal artery stenosis associated with 1 stenotic coronary vessel was 1.76 (95% confidence interval [95% CI], 1.34-2.33, p<0.001). This estimate was confirmed in a multiple logistic regression model adjusting for a series of potential confounders (OR=1.83, 95% CI, 1.34-2.48, p<0.001). On receiver operating characteristic curve analysis (area under the curve: 0.74 +/- 0.05, p<0.001), the presence of 3 diseased coronary vessels provided the best cutoff for the diagnosis of concomitant renal artery stenosis (positive predictive value: 63%; negative predictive value: 76%). CONCLUSIONS: There is a strong parallelism between the number of diseased coronary vessels and the occurrence of renal vascular disease. The presence of 3 diseased coronary vessels may corroborate the decision of performing renal angiography in patients with ischemic heart disease.

Abstract: Before new tests are implemented, it is important to compare their results with those of other measurement methods that are already in use. In the determination of this so-called agreement between methods, one may choose between several statistical approaches. The correlation coefficient is a popular approach to determine the agreement between measurement methods. It is easy to calculate, but has important limitations: it does not provide any information on the type of association and it is extremely sensitive to the range of values within the study. Finally, a correlation coefficient does not reveal whether any difference between two measurements is systematic or random. Therefore, it is highly preferable to use Bland-Altman plots instead, as these reveal both systematic and random errors. Bland-Altman plots are also preferable in case of repeated measurements and calibrations.Kidney International advance online publication, 2 July 2008; doi:10.1038/ki.2008.306.

Abstract: STUDY AIMS: To survey bone mineral disturbances in the hemodialysis (HD) population in Europe and current clinical practice in Europe for the prevention, diagnosis and treatment of secondary hyperparathyroidism (SHPT) in HD patients. PRIMARY OBJECTIVES: First, to estimate the prevalence of Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline achievement in a representative sample of European hemodialysis subjects. As part of this objective, we will investigate the prevalence of achievement by type of dialysis, type of center and time on dialysis (less than or greater than 1 year). Among new dialysis subjects (less than 1 year), we will evaluate prevalence of K/DOQI target achievement until the end of the study. The study will run for 3 years. Second, to estimate the association of bone mineral markers (parathyroid hormone [PTH], calcium [Ca], serum phosphorus [P] and calcium phosphate product [CaxP]) classified by achievement of K/DOQI targets with mortality and overall cardiovascular hospitalization. Third, to characterize the longitudinal changes in bone mineral markers. As part of this objective, we will describe the patterns and predictors of bone mineral markers and achievement, with K/DOQI targets, using repeated measurements on individuals over time. SECONDARY OBJECTIVES: First, To estimate the association of bone mineral markers (PTH, Ca, P and CaxP) classified by achievement of K/DOQI targets with specific cardiovascular outcomes, parathyroidectomy, manifest bone disease (including incidence of symptomatic bone fractures), hospitalizations and vascular access. Second, to evaluate the additional value of albumin and hemoglobin levels in conjunction with bone mineral markers in the prediction of mortality and clinical events.

Abstract:

Abstract: Anemia in chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease. Maintenance of stable hemoglobin (Hb) levels is necessary to effectively manage CKD anemia. The European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) endorsed the present CKD Anaemia Physician Behaviours Survey conducted among nephrologists who regularly manage CKD patients. The survey included a total of 369 nephrologists from France, Germany, Italy, Spain and the United Kingdom, between May and June 2007. There were several aspects on which most of the nephrologists (independently of their country of origin) agreed, such as the complexity of managing anemia in patients with comorbidities -- particularly, cardiovascular disease and diabetes -- the target Hb levels of 11.00 to 12.99 g/dL and the advantages of the flexibility of weekly and monthly dosing. There was also agreement on the fact that most CKD patients are referred to a nephrologist at a late stage of the disease, which makes it difficult to start therapies to reduce morbidity and mortality. The more general implementation of routine glomerular filtration rate estimates in primary care, together with more education and awareness of CKD among primary health care providers, was considered necessary to improve the management of CKD patients.

Abstract: Patients who reach the end-stage phase of renal disease (ESRD) display an exceedingly high risk for cardiovascular (CV) complications. However it is still unclear whether in patients with chronic kidney disease (CKD) a critical glomerular filtration rate (GFR) threshold exists below which CV risk starts to rise. Analyses based on a medical database indicate that starting from the lower limit of the normal range (60 ml/min) a 30-ml/min GFR loss entails a doubling in the CV risk. In contrast, in population-based studies like the Atherosclerosis Risk in the Community (ARIC), the risk excess of stage 3 CKD is much lower, being about 30%. This discrepancy indicates that analyses based on medical databases provide an inflated estimate of the population risk for CV events associated with CKD. However, given the high prevalence of CKD at population level (about 8%-10%), a 30% increase in the risk of CV events would still have enormous public health implications. A considerable proportion of patients with CKD and occult or overt CV disease still remain largely undertreated. Multiple interventions on the multiple, modifiable risk factors of CKD at population and hospital level should be deployed if we are to curb the burden of CV sequelae of the CKD epidemics.

Abstract: Although medical guidelines generally are graded according to their evidence level, low evidence 'judgement' are generally perceived as much as absolute truth by the medical community as high evidence 'guidelines' are. Being aware of this bias, a workgroup appointed by the European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA), the members of which are the authors of the current publication, decided that European nephrology guidelines issued by the Association should be published only as 'guidelines' in the case of high-level evidence; otherwise they should be named 'recommendations' or 'position statements' and be published in a different format. Acknowledging that in nephrology, high levels of evidence are often lacking, it was also decided to rename the responsible body from European Best Practice Guidelines (EBPG) to European Renal Best Practice (ERBP). The present publication reviews the arguments based on which this decision was taken.

Abstract: BACKGROUND: Left ventricular (LV) hypertrophy and decreased kidney function are well-established cardiovascular risk factors in hypertensive patients. STUDY DESIGN: We investigated the relationship between creatinine level, creatinine clearance, and estimated glomerular filtration rate (eGFR) with LV mass (LVM) in a cross-sectional study. PREDICTORS: eGFR and serum creatinine level. OUTCOME: LVM index (LVMI). SETTING & PARTICIPANTS: 400 patients with untreated uncomplicated essential hypertension. MEASUREMENTS: LVMI, eGFR (Modification of Diet in Renal Disease Study equation), Framingham risk factors, and a series of specific risk factors, ie, endothelial function (acetylcholine [ACh]-stimulated forearm blood flow [FBF]), insulin sensitivity (Homeostatic Model Assessment for insulin resistance [HOMA-R] index), C-reactive protein (CRP), and uric acid. RESULTS: Both eGFR and creatinine level were significantly related to LVMI (r = -0.34 and r = 0.35; P < 0.001). In a multiple regression model adjusting for Framingham risk factors, eGFR was independently associated with LVMI. However, this association, although highly significant, lost substantial strength after adjustment for such specific risk factors as HOMA-R index, ACh-stimulated FBF, CRP level, and uric acid level. eGFR interacted with insulin resistance in explaining the variability in LVMI (P = 0.007). LIMITATIONS: The cross-sectional nature of this study precludes cause-effect conclusions. CONCLUSIONS: Independently of other risk factors, decreased kidney function contributes to explain the variability in LVMI in patients with untreated uncomplicated essential hypertension. This association is attributable in part to the link between eGFR and such specific risk factors as HOMA-R index, ACh-stimulated FBF, CRP level, and uric acid level. Decreased kidney function and insulin resistance interact in explaining the variability in LVMI in these patients.

Abstract:

Abstract:

Abstract: Different measures may be used to describe how often disease (or another health event) occurs in a population. Incidence expresses the development of new cases and is mostly used against the background of prevention, to assess disease etiology or to determine the risk factors of disease. Depending on the specific study question, incidence may be reported as risk or as incidence rate. This paper discusses that it is preferable to use incidence rate in case of a dynamic population or in cases where the observation period is sufficiently long for competing risks or loss to follow-up to play a significant role. Prevalence is the number of existing cases, which is affected by both the number of incident cases and the length of disease time. It reflects the burden of disease on a population that may, among others, be measured in terms of costs or morbidity. Knowledge about this burden can be used for the planning of health-care facilities. This paper discusses the different measures of disease occurrence using a number of examples taken from the nephrology literature.

Abstract:

Abstract: In an analysis based on the Mild to Moderate Kidney Disease (MMKD) study, adiponectin, a pleiotropic, insulin-sensitizing, anti-inflammatory and vasculo-protective cytokine, was directly related to renal disease progression. The precise definition of this apparently paradoxical association now requires that the research focus be moved from the study database to the experimental laboratory.

Abstract:

Abstract: BACKGROUND: The New York Heart Association (NYHA) classification is a strong predictor of mortality and an established instrument for risk stratification in patients with heart disease but data on the validity of this classification in end-stage renal disease (ESRD) are sparse. METHODS: In this study, we tested the predictive value of the NYHA in patients with ESRD and compared it with that of two established indexes of disease severity, i.e. the Khan index and the renal disease severity score (RDSS). The study cohort was composed of 1322 incident patients in a dialysis registry (772 male and 550 female, age 61+/-16 years). RESULTS: During the follow-up period (41+/-27 months) 551 patients died. A multivariate COX model including the NYHA classification explained 39% of the variation in mortality, a figure almost identical to that of a model based on the RDSS (37%) and superior (P<0.001) to that provided by the Khan index-based model (32%). The area under the receiver operating characteristic curve of NYHA classification, as related to all-cause mortality, was 0.74 (95% CI: 0.71-0.77, P<0.001). Again, RDSS had a predictive value for mortality (0.74, 95% CI: 0.72-0.77) identical to that of NYHA and higher than that of the Khan index (0.70, 95% CI: 0.67-0.72). CONCLUSION: The NYHA is a powerful predictor of mortality in ESRD and provides prognostic information equal or superior to that given by other established indexes of disease severity. Given the pervasive nature of cardiovascular disease in ESRD, this classification may be recommended for risk stratification in this population.

Abstract: BACKGROUND: Reduced synthesis of nitric oxide (NO) is considered a major proatherogenic mechanism in patients with end-stage renal disease (ESRD), but genetic factors impinging on this mechanism have been little studied in this population. METHODS: We tested the relationship between carotid intima-media thickness (IMT) and three endothelial NO synthase (eNOS) polymorphisms (G894T, T-786C, and 27-bp repeat in intron 4) in an ethnically and geographically homogeneous group of 147 patients with ESRD. RESULTS: The IMT was significantly thicker (P = .01) in patients with the TT genotype (G894T polymorphism) than in patients with TG or GG genotypes, and a similar association was observed for the T-786C polymorphism (P = .02). These relationships remained statistically significant (P = .02 and .01), also in multivariate models including traditional and emerging risk factors for atherosclerosis. Moreover, there was a direct association between the number of risk alleles and IMT (no risk allele: 0.97 +/- 0.22 mm, 1 risk allele: 1.03 +/- 0.20 mm, 2 risk alleles: 1.07 +/- 0.22 mm, > or =3 risk alleles: 1.23 +/- 0.36 mm, P < .001) that remained statistically significant in a multiple regression model. CONCLUSIONS: In patients on dialysis the risk alleles of G894T and T-786C polymorphisms of the eNOS gene are associated with carotid atherosclerosis. The additive effect of the two polymorphisms may contribute to the severity of atherosclerosis independently of other risk factors and of endogenous substances that influence the NO synthesis in this population.

Abstract: BACKGROUND: Low T3 is a frequent alteration in patients with ESRD. This derangement has been recently linked to inflammation in haemodialysis patients. Whether this association holds true in peritoneal dialysis patients has not been studied. METHODS: We investigated the relationship between low-grade inflammation [IL-6, C-reactive protein (CRP) and serum albumin levels] and free tri-iodothyronine (fT3) in a cohort of 41 CAPD patients (mean age, 66 years; M, 26; F, 15) without heart failure and inter-current illnesses. RESULTS: CAPD patients had lower fT3 levels (2.7 +/- 0.8 pg/ml) than healthy subjects (3.7 +/- 1.0 pg/ml, P < 0.001) of similar age. Free T3 levels were directly related to those of serum albumin (r = 0.52, P = 0.001) and inversely to IL-6 (r = -0.30, P = 0.05) and CRP (r = -0.54, P < 0.001). Age (r = -0.61, P < 0.001), haemoglobin levels (r = 0.32, P = 0.05) and diastolic blood pressure (r = 0.50, P = 0.001) were also related to fT3. In multiple regression models adjusting for all variables related to fT3, CRP and albumin were retained as independent correlates of fT3. During the follow-up (2.8 +/- 1.7 years) 27 patients died. Plasma fT3 levels were lower in patients who died (2.5 +/- 0.8 pg/ml) compared with survivors (3.3 +/- 0.5 pg/ml P = 0.001). In Cox analyses, fT3 was a significant predictor of mortality independent of the main traditional as well as non-traditional risk factors. CONCLUSIONS: The relationship between fT3, CRP and serum albumin suggests that inflammation-malnutrition might be involved in the low T3 syndrome in CAPD patients. Thyroid dysfunction might be implicated in the pathogenic pathway which links micro-inflammation to survival in PD patients.

Abstract: BACKGROUND AND METHODS: The endogenous inhibitor of nitric oxide synthase (NOs) asymmetrical dimethyl-arginine (ADMA) has been implicated as a possible modulator of inducible NOs during acute inflammation. We examined the evolution in the plasma concentration of ADMA measured at the clinical outset of acute inflammation and after its resolution in a series of 17 patients with acute bacterial infections. RESULTS: During the acute phase of inflammation/infection, patients displayed very high levels of C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin and nitrotyrosine. Simultaneous plasma ADMA concentration was similar to that in healthy subjects while symmetric dimethyl-arginine (SDMA) levels were substantially increased and directly related with creatinine. When infection resolved, ADMA rose from 0.62 +/- 0.23 to 0.80 +/- 0.18 micromol/l (+29%, P = 0.01) while SDMA remained unmodified. ADMA changes were independent on concomitant risk factor changes and inversely related with baseline systolic and diastolic pressure. Changes in the ADMA/SDMA ratio were compatible with the hypothesis that inflammatory cytokines activate ADMA degradation. CONCLUSIONS: Resolution of acute inflammation is characterized by an increase in the plasma concentration of ADMA. The results imply that ADMA suppression may actually serve to stimulate NO synthesis or that in this situation plasma ADMA levels may not reflect the inhibitory potential of this methylarginine at the cellular level.

Abstract: Left atrial volume (LAV), as indexed by height(2.7), has recently emerged as an useful echocardiographic measurement to refine the estimate of cardiovascular (CV) risk in ESRD. Whether progression or regression in LAV has prognostic value in patients with ESRD is still unknown. The prognostic value for CV events of changes in LAV was tested in a cohort of 191 dialysis patients. Echocardiography was performed twice, 17 +/- 2 mo apart. Changes in LAV that occurred between the second and the first echocardiographic studies were used to predict CV events during the ensuing 27 +/- 13 mo. During the follow-up, there was a significant increase in LAV (from 10.5 +/- 5.0 to 11.6 +/- 5.6 ml/m(2.7); P < 0.001). After the second echocardiographic study, 76 patients died (52 [68%] of CV causes) and 33 had nonfatal CV events. The independent association between changes in LAV and CV events was analyzed in a multiple Cox regression model taking into account a series of potential confounders, including baseline LAV and left ventricular mass and geometry. In these models, a 1-ml/m(2.7) per yr increase in LAV was associated with a 12% increase in the relative risk for fatal and nonfatal CV events (P < 0.001). Changes in LAV predict incident CV events in dialysis patients independent of the corresponding baseline measurement and of left ventricular mass. Monitoring LA size by echocardiography is useful for monitoring CV risk in patients with ESRD.

Abstract: Chronic kidney disease (CKD) is a worldwide public health problem with significant comorbidity and mortality. Improving quality of life and survival of CKD patients necessitates a large number of preventive and therapeutic interventions. To resolve these issues several organizations have developed guidelines, which are difficult to compare comprehensively. The Kidney Disease: Improving Global Outcomes website at http://kdigo.org compares five major guidelines. The section 'compare guidelines' covers 41 topics distributed over five major subjects: (1) general clinics; (2) hemodialysis (HD); (3) vascular access for HD; (4) peritoneal dialysis; and (5) chemistries. The tables compare guideline recommendations and the evidence levels on which they are based, with direct links to each of the guidelines. These data show that the different guideline groups tend to propose similar targets, but that nuances in the guideline statements, their rationale, and grading of evidence levels present some discrepancies, although most guidelines are based on the same literature. We conclude that there is an urgent need to harmonize existing guidelines, and for a global initiative to avoid the parallel development of conflicting guidelines on the same topics. The tables displayed on the website offer a basis for structuring this process, a procedure which has recently been initiated by a body composed of the five guideline development groups.

Abstract:

Abstract:

Abstract: Homocysteine has been implicated in atherosclerotic and thrombotic vascular disease in the general and in the end-stage renal disease (ESRD) population as well. Although not strong, the risk associated with raised homocysteine (25% risk excess for a 5 mum increase) is quite consistent across studies in the general population. Likewise, individuals harboring a polymorphism leading to higher homocysteine levels coherently display an increased risk for cardiovascular events in comparison with individuals without such a polymorphism. Randomized controlled trials of homocysteine-lowering therapy performed so far failed to prove causality but the size effect of these interventions is still compatible with the hypothesis that reducing the plasma levels of this aminoacid may be beneficial. In ESRD, high homocysteine is a coherent predictor of death and adverse cardiovascular events in patients without malnutrition and inflammation. In the sole randomized placebo-controlled study performed in this population folic acid produced a small beneficial effect which, because of the lack of power, failed to achieve statistical significance. In another randomized study testing the effect of a well established homocysteine-lowering agent, N-acetyl-cysteine, a 40% reduction in cardiovascular events was observed. There is still insufficient knowledge to draw definitive conclusions on the causal implication of homocysteine in the high risk of ESRD. The contention that the homocysteine pathway cannot be used for interventions aimed at curbing cardiovascular risk in this population is, at least by now, unwarranted.

Abstract: BACKGROUND: The endogenous inhibitor of nitric oxide synthase (NOS), asymmetric dimethylarginine (ADMA), is implicated in endothelial dysfunction and is a marker of renal disease progression and cardiovascular (CV) complications. Various cell species exhibit the enzymatic system that generates and degrades this methylarginine, but it is unknown whether this machinery is expressed in adipocytes. The question is relevant because adipocyte-derived mediators are implicated both in renal and cardiovascular diseases. METHODS: We measured ADMA concentration in pure adipocytes in culture and measured mRNA levels of the enzymes involved in ADMA metabolism (real-time polymerase chain reaction) both in pure adipocytes in culture and in adipose tissue harvested in 9 healthy subjects. These enzymes included protein arginine N-methyltransferases type I (PRMTs) involved in ADMA synthesis, dimethylarginine dimethylaminohydrolases (DDAHs) responsible for ADMA degradation and constitutive and inducible forms of NOS (i.e., NOS1, NOS2A and NOS3 genes), the main functional target of ADMA. RESULTS: Human adipocytes express the whole gene set that codes for the enzymatic system responsible for the biosynthesis and the degradation of ADMA, and this methylarginine is actually released by adipocytes in culture. NOS gene isoforms have a low level of expression in human adipose tissue, indicating that putative functions of ADMA in fat cells may be in part mediated by mechanisms other than NOS inhibition. CONCLUSIONS: Human adipocytes produce ADMA and express the full enzymatic machinery responsible for ADMA metabolism. Studying the functional implication of these findings may be of relevance for clarifying the role of fat mass expansion in human disease.

Abstract: The endothelium is a fundamental layer in the arterial wall both for the local regulation of flow to critical organs like the heart, brain and kidney, and for the protection of the vascular system from atherogenic insults. Inhibition of nitric oxide (NO) synthesis has profound effects at systemic and renal levels. Low NO bioavailability may occur in essential hypertension and in a variety of conditions associated with high cardiovascular risk. High oxidative stress and low availability of the substrate of NO-synthase, l-arginine, as well as an increase of endogenous NO inhibitors such as asymmetric dimethylarginine (ADMA) may engender endothelial dysfunction. This alteration is very frequent in patients with chronic kidney disease (CKD) and may contribute to accelerated progression of CKD, hypertension and cardiovascular complications. The kidney not only reabsorbs but also synthesizes l-arginine and appears to be a central organ for the catabolism of ADMA, mainly because it is richly endowed with the enzyme that degrades ADMA, dimethylarginine dimethylaminohydrolase (DDAH). Recent studies demonstrated that ADMA accumulation predicts both progression to end-stage renal disease and death in patients with CKD, again further suggesting that ADMA is a potentially important treatment target in clinical trials aimed at reducing the rate of loss of renal function in these patients.

Abstract: In studies on the effects of therapy (or other interventions), the randomized controlled trial (RCT) is an almost unbeatable standard in clinical research. The value of RCTs leaves unabated the valuable contributions of observational studies to medicine. This paper discusses some limitations of RCTs providing examples where these are not possible, inappropriate, inadequate, or unnecessary. Thereafter, it focuses on observational studies and gives a number of examples of studies on etiology, diagnosis, prognosis, and adverse effects, where observational designs have provided answers to research questions that could not have been answered by RCTs. Strengths and weaknesses of the different observational study designs are discussed. Finally, it is concluded that both observational studies and RCTs fulfill a complementary and valuable role in nephrology.

Abstract: We investigated the relationship between microalbuminuria (an indicator of systemic and renal endothelial dysfunction), inflammation (high-sensitivity C-reactive protein [CRP]) and endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm) in 110 never-treated subjects with uncomplicated essential hypertension and serum creatinine within the normal range. Microalbuminuria was associated with the hemodynamic response to ACh (r=0.27, p=0.006) and with serum creatinine (r=0.34, p<0.001), and these associations held true in multivariate analyses. On the other hand, microalbuminuria was largely independent of serum CRP. Since microalbuminuria, response to ACh and serum CRP are all considered risk factors for renal insufficiency and since these factors were significantly related to creatinine at univariate analysis, we tested their association with creatinine in a multiple regression model including also the full set of Framingham risk factors. In this analysis, serum CRP and microalbuminuria maintained a significant association with serum creatinine, while the hemodynamic response to ACh lost substantial predictive value for serum creatinine. In conclusion, microalbuminuria in essential hypertension is weakly related to the vasodilatory response to ACh and unrelated to inflammation but maintains an independent link with serum creatinine. Collectively, these associations suggest that microalbuminuria reflects a local (renal) endothelial dysfunction and that it may contribute to renal impairment independently of inflammation and hemodynamic endothelial dysfunction in hypertensive patients.

Abstract:

Abstract: BACKGROUND: In mice, neuropeptide Y (NPY) decreases bone turnover by means of a parathyroid hormone-independent effect on osteoblast activity. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: We studied the relationship between levels of NPY and biomarkers of osteoblast activity in 161 nondiabetic patients with end-stage renal disease (131 patients, hemodialysis; 30 patients, continuous ambulatory peritoneal dialysis). PREDICTORS & OUTCOMES: We performed an analysis of demographic and clinical variables associated with NPY as a dependent variable and a second analysis testing the association of NPY (as an independent variable) with markers of osteoblast activity. RESULTS: Peritoneal dialysis as treatment modality (beta = 0.37; P < 0.001) and longer duration of dialysis therapy (beta = 0.24; P < 0.01) were independently related to plasma NPY. NPY level was related inversely (P < 0.001) to serum alkaline phosphatase and bone alkaline phosphatase levels (P = 0.01). The NPY-alkaline phosphatase link was confirmed in a multiple regression analysis adjusting for a series of potential confounders, including parathyroid hormone. In a categorical analysis in which the study population was divided according to NPY quartiles, the proportion of patients with low alkaline phosphatase levels was lowest in the first 2 NPY quartiles (26%) and highest in NPY quartile 4 (80%; P < 0.001), and this association held true in a multiple logistic regression analysis, indicating that the risk of low alkaline phosphatase level increases in parallel with NPY level. LIMITATIONS: The hypothesis generated by this cross-sectional study needs to be confirmed in cohort studies. CONCLUSIONS: The inverse relationships between levels of NPY and biomarkers of bone turnover support the hypothesis that NPY may be implicated in low bone turnover in dialysis patients by a central parathyroid-independent mechanism.

Abstract: The purpose of this paper is to discuss whether the randomized clinical trial (RCT) is indeed the gold standard among epidemiological studies. This paper illustrates to what extent different study designs may contribute to the answer of the following therapeutic research question based on a study of Wanner et al.: 'Is the use of a statin associated to less cardiac mortality in patients with type 2 diabetes mellitus who receive hemodialysis?' If a therapeutic study is feasible, like the research question of the clinical example, the RCT is almost unbeatable: the problems that may occur in the other study designs do not exist or to a lesser extent using an RCT. The main advantage of an RCT is that the randomization procedure helps to prevent selection bias by the clinician by breaking the link between the clinician's therapy prescription and the patient's prognosis. Within observational studies, however, selection by the clinician may occur, and, even after adjustment for potential confounders in the statistical analysis, it may not be possible to make a fair comparison between the groups. Usually, results from observational studies are needed to come to a hypothesis that can subsequently be tested within an RCT. Moreover, observational data are most often more useful than RCTs for non-therapeutic studies.

Abstract: BACKGROUND: Evidence linking chronic kidney disease (CKD) with the increased risk of cardiovascular (CV) complications is firm. It is becoming clear that testing functions of the vascular endothelium in conjunction with various biomarkers may better the definition of CV risk profile in CKD patients. METHODS: Using Multiplexed analysis of 16 markers reflecting pro-inflammatory, anti-inflammatory, angiogenic, metabolic and anti-fibrinolytic factors in a series of 75 patients with CKD, who underwent echo-coloured Doppler study of carotid arteries, we analysed the contribution of each parameter to the characterization of atherosclerotic burden. As control group we enrolled 33 healthy individuals. RESULTS: On univariate analysis, intima-media thickness, number of atherosclerotic plaques and internal diameter of carotid arteries were strongly interrelated. Starting with these indicators of carotid atherosclerosis, we extracted by principal component analysis a single composite atherosclerosis severity score that accounted for 68% of the total variance of original variables. Biomarkers significantly related to severity of carotid atherosclerosis were MMP9, t-PAI-1, IL-6, NT-proBNP, IL-8 and VEGF. In multiple linear regression models adjusting for clinical variables the gain in prediction power was achieved when we added MMP9 and t-PAI-1 to the basic model. IL-6 produced the highest increase in the multiple R2 of the basic model. The combination of MMP9, t-PAI-1, IL-6, NT-proBNP, IL-8 and VEGF added to the basic model achieved gain in prediction power of + 7.5%. In this expanded model, IL-6 was the only biomarker that significantly predicted the severity of atherosclerosis. CONCLUSION: Multiplexed screening revealed that IL-6, MMP-9, tPAI-1 and VEGF showed a tight correlation with carotid atherosclerotic burden in patients with CKD.

Abstract: Epidemiological studies aim at assessing the relationship between exposures and outcomes. Clinicians are interested in knowing not only whether a link between a given exposure (e.g. smoking) and a certain outcome (e.g. myocardial infarction) is statistically significant, but also the magnitude of this relationship. The 'measures of effect' are indexes that summarize the strength of the link between exposures and outcomes and can help the clinician in taking decisions in every day clinical practice. In epidemiological studies, the effect of exposure can be measured both in relative and absolute terms. The risk ratio, the incidence rate ratio, and the odds ratio are relative measures of effect. Risk difference is an absolute measure of effect and it is calculated by subtracting the risk of the outcome in exposed individuals from that of unexposed.

Abstract: BACKGROUND: E-selectin is a key adhesion molecule which plays a fundamental role in endothelial progenitor cell-dependent reparative mechanisms in experimental ischaemia and it serves to anchor leucocytes to the endothelium in inflammatory processes. Inflammation is one of the strongest risk factors for death and cardiovascular (CV) events in end-stage renal disease (ESRD). OBJECTIVE: The objective of the current study was to evaluate whether E-selectin is a useful biomarker of clinical outcome in ESRD patients. We tested the prediction power of circulating E-selectin for mortality and CV events in a cohort of 265 ESRD patients. RESULTS: During the follow-up, 59 patients died and 58 had CV events. All-cause mortality was inversely related to serum E-selectin, the risk of death being the lowest in patients in the third E-selectin tertile (HR: 1, reference group), intermediate in those in the second tertile (HR: 1.30) and the highest in patients in the first tertile (HR: 2.02, P = 0.01). Similarly, the risk of fatal and nonfatal CV events followed an inverse pattern being lowest in the third tertile (reference group) and highest in the first tertile (HR: 1.73, P = 0.03). The prediction power of E-selectin for death and CV events was confirmed in a Cox regression analysis where E-selectin emerged as an inverse predictor of these outcomes, particularly so in patients with severe inflammation. CONCLUSIONS: These data are in keeping with the hypothesis that in systemic inflammation altered E-selectin shedding may play a role in arterial damage and implicates this adhesion molecule in atherosclerotic complications in a high-risk condition like ESRD.

Abstract:

Abstract:

Abstract: This review focuses on a series of risk factors involved in the pathogenesis of cardiovascular complications in patients undergoing Regular Dialysis Treatment (RDT). Many of them are not modifiable by any pharmacological strategies or dialysis therapy, others - such as phosphate overload - can be corrected successfully, thus slowing progression of vascular calcification. Another important reason to control serum phosphate is that its accumulation in the body plays a key role in trigger-ing, directly or indirectly, PTH secretion with important metabolic consequences, mainly in the bone. The need to control serum phosphate levels relies mostly on the use of phosphate binders and in this review the pro-con analysis of several P binders (Calcium Salts, Sevelamer, Lanthanum Carbonate) is presented in terms of safety and efficacy.

Abstract: The endogenous inhibitor of the nitric oxide synthase, asymmetric dimethylarginine (ADMA), by reducing nitric oxide (NO) availability, may trigger pro-atherogenic effects. A high plasma concentration of this substance has been associated to intima-media thickening, left ventricular hypertrophy and all-cause and cardiovascular mortality in patients with end-stage renal disease, and to coronary events in males in the general population. Recent studies show that ADMA predicts renal disease progression and death in patients with moderate to severe renal insufficiency. ADMA may be at the crossroad of the atherosclerosis process and may represent an important factor in the high risk associated with renal insufficiency.

Abstract: In the last few years the Italian Society of Nephrology has addressed many technical-scientific and management aspects to better patient satisfaction. Project No. 1 of the 2004-2006 programme on 'Quality and Accreditation of National Renal Units' focuses on four essential points. The first is the questionnaire mailed to all the Presidents and Regional Delegates on the relationship between Nephrology units, Local Government Health-System and the Regional Healthcare Agency. The results evidence that the 'political' decision-making power of nephrologists decreases in the absence of a national strategy. The second point, in collaboration with the National Census Group, includes the quality analysis and the standardization of resources (human and structural) and management of the Renal Units. The third point is based on 'Educational Courses for Quality and Accreditation' held in Rome (3-5 October 2005: L'Accreditamento all'Eccellenza dell'Unita' Operativa di Nefrologia, Dialisi e Trapianto; 17-19 October 2005: Il Manuale di Accreditamento della Specialità di Nefrologia). The courses aim at training members responsible for each region to hold courses in their specific region to create a network including each single Renal Unit to create an acceptable homogenous language on the models of analysis and on the correct use of 'The Guide for Excellence Accreditation'. The fourth point concerns both the on-line Guide for Excellence Accreditation and 'Peer Review Accreditation' and the NEQUASY (Nephrology Quality System) project. The manual must be 'user friendly' allowing each Centre to self-evaluate using national and regional standards.

Abstract: Renal insufficiency in essential hypertension represents the expression of a medium- and small-size arteriolopathy characterized by intimal hyperplasia, hyalinosis, and smooth muscle cell hypertrophy (nephroangiosclerosis). Because in animal models endothelial dysfunction plays a role in this alteration, nephroangiosclerosis and the attendant renal insufficiency may be the expression of a systemic dysfunction of vascular endothelium. Endothelial function in the kidney vasculature of hypertensive individuals has been investigated little because studies on the hemodynamic response of the kidney to nitric oxide activation and blockade are laborious to perform. There is no direct proof that endothelial dysfunction in the forearm or in the coronary circulation is paralleled by a similar hemodynamic dysfunction in the kidney. A recent study in a large population of patients with essential hypertension showed that, independent of other risk factors, the GFR in these patients is strongly related to the forearm blood flow response to acetyl choline (an established test of endothelial function). Furthermore, in this study, C-reactive protein was inversely related to the GFR and with the vasodilatory response to acetyl choline, pointing to inflammation as a likely mechanism to explain the association between endothelial dysfunction and impaired renal function in essential hypertension. A dysfunctional endothelium may represent a critical link accounting for the risk for both renal impairment and cardiovascular complications in essential hypertension.

Abstract: There are 44,000 dialysis patients in Italy and it is estimated that about 50% of them are hypertensive. In dialysis patients arterial blood pressure (BP) is highly variable, as it gradually increases in the interdialytic interval and decreases more or less rapidly during dialysis. Sodium retention and volume expansion play a major role in hypertension in these patients; and therefore, this alteration constitutes a main treatment target in this patient population. The great majority of patients also require antihypertensive drugs. The pharmacokinetics of these drugs are often modified by renal failure and peculiar dose adjustments must be adopted in this setting.

Abstract: The relationship among inflammation (plasma high-sensitivity C-reactive protein [CRP]), endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm), and renal function (serum creatinine and GFR [Modification of Diet in Renal Disease formula]) was investigated in 264 never-treated individuals with uncomplicated essential hypertension and serum creatinine within the normal range. Multiple regression models of renal function (creatinine) were constructed in sequence including Framingham risk factors as well the hemodynamic response to ACh and plasma CRP. The inclusion of endothelial function into a model based on Framingham risk factors added highly significant (P < 0.001) power to this model (+5%). Of note, in an alternative model that included CRP (instead of endothelial function), the creatinine variance explained by this factor was two times higher (+10%) than that associated with endothelial function in the first model. In the full model that included both endothelial function and CRP, CRP maintained a much stronger independent link with the outcome measure than endothelial function. In individuals with untreated, uncomplicated essential hypertension, multivariate modeling indicated that inflammation is a crucial mechanism mediating the endothelial-renal function link. The proatherogenic potential of inflammation associated with subtle impairment in renal function may contribute to the cardiovascular risk of essential hypertension.

Abstract: Although it is well established that compromised systolic function predicts cardiovascular (CV) complications in symptomatic and asymptomatic patients with ESRD, it still is unknown whether repeated echocardiographic measurements of systolic function in asymptomatic patients with ESRD is useful for monitoring the evolution of cardiomyopathy in these patients. The prognostic value for CV events of changes in systolic function, as measured by midwall fractional shortening (mwFS) in a cohort of 191 dialysis patients, was tested. Echocardiography was performed twice, 17 +/- 2 mo apart. Changes in mwFS (ch-mwFS) that occurred between the second and the first echocardiographic studies then were used to predict CV events during the ensuing 27 +/- 13 mo. After the second echocardiographic study, 85 patients had incident CV events. In a Kaplan-Meier analysis, there was a graded increase in the risk for fatal and nonfatal CV events across ch-mwFS quartiles (P = 0.005). On multivariate Cox regression analysis, ch-mwFS maintained an independent association with CV outcomes. In this analysis, the risk for CV events was 51% lower in patients who manifested an increase in mwFS (hazard ratio 0.49; 95% confidence interval 0.27 to 0.88; P = 0.02) than in those who had a decrease in mwFS. Changes in mwFS have an independent prognostic value for CV events, and periodic echocardiographic studies of systolic function are useful for monitoring asymptomatic dialysis patients.

Abstract: BACKGROUND: E-selectin is a cell surface glycoprotein that mediates the adhesion of leucocytes to vessels endothelium, an important early step in the atherosclerotic process. End-stage renal disease (ESRD) is a highly atherogenic disease but it is unknown whether genetic polymorphism(s) in the E-selectin gene plays a role in the severity of arterial damage in this condition. Method. In this study, we tested whether the Leu554Phe variant in the E-selectin gene is linked to carotid atherosclerosis in 134 well-characterized ESRD patients. The frequency of this polymorphism was also measured in a population sample of the same geographical area. RESULTS: A total of 84% patients had the CC genotype, 13% had the CT genotype, 3% had the TT genotype and this distribution did not differ from that in the control population. Intima-media thickness (IMT) (P = 0.01) and cross-sectional area (P = 0.02) were significantly higher in patients with the T-allele than in those without this allele. Furthermore, the degree of carotid stenosis was significantly higher (P = 0.02) in patients with T-allele than in CC patients. On multivariate analyses including the traditional and non-traditional risk factors, the Leu554Phe polymorphism was confirmed as an independent correlate of IMT (P = 0.02), cross-sectional area (P = 0.03) and carotid stenosis (P = 0.02). CONCLUSION: In ESRD, the Leu554Phe polymorphism of E-selectin gene is associated with the severity of carotid atherosclerosis, suggesting that genetically-determined alterations in the E-selectin molecule may render ESRD patients with this gene variant particularly susceptible to the detrimental effects of inflammation on the arterial wall.

Abstract: BACKGROUND: Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation. METHODS: In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders. RESULTS: Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22). CONCLUSIONS: Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.

Abstract: BACKGROUND: Oxidative stress is related to endothelial dysfunction (ED) and cardiovascular outcomes in patients with chronic kidney disease. Increased asymmetric dimethylarginine (ADMA) levels are among the main causes of ED. We aim to investigate any association between ED and ADMA levels, as well as levels of oxidative stress markers, in patients with chronic kidney disease. METHODS: One hundred fifty-nine patients without diabetes with chronic kidney disease were studied. Staging was performed according to glomerular filtration rate, determined as stages 1 to 5 according to the Kidney Disease Outcomes Quality Initiative (n = 30, 33, 28, 32, and 36, respectively). The control group consisted of 30 healthy subjects. Oxidative stress markers (plasma malondialdehyde [MDA], erythrocyte superoxide dismutase [SOD], glutathione peroxidase [GSH-Px]), trace elements (erythrocyte zinc [EZn], erythrocyte copper [ECu]), plasma selenium (Se), and serum ADMA were studied. Brachial artery endothelium-dependent vasodilatation (FMD) was calculated for all. RESULTS: FMD, SOD, GSH-Px, EZn, ECu, and Se values were lower, whereas MDA and ADMA levels were higher in patients than controls. Glomerular filtration rate correlated negatively with MDA and ADMA levels and positively with FMD, SOD, and GSH-Px values. These parameters were significantly different among patients with stages 2, 3, 4, and 5 (hemodialysis group; P < 0.001 for all). Regression analysis showed that ADMA (beta = -0.228; P < 0.01), SOD (beta = 0.405; P < 0.001), and oxidized low-density lipoprotein levels (beta = -0.428; P < 0.001) were related independently to FMD, whereas glomerular filtration rate was not involved in the model. CONCLUSION: The present results imply that FMD, oxidative stress, and ADMA levels all are associated with stage of chronic kidney disease. Additionally, levels of oxidative stress markers and ADMA independently determine endothelial function.

Abstract:

Abstract: PURPOSE OF REVIEW: This review summarizes current knowledge on asymmetric dimethylarginine, renal function in health and disease, and renal disease progression and examines interventions that may modify the plasma concentration of this methylarginine. RECENT FINDINGS: Nitric oxide deficiency may occur in patients with chronic kidney disease and may contribute to accelerate progression of chronic kidney disease, hypertension and cardiovascular complications. An increase of endogenous nitric oxide inhibitors like asymmetric dimethylarginine seems to play a major role in this process. The kidneys are crucial in both, in re-absorbing and generating L-arginine as well as in eliminating asymmetric dimethylarginine primarily by the enzyme dimethylarginine dimethylaminohydrolase and to a minor degree by urinary excretion. Asymmetric dimethylarginine accumulation predicts both accelerated renal function loss and death in patients with chronic kidney disease and incident cardiovascular complications in patients with end stage renal disease. SUMMARY: Asymmetric dimethylarginine is a new risk factor potentially implicated in the progression of renal insufficiency and in the high rate of cardiovascular complications of patients with chronic kidney disease.

Abstract: The current implementation into nephrology clinical practice of guidelines on treatment of cardiovascular (CV) risk factors in chronic kidney disease (CKD) is unknown. We designed a cross-sectional analysis to evaluate the prevalence and treatment of eight modifiable CV risk factors in 1058 predialysis CKD patients (stage 3: n=486; stage 4: n=430, stage 5: n=142) followed for at least 1 year in 26 Italian renal clinics. The median nephrology follow-up was 37 months (range: 12-391 months). From stages 3 to 5, hypertension was the main complication (89, 87, and 87%), whereas smoking, high calcium-phosphate product and malnutrition were uncommon. The prevalence of proteinuria (25, 38, and 58%), anemia (16, 32, and 51%) and left ventricular hypertrophy (51, 55, and 64%) significantly increased, while hypercholesterolemia was less frequent in stage 5 (49%) than in stages 4 and 3 (59%). The vast majority of patients received multidrug antihypertensive therapy including inhibitors of renin-angiotensin system; conversely, diuretic treatment was consistently inadequate for both frequency and dose despite scarce implementation of low salt diet (19%). Statins were not prescribed in most hypercholesterolemics (78%), and epoietin treatment was largely overlooked in anemics (78%). The adjusted risk for having a higher number of uncontrolled risk factors rose in the presence of diabetes (odds ratio 1.29, 95% confidence interval 1.00-1.66), history of CV disease (odds ratio 1.48, 95% confidence interval 1.15-1.90) and CKD stages 4 and 5 (odds ratio 1.75, 95% confidence interval 1.37-2.22 and odds ratio 2.85, 95% confidence interval 2.01-4.04, respectively). In the tertiary care of CKD, treatment of hypertension is largely inadequate, whereas therapy of anemia and dyslipidemia is frequently omitted. The risk of not achieving therapeutic targets is higher in patients with diabetes, CV disease and more advanced CKD.

Abstract: Like blood pressure and cholesterol, homocysteine shows a paradoxical inverse relationship with cardiovascular complications in end-stage renal disease (ESRD). A paper by Ducloux et al. in this issue adds perhaps decisive evidence on malnutrition-hypoalbuminemia as the main factor explaining the counterintuitive association between homocysteine and clinical outcome reported in previous studies.

Abstract: Chronic kidney disease has emerged as a public health problem of primary importance, mainly because of the high risk for coronary heart disease and other cardiovascular complications of this condition. Patients with end-stage renal disease are at a uniquely high risk for a severe form of the disease but most of the population burden generated by atherosclerotic complications derives from patients with moderate and severe degrees of kidney disease. A reduction in coronary heart disease and cardiovascular events as related to chronic kidney disease demands large-scale preventive measures targeting individuals with evidence of renal dysfunction, well before the end-stage renal disease phase.

Abstract: Associations between environmental exposures and disease in epidemiological studies often are confounded and may result in erroneous interpretations. The random assortment of genes from parents to offspring at gamete formation--Mendelian randomization--is emerging as a useful method for studying the nature (causal or not) of environmental exposures. This occurs because the association between a disease and a polymorphism that mimics the biological link between a given exposure and the same disease is unaffected by the reverse causation that may complicate the interpretation of observational studies. Thus, similarly to randomized trials, association studies between gene polymorphisms with a well-established function may be useful for excluding confounding as an explanation for a given epidemiological relationship. The rationale behind this concept is that transmission of genes occurs in a random way; therefore, offspring have an equal chance of inheriting either of the 2 alleles that their parents have at any particular locus, a phenomenon independent from environmental factors. This is similar to the construct of randomized trials, in which randomization is expected to produce similar distributions of measured and unmeasured confounders between treated and untreated (control) groups. The equivalence between random assortment of alleles and random assignment of interventions in randomized studies is particularly useful because it may give a clue for interpreting associations that may be produced as both the effect of a gene or result of an environmental exposure. Examples are provided about the use of this concept to elucidate paradoxical inverse associations in epidemiological studies in the general and end-stage renal disease populations.

Abstract: Urotensin II (UTN) is a vasoactive substance that may induce vasoconstriction or vasodilatation. Although this peptide is seen as a vasculotoxic substance, to date there is no prospective study examining the relationship between UTN and hard end points like cardiovascular (CV) events. UTN is much increased in end-stage renal disease (ESRD) and this disease may represent a useful natural model to explore the relationship between UTN and CV outcomes. In this study, we analysed the relationship between plasma UTN and incident CV events (fatal and non-fatal) in a cohort of 191 haemodialysis patients followed up for an average time of 3.6 years (range 0.07-5.8 years). Plasma UTN in haemodialysis patients (median: 6.5 ng/ml) was twice higher than in healthy subjects (median: 3.3 ng/ml). During the follow-up period, 94 patients died and 88 had incident fatal and non-fatal CV events. UTN was significantly lower in patients with incident CV events (median: 5.3 ng/ml) than in events-free patients (median: 7.1 ng/ml), and in a Kaplan-Meier analysis, high UTN was strongly and inversely associated with incident CV events (P<0.001). Multivariate Cox's regression analysis fully confirmed plasma UTN as an inverse predictor of adverse CV outcomes, and in this analysis, UTN resulted to be the third factor in rank, after age and diabetes, explaining the incidence of CV events. UTN is an inverse predictor of CV outcomes in ESRD. Our data suggest that UTN should not be necessarily seen as a vasculotoxic peptide in haemodialysis patients.

Abstract: Patients with chronic kidney disease (CKD) represent an important segment of the population (7-10%) and, mostly because of the high risk of cardiovascular complications associated with renal insufficiency, detection and treatment of CKD is now a public health priority. Traditional risk factors can incite renal dysfunction and cardiovascular damage as well. As renal function deteriorates, non-traditional risk factors play an increasing role both in glomerular filtration rate (GFR) loss and cardiovascular damage. Secondary analyses of controlled clinical trials suggest that inflammation may be a modifiable risk factor both for cardiac ischemia and renal disease progression in patients with or at risk of coronary heart disease. Homocysteine predicts renal function loss in the general population and cardiovascular events in end-stage renal disease (ESRD), but evidence that this sulfur amino acid is directly implicated in the progression of renal disease and in the high cardiovascular mortality of uremic patients is still lacking. High sympathetic activity and raised plasma concentration of asymmetric dimethylarginine (ADMA) have been associated to reduced GFR in patients with CKD and to cardiovascular complications in those with ESRD but again we still lack clinical trials targeting these risk factors. Presently, the clinical management of CKD patients remains largely unsatisfactory because only a minority of these attain the treatment goals recommended by current guidelines. Thus, in addition to research into new and established risk factors, it is important that nephrologists make the best use of knowledge already available to optimize the follow-up of these patients.

Abstract: OBJECTIVES AND METHODS: Low free plasma triiodothyronine (fT3) is associated with inflammation and cardiovascular damage in patients with end-stage renal disease (ESRD). We investigated the relationship between fT3, left ventricular systolic function and left ventricular mass in a group of 234 dialysis patients, and modelled the association between fT3 and cardiomyopathy in statistical analyses including both direct (interleukin-6 and C-reactive protein) and inverse (serum albumin) acute phase inflammation markers. RESULTS: Plasma fT3 concentration in dialysis patients was significantly (P < 0.001) reduced in comparison with healthy participants and clinically euthyroid patients with normal renal function. Left ventricular systolic function was depressed (P <or= 0.003) and left ventricular mass increased (P < 0.001) in patients in the first fT3 quartile as compared with patients in other quartiles. In multiple regression analyses these associations remained significant also after adjustment for Framingham risk factors and antihypertensive therapy (P </= 0.01), and for risk factors peculiar to ESRD (P = 0.03). Adjustments for interleukin-6 or for albumin, however, abrogated these relationships. CONCLUSIONS: Low triiodothyronine is associated with left ventricular dysfunction and left ventricular hypertrophy in ESRD patients. These associations appear largely mediated by inflammation. Low fT3 may be an intermediate mechanism implicated in the adverse cardiac effects of inflammation in patients with ESRD.

Abstract: Endocannabinoids are a group of biologically active endogenous lipids that have recently emerged as important mediators in energy balance control. The two best studied endocannabinoids, anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the endogenous ligands of the central and peripheral cannabinoid receptors. Furthermore, AEA binds to the transient receptor potential vanilloid type-1 (TRPV1), a capsaicin-sensitive, non-selective cation channel. The synthesis of these endocannabinoids is catalyzed by the N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and the sn-1-selective diacylglycerol lipase (DAGL), whereas their degradation is accomplished by the fatty acid amide hydrolase (FAAH) and the monoglyceride lipase (MGL), respectively. We investigated the presence of a functional endocannabinoid system in human adipose tissue from seven healthy subjects. Subcutaneous abdominal adipose tissue underwent biochemical and molecular biology analyses, aimed at testing the expression of this system and its functional activity. AEA and 2-AG levels were detected and quantified by HPLC. Real time PCR analyzed the expression of the endocannabinoid system and immunofluorescence assays showed the distribution of its components in the adipose tissue. Furthermore, binding assay for the cannabinoid and vanilloid receptors and activity assay for each metabolic enzyme of the endocannabinoid system gave clear evidence of a fully operating system. The data presented herein show for the first time that the human adipose tissue is able to bind AEA and 2-AG and that it is endowed with the biochemical machinery to metabolize endocannabinoids.

Abstract:

Abstract: Because atherogenesis represents a type of chronic inflammation that involves multiple elements of the inflammatory-immune response, the simultaneous prediction power for death of C-reactive protein (CRP) and proinflammatory cytokines (IL-1 beta, IL-6, IL-18, and TNF-alpha) was tested in a cohort of 217 patients with ESRD. During the follow-up period (average 41 mo), 112 patients died. In an analysis that was adjusted for other risk factors, the relative risks for death of patients who were exposed to high levels of one, two, three, and four or more inflammation biomarkers were 1.48, 1.64, 2.76, and 3.05 times higher, respectively, than that of patients in the reference category (no inflammation). In this model, the explained variation in mortality that was attributable to overall inflammation burden (+9.1%) was marginally higher (P = 0.06) than that provided by IL-6 alone (+6.1%). In an alternative analysis based on the Bayesian approach (receiver operating characteristic curves analysis), the prediction power of the combined inflammatory burden was identical to that provided by the sole IL-6 (0.59 +/- 0.04 versus 0.59 +/- 0.04). IL-6 captures almost entirely the prediction power of the overall inflammation burden in patients with ESRD. IL-6 seems to be an almost ideal indicator of the severity of inflammation. The use of this biomarker can be recommended in clinical studies that aim to better the understanding of inflammation or to modify it in this population.

Abstract: The nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an emerging risk biomarker in cardiovascular and renal diseases. Apparently amlodipine and valsartan produce substantial reductions in the plasma concentration of this methylarginine in hemodialysis patients. These findings are of relevance for designing studies aimed at testing the etiologic relevance of ADMA to the high cardiovascular risk of ESRD.

Abstract: Recent epidemiologic and experimental evidence suggests that serum uric acid (UA) is an independent risk factor for cardiovascular and renal diseases. However, endothelial dysfunction is an early predictor of cardiovascular events, particularly in hypertensive patients. For assessment of the association between UA and endothelial function, 217 (108 men, 109 women; aged 48.0 +/- 10.6 yr) white never-treated hypertensive patients were studied. All patients underwent the following procedures: BP measurements, laboratory tests (C-reactive protein [CRP], insulin resistance by homeostasis model assessment, serum creatinine, and UA), and endothelial function evaluated by intra-arterial infusion of acetylcholine (ACh). Serum creatinine, CRP, and maximal vasodilatory response to ACh were related to the UA (all P < 0.0001). In the multiple regression analysis, serum UA ranked as the third correlate of peak of forearm blood flow predictor, after homeostasis model assessment and CRP. The data show an independent link between UA and endothelial function, also in a statistical model that included CRP. In conclusion, the data demonstrate an inverse and significant relationship between UA and ACh-stimulated vasodilation in patients with uncomplicated, untreated essential hypertension, independent of traditional cardiovascular risk factors. Probably, the chronic inflammation that was documented in these patients may be considered the mechanistic link between serum UA and vascular damage.

Abstract: In clinical practice we formulate direct questions related to patient management that should be answered on the basis of results of valid studies. Bias problems are dealt with using different approaches in observational studies and in clinical trials. The clinical trial is the standard for assessing the efficacy of treatments while the efficiency of treatments at community level is better captured by observational studies. Electronic medical records have now emerged as a precious, matchless data source for clinical audits. The value of an audit cannot be taken for granted and should be tested in the specific health care setting where it is applied. Electronic medical records and high quality clinical databases offer a great opportunity for performing observational studies and for reducing the cost of clinical trials. Research on audit and feedback functionality is a new, useful and stimulating research area which may be of great interest to nephrologists.

Abstract:

Abstract:

Abstract: 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 height 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 Cox's 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 height displays prognostic value beyond and above that provided by LV mass and function.

Abstract:

Abstract: BACKGROUND: Urotensin II (UTN), a cyclic undecapeptide widely distributed in various organs and tissues, is found in high concentration in atheromatous lesions. Because UTN accumulates in patients with chronic renal failure, the association between plasma UTN and biomarkers of atherosclerosis and endothelial activation needs to be better understood. METHODS: We tested by a robust statistical approach (Holm method) the association between plasma UTN and biomarkers of atherosclerosis and endothelial activation in a population of 191 patients undergoing chronic hemodialysis. RESULTS: Plasma UTN was significantly higher in patients with end-stage renal disease (median: 6.5 ng/mL) than in healthy subjects (median: 3.1 ng/mL) (P < .001), and in both patients and control subjects it was independent of age and sex. Interestingly, UTN was inversely related to fibrinogen (r = -0.50, P < .004), intracellular adhesion molecule-1 (r = -0.24, P < .004) and with NO synthesis inhibitor asymmetric dimethyl-arginine (r = -0.40, P < .004). These links were paralleled by direct correlations with albumin (r = 0.21, P < .006) and with transforming growth factor-beta1 (TGFbeta1) (r = 0.36, P < .004). Of note, on multiple regression analysis, these associations remained highly significant also after data adjustment for potential confounders. CONCLUSIONS: The inverse links between UTN with biomarkers of atherosclerosis and endothelial activation suggest that downregulation of UTN may be a counter-regulatory response aimed at mitigating cardiovascular damage or that UTN itself is a protective factor.

Abstract: Metabolic syndrome is a cluster of traditional risk factors including hypertension, abdominal obesity, hypertriglyceridemia, low HDL cholesterol and fasting hyperglycemia. This syndrome is a noxious condition not only for the cardiovascular (CV) system but also for the kidney. In a recent analysis of the NHANES III study the prevalence rate of chronic kidney disease (CKD) was very low in patients without risk factors, but reached 9% in those with five risk factors. Furthermore, in the NHANES III survey it was also found that mild renal insufficiency is frequent in the US population affecting about one-third of individuals. Recent estimates in Europe indicate that mild renal insufficiency is at least as frequent as it is in the US. While research on emerging risk factors in CKD is flourishing, clinical outcomes in these patients remain poor. This could depend on the fact that pathophysiological knowledge of the high renal and CV risk associated with CKD is still largely incomplete. Yet recent surveys have shown that treatment targets in these patients are largely unmet. Therefore, there is ample room for improving clinical outcomes in CKD by the systematic application of available treatments according to the recommendations of current clinical guidelines.

Abstract: BP readings that are obtained in the dialysis unit are commonly used to make therapeutic decisions by clinicians and to predict morbidity and mortality by epidemiologists. Dialysis unit BP are also incorporated in the recent guidelines to target BP control. The magnitude of the difference, overestimation or underestimation, and agreement between dialysis unit BP and ambulatory BP (ABP) are unknown. Articles were selected from Medline to identify those that reported both ABP and dialysis unit BP in hemodialysis patients. Bias was calculated as the difference between dialysis unit and the corresponding ABP. Agreement limits between the BP measurement techniques were assessed by pooled SD of the difference using Bland-Altman methods. Predialysis systolic BP generally overestimated ABP by a variable amount. The heterogeneity between BP measurements did not allow for pooling of the estimates. The agreement limits between the two BP was 41.7 to -25.2 mmHg. Predialysis diastolic BP also generally overestimated the ABP with wide agreement limits (23.7 to -18.9 mmHg). In contrast, postdialysis BP underestimated average ABP with wide agreement limits for both postdialysis systolic BP (33.1 to -36.3 mmHg) and diastolic BP (19.3 to -23.9 mmHg). Dialysis unit BP measurements are imprecise estimates of ABP. Better methods are needed for the assessment of BP in hemodialysis patients for clinical decision making.

Abstract: The rationale of this study is based on the fact that, both proteinuria and elevated asymmetric dimethyl arginine (ADMA) levels have been linked to the progression of vascular disease. Currently, there is not enough knowledge about any association between the levels of proteinuria and ADMA levels. Seventy-eight non-diabetic patients (42 men, 36 women, mean age of 26.1+/-5.2 years) with proteinuria having normal glomerular filtration rate were enrolled along with 38 healthy subjects (20 men, 18 women, mean age of 26.9+/-5.9 years). Proteinuria was below 3.5 g/day in 40 patients and above 3.5 g/day in 38 patients. Both groups had similar age, gender, and body mass index distributions. Serum ADMA, symmetric dimethyl arginine (SDMA), immunoreactive insulin, and high sensitivity C reactive protein (hsCRP) levels were measured. Insulin resistance was determined by homeostasis model assessment (HOMA). Serum ADMA, SDMA, insulin, hsCRP levels, and HOMA indexes were significantly higher in patients than in healthy control subjects. The above parameters were higher in the nephrotic range proteinuria group when compared to patients having protein levels below 3.5 g/day. There were significant correlations between the levels of proteinuria and the above parameters. According to the regression analysis, levels of proteinuria and hsCRP were significant determinants of serum ADMA levels. Our results indicate that, independent of other risk factors, ADMA is directly associated with proteinuria. Further studies are recommended to find out whether elevated ADMA levels are implicated in the high cardiovascular risk of proteinuric nephropathies.

Abstract: Troponin T is specifically qualified as a predictor of circulatory overload in peritoneal dialysis (PD) patients. Given the good standardization and the high reproducibility of the troponin T assay, this measurement may prove useful in the clinical management of PD patients. It still remains to be tested whether clinical policies incorporating troponin T may actually produce better outcomes in PD patients.

Abstract: Plasma triiodothyronine (fT3) is a strong predictor of adverse clinical outcomes in various clinical conditions. Since fT3 in patients with end-stage renal diseases (ESRD) is frequently reduced and is associated with inflammation and cardiovascular damage, we prospectively tested the hypothesis that it predicts death in a cohort of 200 hemodialysis patients. Plasma fT3 was lower in ESRD patients (P<0.001) than in healthy subjects and in clinically euthyroid patients with normal renal function. During the follow-up 102 patients died. Patients who died had significantly lower plasma fT3 than those who survived (P<0.001) and in a Kaplan-Meyer analysis plasma fT3 was associated with death (P<0.001). On multivariate Cox's regression analyses, adjusting for a series of traditional and emerging risk factors including inflammation markers, patients with relatively higher plasma fT3 (hazard ratio (HR) (1 pg/ml increase in fT3)) had a 50% reduction in the risk of death (HR=0.50, 95% CI: 0.35-0.72) as compared to those having relatively lower fT3 levels. Of note, plasma fT3 captured most of the predictive power of interleukin-6 (IL-6) because this latter variable emerged as a significant predictor of death only in a model excluding fT3. Low fT3 is an independent predictor of death in hemodialysis patients. These data lend support to the hypothesis that thyroid dysfunction is implicated in the high risk of the ESRD population.

Abstract: Nephrosclerosis is usually diagnosed in patients with essential hypertension with no or mild proteinuria and no urinary abnormalities. Microalbuminuria is considered to be a marker of high risk for progressive renal disease in patients with diabetes mellitus but there is still no solid evidences that this alteration entails an adverse renal prognosis in essential hypertension. Independently of hypertension, nephrosclerosis is associated with endothelial dysfunction and evidence is accruing that genetic factors and a low number of nephrons at birth are important determinants of this disease.

Abstract: High plasma asymmetrical dimethylarginine (ADMA) signals endothelial dysfunction and atherosclerosis in the general population and predicts mortality in ESRD. The relationship among plasma levels of ADMA, renal function, and the risk for progression to ESRD (halving GFR or dialysis start) and death in an incident cohort of 131 patients with chronic kidney disease was investigated. Cox's competing risk regression was used to model double-failure times (progression to ESRD and death) as a function of ADMA. Covariates that were considered for adjustment included clinical characteristics, baseline GFR (Modification of Diet in Renal Disease equation 7 formula), proteinuria, traditional cardiovascular risk factors, serum C-reactive protein, homocysteine, and concomitant therapies. Mean age at enrollment was 71 +/- 11 yr, and 24% of patients had diabetes. Baseline GFR ranged from 8 to 77 ml/min per 1.73 m2 (average 31 +/- 15 ml/min per 1.73 m2). ADMA was inversely related to GFR, ranking as the third predicting factor (partial r = -0.22, P = 0.01), after hemoglobin and urinary protein, in a general linear model that included multiple correlates of GFR. After a mean follow-up of 27 mo (range 3.4 to 36), 29 patients progressed to ESRD and 31 died. ADMA (hazard ratio per 0.1 muM/L 1.203; 95% confidence interval 1.071 to 1.350) predicted event occurrence independent of other potential confounders, including GFR, proteinuria, hemoglobin, and homocysteine. In patients with mild to advanced chronic kidney disease, plasma ADMA is inversely related to GFR and represents a strong and independent risk marker for progression to ESRD and mortality. These novel findings further expand the implications of previous observations in ESRD patients and generate hypotheses on the role of ADMA in progressive chronic nephropathies.

Abstract: Because inflammation influences thyroid function, it was hypothesized that low plasma free triiodothyronine (fT3) in ESRD may be an unsuspected expression of the inflammatory state of these patients. This study investigated (1) the steady-state relationship between fT3 and inflammation markers (IL-6 and C-reactive protein) and markers of endothelial activation (intercellular adhesion molecule-1 [ICAM-1] and vascular cellular adhesion molecule-1 [VCAM-1]) in 200 hemodialysis (HD) patients and (2) the effect of intercurrent acute inflammatory/infectious processes on plasma fT3 in a group of 17 patients with chronic kidney disease (CKD). HD patients displayed lower (P < 0.001) plasma fT3 than healthy subjects (n = 31) and clinically euthyroid patients with chronic diseases and normal renal function (n = 262). When HD patients were subdivided into IL-6 tertiles, fT3 was progressively lower across tertile increments (P < 0.001). Accordingly, regression analysis showed strong and inverse associations (P < or = 0.002) between fT3 and IL-6, C-reactive protein, ICAM-1, and VCAM-1, and, with the exception of the ICAM-fT3 relationship, these associations remained highly significant (P < or = 0.004) in multiple regression analyses adjusting for demographic variables, risk factors, and other potential confounders. In patients who had CKD and were studied during intercurrent inflammatory/infectious processes, fT3 was significantly lower (P = 0.008) at the zenith of inflammation than after its resolution. Low circulating fT3 is frequently observed in inflammatory illnesses, and the same association exists in patients with CKD and in ESRD. This association may entail a causal link because fT3 is acutely and reversibly suppressed in patients with CKD during inflammatory processes triggered by intercurrent infections.

Abstract: BACKGROUND: Cardiovascular risk stratification is important in the clinical management of patients with end-stage renal diseases (ESRD) and biomarkers are increasingly used in these patients. METHODS: In a cohort of 246 dialysis patients without heart failure at baseline we tested the combined prognostic power of three well-established biomarkers: brain natriuretic peptide (BNP), C-reactive protein (CRP), and asymmetric dimethyl arginine (ADMA). The independent prognostic value of individual and combined biomarkers was estimated in separate Cox models, including standard risk factors in dialysis patients and comorbidities. RESULTS: When the prediction power of the three biomarkers was evaluated individually, BNP, ADMA, and CRP added significant predictive value (P< or = 0.01) to all-cause and cardiovascular mortality models and the explanatory gain attributable to these biomarkers were of similar degree (ranging from 3.3% to 5.7%). When the biomarkers were evaluated jointly, a score based on the BNP-CRP combination, increased by 9.9% (all-cause) and by 10.5% (cardiovascular) the explained mortality variance of standard Cox models and such gain in power was similar to that achieved by the CRP-ADMA combination (all-cause death 9.0% and cardiovascular death 8.4%). Of note, the explanatory gain derived by the simultaneous use of the three biomarkers was very similar (all-cause death 11.6% and cardiovascular death 10.5%) to that achieved by the use of two biomarkers. CONCLUSION: These findings indicate a potential role for CRP, BNP, and ADMA to be incorporated into diagnostic and therapeutic strategies aimed at detection and treatment of atherosclerotic complications and at preventing heart failure in the dialysis population.

Abstract: BACKGROUND: End-stage renal disease (ESRD) is a situation with a cardiovascular (CV) risk profile of almost unique severity. While traditional risk factors dominate the scene in the general population, in chronic kidney disease (CKD), nontraditional risk factors play an increasingly important role, being perhaps dominant in ESRD patients. OBJECTIVE: We review the role inflammation [C-reactive protein (CRP)], hyperhomocysteinemia, high plasma norepinephrine, and accumulation of the endogenous inhibitor of the nitric oxide synthase asymmetric dimethylarginine (ADMA) in the high all-cause and CV mortality of patients on continuous ambulatory peritoneal dialysis (CAPD). RESULTS: The association between CRP and clinical outcomes in patients on peritoneal dialysis (PD) was examined in six studies totaling 692 subjects. The largest of these studies in Caucasians indicates that the independent risk of CV events in patients in the top CRP quartile is about five times higher than in the bottom quartile. Seven prospective studies, including over 1000 hemodialysis and 176 CAPD patients, reported both positive and negative associations between homocysteine and mortality and/or CV events. Because homocysteine circulates bound to albumin, negative associations--rather than negating the vasculotoxicity of homocysteine--most likely reflect the very deleterious effects of malnutrition. Plasma norepinephrine is higher in CAPD than in hemodialysis patients, and multivariate analyses suggest the difference quantitatively entails a 16% higher risk of incident CV events. Likewise, ADMA is more elevated in CAPD patients and such an elevation corresponds to a 15% increase in risk. CONCLUSION: Nontraditional risk factors are far more prevalent in ESRD patients than in the general population. ADMA and norepinephrine may play a greater role in CV risk in CAPD than in hemodialysis patients.

Abstract: From an evolutionary perspective, Darwinian selection has favored insulin-resistant individuals, ie, those with a trait ensuring brain functioning in situations of extreme fuel deprivation. The ability to mount a powerful inflammatory response to infection was another survival advantage in our ancestors, and we now have solid evidence showing that these 2 traits, insulin resistance and inflammation (as measured by serum C-reactive protein [CRP]), are associated in modern human beings. In an analysis of 192 nondiabetic hemodialysis patients, leptin and adiponectin were related in an opposite fashion with insulin sensitivity in end-stage renal disease (ESRD) and interacted in determining insulin resistance in these patients. The risk of insulin resistance was about 6 times higher in ESRD patients with an unfavorable combination of the 2 adipokines (high leptin and low adiponectin) than in those with a favorable combination (low leptin and high adiponectin). Low adiponectin but not high leptin predicted incident cardiovascular events in this cohort. Neither leptin nor adiponectin were associated with CRP in a cross-sectional analysis, but they were linked in an opposite fashion to CRP in a longitudinal study in 21 patients with acute inflammation secondary to infection. High sympathetic activity predicts adverse cardiovascular outcomes in ESRD. Of note, we found that the risk for cardiovascular events is more than 3 times higher in patients with high sympathetic activity and low adiponectin than in those with high adiponectin and low sympathetic activity. The adipocyte hormones leptin and adiponectin are associated in an opposite fashion to insulin sensitivity and inflammation in ESRD patients. Relatively lower plasma adiponectin levels are associated with a higher rate of incident cardiovascular events. Finally, low adiponectin and high norepinephrine seem to be interacting factors in the dismal cardiovascular outcomes with ESRD.

Abstract: OBJECTIVES: We investigated the relationship between ADMA plasma levels and endothelium-dependent vasodilation in 36 never-treated essential hypertensives and in 8 normotensive healthy subjects. BACKGROUND: It has been demonstrated that endothelium-dependent vasodilatation is impaired in essential hypertension. The potential contribution of asymmetric dimethylarginine (ADMA) to endothelial dysfunction of hypertensive humans has received poor attention. METHODS: Endothelial function was measured during intra-arterial infusion of acetylcholine (ACh), alone and during co-infusion of L-arginine, and sodium nitroprusside at increasing doses. Concentrations of ADMA and L-arginine in plasma were measured by high-performance liquid chromatography. RESULTS: Hypertensive subjects had significantly higher ADMA and L-arginine plasma concentrations than normotensive healthy controls; ACh-stimulated forearm blood flow (FBF) was significantly reduced in hypertensive subjects in comparison to normotensive control subjects (p < 0.0001). Intra-arterial coinfusion of L-arginine induced a further significant enhancement in ACh-stimulated vasodilation in hypertensive patients. In these, ADMA was strongly and inversely associated with the peak increase in FBF. In a multivariate model, only ADMA and L-arginine were independent correlates, accounting for 33.9% and 8.9% of the variability in the peak FBF response to ACh (p < 0.0001), respectively. CONCLUSIONS: The main finding in this study is that in essential hypertensives the L-arginine and endogenous inhibitor of nitric oxide synthase, ADMA, are inversely related to endothelial function.

Abstract: PURPOSE OF REVIEW: I review recent knowledge on the interference of neuropeptide Y with energy balance and cardiovascular and renal disease and on the central regulation of bone mass. RECENT FINDINGS: Although neuropeptide Y is mainly seen as a vasoconstrictor, rats overexpressing the neuropeptide Y gene show reduced blood pressure and longer life span in comparison with control rats. Due to its strong mitogenic effects on vascular smooth muscle cells, neuropeptide Y induces occlusive lesions in a rat model of atherosclerosis induced by balloon angioplasty. The involvement of neuropeptide Y in experimental atherosclerosis is complex and may include also favourable, compensatory, mechanisms because, at physiological concentrations, it also activates a potent neoangiogenic response to ischemia. Subjects with a common genotype in the neuropeptide Y gene, which underlies increased intracellular neuropeptide Y storage, display slightly raised blood pressure, high serum cholesterol and increased carotid intima media thickness. In patients with end-stage renal disease high neuropeptide Y in plasma has been associated consistently with concentric left-ventricular hypertrophy and cardiovascular mortality. Finally, recent studies have shown that neuropeptide Y constitutes an important central regulator of bone mass and that it may be involved in inflammation and immune regulation. SUMMARY: Evidence has accrued in experimental animals that altered neuropeptide Y is involved in obesity and the attendant metabolic complications. Recent data also suggest that this peptide may play a role in atherosclerosis and related cardiovascular complications.

Abstract:

Abstract: BACKGROUND: In chronic nephropathies, inhibition of angiotensin-converting enzyme (ACE) is renoprotective, but can further renoprotection be achieved by reduction of blood pressure to lower than usual targets? We aimed to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease. METHODS: We undertook a multicentre, randomised controlled trial of patients with non-diabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril (2.5-5 mg/day). We randomly assigned participants either conventional (diastolic <90 mm Hg; n=169) or intensified (systolic/diastolic <130/80 mm Hg; n=169) blood-pressure control. To achieve the intensified blood-pressure level, patients received add-on therapy with the dihydropyridine calcium-channel blocker felodipine (5-10 mg/day). The primary outcome measure was time to end-stage renal disease over 36 months' follow-up, and analysis was by intention to treat. FINDINGS: Of 338 patients who were randomised, three (two assigned intensified and one allocated conventional blood-pressure control) never took study drugs and they were excluded. Over a median follow-up of 19 months (IQR 12-35), 38/167 (23%) patients assigned to intensified blood-pressure control and 34/168 (20%) allocated conventional control progressed to end-stage renal disease (hazard ratio 1.00 [95% CI 0.61-1.64]; p=0.99). INTERPRETATION: In patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown.

Abstract: BACKGROUND: To date, the relationship between vascular access (VA) failure and plasma total homocysteine level has been investigated only in mixed dialysis populations (ie, patients with a native arteriovenous [AV] fistula or arterial graft), whereas almost no data exist for hemodialysis patients with a native AV fistula. METHODS: In this prospective cohort study, we examined the relationship between plasma total homocysteine level and the methylenetetrahydrofolate reductase (MTHFR) gene and VA-related incident morbidity in a cohort of 205 hemodialysis patients, all with a native AV fistula. RESULTS: During follow-up, 78 patients experienced 1 or more VA thrombotic episodes. Patients with incident VA thrombosis had a significantly greater plasma total homocysteine level compared with patients without this event (P = 0.046). In Kaplan-Meier survival analysis, the hazard ratio for VA thrombosis increased in parallel with homocysteine level, such that patients in the third homocysteine level tertile had a relative risk for this outcome 1.72 times (95% CI, 1.21 to 2.24) greater than in those in the first tertile (log-rank test, 6.81; P = 0.009). In a multiple Cox regression model, plasma total homocysteine level was confirmed to be an independent predictor of AV fistula outcome. Plasma total homocysteine level was significantly greater (P < 0.001) in patients with the TT genotype of the MTHFR gene than in those with the CT or CC genotype. CONCLUSION: VA thrombosis in dialysis patients is associated with hyperhomocysteinemia. Intervention studies are needed to clarify whether decreasing plasma homocysteine concentrations may prevent VA failure in hemodialysis patients.

Abstract: Inflammation is a major risk factor for mortality and cardiovascular (CV) complications in patients with ESRD. The predictive value of C-reactive protein (CRP) of the main proinflammatory cytokines (IL-1beta, IL-6, IL-18, and TNF-alpha) and of two adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in 217 dialysis patients was compared. Serum IL-6 and CRP added significant prediction power to the multivariate Cox model of all-cause death, and the gain in the prediction power attributable to IL-6 was approximately two times higher than that of CRP. Patients in the third tertiles of serum IL-6 and CRP had a relative risk of all-cause mortality 2.5 and 1.8 times higher than those in the first corresponding tertiles, and there was no statistical difference between these two relative risks. The gain in prediction power associated with TNF-alpha, IL-beta, IL-18, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was of small degree (P = NS). Similarly, serum IL-6 added the highest prediction power to the CV death model, and the IL-6 attributable gain was approximately two times higher than that of serum CRP. However, the risk estimate for CV mortality of patients with high serum IL-6 did not differ significantly from that of patients with high serum CRP. IL-6 adds significantly greater predictive power for all-cause and CV death to statistical models based on traditional and nontraditional risk factors in ESRD patients. However, the risk estimate by CRP being reasonably close to that of IL-6, CRP may be a cheap alternative to IL-6 in clinical practice.

Abstract:

Abstract: End stage renal disease (ESRD) is a situation with a cardiovascular risk profile of almost unique severity. While traditional risk factors dominate the scene in the general population, non traditional risk factors like inflammation (high C Reactive Protein, CRP), high brain natriuretic peptide, as an expression of left ventricular hypertrophy and left ventricular dysfunction, and accumulation of the endogenous inhibitor of the NO synthase, asymmetric dimethyl arginine are all markers of high CV risk of ESRD patients. To obtain a quantitative insight on the predictive power of traditional and emerging risk factors in ESRD, we performed a detailed multivariate survival analysis in the cardiovascular risk extended evaluation (CREED) cohort database. As expected, traditional risk factors (ie, age, sex, smoking, diabetes, and risk factors peculiar to the uremic state such as low serum albumin level) and treatment modality contributed to explain the all-cause mortality (37%) and cardiovascular variation mortality (24%) variation as well. When cardiovascular comorbidities were considered in this analysis, the explained variation in mortality increased to 45.4% and 36.4%, respectively. Furthermore, a combined score based on 2 biomarkers (brain natriuretic peptide and C-reactive protein levels) increased the explanatory power of these models by about 10%. In conclusion, traditional risk factors explain about half of all-cause and cardiovascular mortality variation in the ESRD population. The combined use of 2 biomarkers reflecting inflammation and left ventricular mass and function increases by about one fifth the explained mortality variation in this population. Biomarkers give information beyond that provided by traditional risk factors and therefore represent an useful adjunct for the definition of the risk profile of ESRD patients.

Abstract: BACKGROUND: Urotensin II (UTN) is a peptide highly conserved across species with disparate effects on the vascular system and it is currently unclear whether high plasma UTN levels play a vasculotoxic or a vasculoprotective role. METHODS: In this study, we investigated the relationship between plasma UTN and sympathetic activity and cardiac natriuretic hormones in 191 hemodialysis (HD) patients without clinical evidence of heart failure. RESULTS: Plasma UTN was significantly higher in patients with end-stage renal disease (ESRD) (median: 6.5 ng/mL) than in age matched healthy subjects (median: 3.1 ng/mL) (p<0.001). On univariate analysis, UTN was inversely related to heart rate (r=-0.24), dialysis treatment duration (r=-0.27), norepinephrine (r=-0.28), neuropeptide Y (NPY) (r=-0.66), brain natriuretic peptide (BNP) (r=-0.41) and atrial natriuretic peptide (ANP) (r=-0.28) (all p<0.008). Of note, in multiple regression analyses these associations maintained strength similar to that of the corresponding unadjusted correlation coefficients. CONCLUSIONS: The inverse links between UTN and neuro-hormonal factors indicate that UTN down-regulation in the presence of high sympathetic activity and high BNP could be a counter-regulatory response aimed at mitigating cardiovascular (CV) damage or that UTN itself acts as a protective factor.

Abstract: OBJECTIVE: Plasma fibrinogen (Fib) and calcium x phosphate product have emerged as cardiovascular (CV) event predictors in hemodialysis (HD) patients, but their role in peritoneal dialysis (PD) is less studied. DESIGN AND SUBJECTS: We investigated whether Fib and calcium x phosphate product predict CV events in a prospective cohort study of 47 continuous ambulatory PD (CAPD) patients (mean follow-up 34.6 months). RESULTS: During the follow-up, 29 patients experienced CV events, which were fatal in 11 of them. Plasma Fib was markedly elevated in the entire population studied (median 612 mg/dL inter-quartile range (IQ): 566-718 mg/dL). On univariate analysis, Fib was higher (p=0.02) in those patients who had fatal or non-fatal CV events (median 654 mg/dL, IQ: 577-801) than in event-free patients (median 579 mg/dL, IQ: 532-629). Patients with incident CV events also tended to have higher calcium x phosphate product (51.6 +/- 12.8 vs. 43.8 +/- 13.9 mg2/dL2, p=0.06). On multivariate Cox's regression analyses, including traditional risk factors and history of previous CV events, Fib (hazard ratio (HR) associated with 100 mg/dL increase in plasma Fib 1.29 95% confidence interval (CI) 1.03-1.63 (p=0.03)) and calcium x phosphate product (HR associated with a 5 mg2/dL2 increase 1.25 95% CI 1.05-1.49 (p=0.01)) emerged as independent CV event predictors. CONCLUSIONS: Calcium x phosphate product and Fib are CV event predictors in CAPD patients.

Abstract: BACKGROUND: We investigated whether the eNOS G/T polymorphism (Glu298Asp variant) is linked to the severity of carotid atherosclerosis and whether it is independent of asymmetric dimethylarginine (ADMA) in determining vascular damage in patients with end-stage renal disease (ESRD). METHODS: The eNOS polymorphism, ADMA, carotid intima-media thickness (IMT), and carotid artery (CCA) wall-to-lumen ratio (an indicator of arterial remodeling) were determined/measured in 131 patients with ESRD. RESULTS: Both in the co-dominant and dominant model approach, IMT as well as CCA wall-to-lumen ratio were directly related to the T allele (P < or = .009) and these relationships held true in multiple linear regression analyses including ADMA and traditional and emerging risk factors. The relationship between eNOS genotypes and CCA wall-to-lumen ratio was further analyzed by a categorical approach and in a multiple logistic regression analysis, the odds ratio (OR) of increased CCA wall-to-lumen ratio was strongly associated to the T allele (codominant model: GG, OR = 1; GT, OR = 2.1; TT, OR = 8.2; P for trend = .01; dominant model: GG, OR = 1; GT and TT, OR = 2.7; P = .02). CONCLUSIONS: The T allele of eNOS gene is an independent predictor of intimal lesions and vascular remodeling and it is associated with the severity of atherosclerosis independently of ADMA.

Abstract: Adipose tissue is now considered an important system operating strictly in concert with other systems. The adipocyte is the main producer of two pleiotropic compounds, leptin and adiponectin, modulating inflammation and having multiple effects in disparate organs including the cardiovascular and the central nervous system. Leptin has disparate influences on various physiologic and organ systems including glucose homeostasis, hematopoiesis and the reproductive and cardiovascular systems and is a crucial hormone for the regulation of food intake and body weight. Peripherally, leptin modulates insulin sensitivity and high leptin triggers insulin resistance and vice versa. Obesity, a situation where circulating leptin attains very high levels is accompanied by increased bone mass, a phenomenon which may depend on direct stimulation of osteoblasts by leptin. However in animal models the stimulating effect of leptin on the osteoblast is counterbalanced by a strong inhibitor effect on bone formation in the central nervous system. Two recent studies reported an inverse link between leptin, bone mass and PTH in dialysis patients suggesting that leptin may be implicated in low bone turnover in these patients, likely by a mechanism involving the central nervous system. Leptin induces vascular calcifications in vitro. In uremic man leptin is unrelated to valvular calcifications but predicts incident cardiovascular events in overweight and obese dialysis patients. Leptin seems to be a relevant player in the emerging connection between bone and cardiovascular alterations in patients with end stage renal disease.

Abstract: The relationship between hyperhomocysteinemia and cardiovascular damage is well known, whereas the role of this alteration in renal disease progression has been scarcely studied. Experimental studies demonstrated that exposure to high levels of homocysteinemia causes glomerular and interstitial damage which is remarcably proportional to the serum concentration of this aminoacid. Until now the renal effects of hyperhomocysteinemia in man has been investigated only in observational studies. The Hoorn study, a prospective study in a Dutch population, showed that the plasma homocysteine is a strong predictor of proteinuria in diabetic and non diabetic subjects. Findings in this study were recently confirmed in a cohort study in 7500 Japanese because plasma homocysteine predicted the onset of renal failure in this population. NO-dependent endothelial dysfunction triggered by homocysteine via reduction of the activity of the enzyme that metabolizes Asimmetric Dymethilarginine (dmethylarginine dymethilaminohydrolase) is a likely mechanism whereby hyperomocysteinemia causes cardiovascular and renal damage as well.

Abstract: The idea that asymmetric dimethylarginine (ADMA) accumulation may be a cardiovascular risk factor in patients with end-stage renal disease was advanced by Vallance in 1992. During the last decade, the relationship between ADMA and adverse cardiovascular events, including death, in dialysis patients has been investigated thoroughly. Several studies have shown that, independently of other risk factors, ADMA is strongly associated with intima-media thickness of the carotid artery and left ventricular mass, particularly concentric left ventricular hypertrophy. Furthermore, cohort studies in both the general population and the dialysis population showed a strong and independent link between ADMA, all-cause mortality, and cardiovascular events. Circumstantial evidence indicates that norepinephrine and ADMA may be in the same causal pathway leading to cardiovascular complications in patients with end-stage renal disease. Several lines of evidence show that high ADMA levels may exert toxic effects in various cell types. High ADMA levels have been associated with alterations in the regulation of cerebral blood flow and neural function, with insulin resistance, thyroid dysfunction, and alterations in bone homeostasis, fertility, and erectile function. The clinical significance of decreasing plasma ADMA concentrations, if any, is unknown. Well-designed and carefully conducted studies are needed to further clarify the role of ADMA in the pathophysiological states of renal disease and explore possible treatment options to improve the prognosis of patients with elevated ADMA levels. ADMA may enable us to predict risk and follow up the course of renal diseases.

Abstract: BACKGROUND: Guidelines have indicated the achievement of blood pressure target (BP <130/80 mmHg) as a priority in the conservative treatment of chronic kidney disease (CKD), but the current implementation of these recommendations in clinical practice is unknown. METHODS: We assessed control rates, treatment and clinical correlates of hypertension in 1201 adult non-dialyzed CKD patients followed up by a nephrologist for at least 6 months. RESULTS: Estimated glomerular filtration rate (GFR) was 32 (SD 15) mL/min/1.73 m2. BP target was not achieved in 88% of patients (95% confidence interval (95% CI): 86-90%). In 84% of patients, BP levels were also above the target at the first visit to the nephrology unit 4.5 yrs previously. The risk of not achieving BP target during the nephro-logy follow-up was associated with older age (odds ratio (OR): 1.24, 95% CI 1.06-1.45, p=0.008), diabetes (OR: 2.25, 95% CI 1.20-4.20, p=0.011), and the duration of hypertension (OR: 1.13, 95% CI 1.02-1.24, p=0.016). Among patients with uncontrolled BP, about 70% received multidrug antihypertensive therapy including renin-angiotensin system (RAS) inhibitors; conversely, diuretic treatment was prescribed in a minority of patients (37%), and at insufficient doses in half the cases, despite the insufficient implementation of a low salt diet (18%). CONCLUSIONS: BP target was not reached in most CKD patients routinely seen in the renal clinics. The main barrier to guideline implementation is possibly the inadequate treatment of extracellular volume expansion despite the large prevalence of factors, such as older age and diabetes, which further enhance the intrinsic BP salt sensitivity of CKD.

Abstract: OBJECTIVES: Impaired nitric oxide generation and accumulation of the endogenous inhibitor of nitric oxide synthase (NOS), asymmetric dimethylarginine (ADMA), have been identified as strong predictors of cardiovascular outcomes in patients with end-stage renal disease (ESRD). We evaluated the role of endothelial NOS (eNOS) gene polymorphisms and its interaction with plasma ADMA in the high cardiovascular complications rate of these patients. METHODS: The relationship between the Glu298Asp variant of eNOS and all-cause and cardiovascular mortality was assessed in a cohort study including 261 ESRD patients that were followed up for an average of 42 months. RESULTS: During the follow-up period, 138 patients died, 81 of them (i.e. 59% of total deaths) of cardiovascular causes. On univariate Cox's regression analysis, eNOS genotype tended to be related to all-cause death but failed to reach formal statistical significance (P for trend=0.11). However, eNOS genotype showed a significant association with cardiovascular mortality in statistical models, including traditional risk factors and factors peculiar to ESRD, and became even stronger when plasma ADMA was forced into the Cox model (P=0.006). Furthermore, the risk of cardiovascular death was maximum in heterozygotes and homozygotes patients carrying the risk allele and in those having high ADMA levels (hazard ratio=2.71, 95% confidence interval 1.38-5.35, P=0.004) compared to those having just one of these two risk factors. CONCLUSIONS: The T allele of the Glu298Asp polymorphism predicts cardiovascular mortality and interacts with plasma ADMA in determining this outcome in dialysis patients.

Abstract: BACKGROUND: The use of 24-hour ambulatory blood pressure monitoring is increasing in end-stage renal disease (ESRD) patients but the prediction power for cardiovascular complications of time-averaged ambulatory blood pressure components has been little investigated in these patients. METHODS: We analyzed the prognostic power of 24-hour ambulatory blood pressure monitoring for all-cause and cardiovascular mortality in 168 nondiabetic, events-free hemodialysis patients selected from a total dialysis population of about 450 patients. RESULTS: During the follow-up period (38 +/- 22 months), 48 patients died, 29 of them of cardiovascular causes. On univariate Cox regression analyses, the night/day systolic ratio resulted to be the sole blood pressure indicator to be associated with all-cause and cardiovascular mortality while left ventricular hypertrophy (LVH) was a strong predictor of these outcomes. In multivariable Cox models not including LVH, the night/day systolic ratio maintained an independent prognostic value for incident outcomes. However, when both risk factors, LVH and night/day systolic ratio, were introduced into Cox models, LVH was no longer a significant predictor while the night/day systolic ratio became a predictor of marginal statistical significance. CONCLUSION: The night/day ratio emerges as the sole ambulatory blood pressure monitoring-derived indicator providing significant prognostic information in patients with ESRD. However, this indicator as well as LVH loses substantial prediction power in statistical models including both risk factors. The results suggest that the night/day systolic ratio and LVH provide overlapping prognostic information, a phenomenon in keeping with the hypothesis that they represent a common pathway leading to adverse outcomes in ESRD.

Abstract: PURPOSE OF REVIEW: Biomarkers are substances that reflect the presence of a given disease, its pathophysiology or organ damage. These indicators are increasingly proposed to assess prognosis or the response to treatment. This review examines the value of a series of biomarkers which have been recently tested in prospective studies in chronic kidney disease and end-stage renal disease patients. RECENT FINDINGS: C reactive protein has coherently emerged as an early marker of renal dysfunction. The usefulness of this measurement for predicting the evolution of chronic kidney disease or for monitoring the response to renoprotective treatment, however, still remains unproven. On the other hand the measurement of C reactive protein can be recommended for monitoring the risk of atherosclerotic complications in patients with chronic kidney disease and end-stage renal disease, particularly in those with evidence of coronary heart disease or other cardiovascular complications (i.e. in the vast majority of patients followed up in nephrology clinics). There is growing interest in homocysteine and asymmetric dimethyl arginine as biomarkers of cardiovascular and renal risk but the usefulness of these biomarkers in clinical practice remains to be proven. Brain natriuretic peptide and troponin T are strongly related to cardiovascular outcomes in end-stage renal disease patients but their value in this population still requires to be proper tested in specifically designed intervention studies. SUMMARY: Among emerging biomarkers C reactive protein is the only one which is very near to fulfilling the methodological requirements for being recommended in clinical practice.

Abstract: BACKGROUND: Regression of left ventricular hypertrophy (LVH) in the setting of a well-planned intervention study has been associated with longer survival in hemodialysis patients. Whether changes in left ventricular mass (LVM) in clinical practice predict survival and cardiovascular events in these patients is still unknown. METHODS: In a prospective study in 161 hemodialysis patients we tested the prognostic value of changes in LVM on survival and incident cardiovascular events. Echocardiography was performed twice, 18 +/- 2 SD months apart. Changes in LVM occurring between the first and the second echocardiographic study were then used to predict mortality and cardiovascular events during the ensuing 29 +/- 13 months. The prognostic value of LVM changes was tested in a multivariate Cox's model with LVM index (LVMI) [expressed as LVM/height(2.71)], included as a covariate to control for regression to the mean. RESULTS: The rate of increase of LVMI was significantly (P= 0.029) higher in patients with incident cardiovascular events than in those without such events. Accordingly, cardiovascular event-free survival in patients with changes in LVMI below the 25th percentile was significantly (P= 0.004) higher than in those with changes above the 75th percentile. In a multiple Cox regression analysis, including age, diabetes, smoking, homocysteine, 1 g/m(2.7)/month increase in LVMI was associated with a 62% increase in the incident risk of fatal and nonfatal cardiovascular events [hazard ratio 1.62 (95% CI 1.13-2.33), P= 0.009]. CONCLUSION: Changes in LVMI have an independent prognostic value for cardiovascular events and provide scientific support to the use of repeated echocardiographic studies for monitoring cardiovascular risk in dialysis patients.

Abstract: A large body of evidence supports the validity of lowering blood pressure (BP) to prevent cardiovascular (CV) disease in the general population. This issue becomes even more critical in renal patients because they carry a greater CV risk across the entire spectrum of chronic kidney disease (CKD). In these patients, achievement of lower BP levels also is fundamental to limit the progression of renal damage, especially in the presence of significant proteinuria. Although expert panels have strongly recommended to intensively decrease BP in patients with CKD, management of hypertension in these patients remains inadequate. Armed with the knowledge of the extreme salt-sensitivity of BP in patients with CKD, it is reasonable to hypothesize that more aggressive treatment of volume expansion can be helpful. Nevertheless, although abundant literature has evidenced that dietary sodium restriction decreases BP levels in patients with essential hypertension, no large and prospective study has been conducted to date on this issue in patients with CKD. A potential reason is the low compliance of patients with CKD to dietary prescriptions; however, this problem can be overcome by specific counseling. Alternatively, loop diuretics administered at a high dose should represent the cornerstone of therapy, but, again, well-designed studies verifying the effectiveness of these agents in a large CKD population are still awaited. Nephrologists seem to be reluctant to adequately administer diuretics because of the fear of adverse events. Conversely, the major detrimental effect, that is, excessive hypovolemia, can be prevented if daily body weight loss is limited to 0.3 to 0.5 kg during the initial period of treatment.

Abstract: 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.

Abstract: BACKGROUND: Cardiovascular (CV) calcifications constitute a strong risk marker, and recent studies in continuous ambulatory peritoneal dialysis patients have associated valvular calcifications to inflammation, mortality, and CV events. The prognostic value of cardiac valve calcifications and their relationship with left ventricular hypertrophy and background cardiovascular risk in hemodialysis patients is still unknown. METHODS: The prognostic value of heart valve calcifications (detected by echocardiography) for all-cause and CV death was tested in a cohort of 202 hemodialysis (HD) patients. RESULTS: Forty-seven patients had 1 or more calcified valves. Background CV complications were more frequent (P = 0.001) and left ventricular hypertrophy was more severe (P < 0.001) in patients with calcified valves than in those without this alteration. During the follow-up period (44 +/- 23 months), 96 patients died, 66 patients (69%) of CV causes. Valve calcifications were significantly associated with all-cause (P = 0.02) and CV mortality (P < or = 0.001). However, in statistical models adjusting for traditional and nontraditional CV risk factors and background CV complications and left ventricular mass index (LVMI), the relationship between calcified valves and incident all-cause and CV mortality was not significant. CONCLUSION: In HD patients, cardiac valve calcifications predict all-cause and CV mortality in unadjusted analyses, but these associations are not evident in models adjusting for background CV complications, LVMI, and other risk factors. Cardiac valve calcifications do not provide an independent contribution in the prediction of death and CV mortality.

Abstract: 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.

Abstract: Traditional risk factors only in part explain the risk differential between the general population and the population of patients with chronic nephropathies. Uncontrolled hyperphosphatemia and high calcium phosphate product constitute risk factors for cardiovascular calcifications, cardiac ischemia, and adverse cardiovascular outcomes, yet inflammation may be an even more important trigger of vascular calcification than these metabolic derangements. Homocysteine predicts cardiovascular events in ESRD, but evidence that this sulfur amino acid is directly implicated in the high cardiovascular mortality of uremic patients is still lacking. It seems unlikely that Chlamydia pneumoniae is a major risk factor in dialysis patients because the association between anti-Chlamydia antibodies and incident cardiovascular events seems to depend largely on the confounding effect of some traditional risk factors. Oxidative stress and raised plasma concentration of asymmetric dimethylarginine (ADMA) are pervasive in ESRD, and high ADMA in these patients may be at least in part the expression of the high rate of generation of oxidants. ADMA per se seems responsible for a 52% increase in the risk of death and for a 34% increase in the risk of cardiovascular events in dialysis patients.

Abstract: Hypertension in end-stage renal disease (ESRD) is an important risk factor for left ventricular hypertrophy (LVH), cardiac failure, coronary artery disease (CAD), and arrhythmia. LVH is generally considered an integrator of the long-term effects of hypertension and other cardiovascular (CV) risk factors and represents the strongest predictor of adverse CV outcomes in ESRD patients. The risk of heart failure is higher in patients with a history of hypertensive renal disease than in those with other diagnoses. Both coronary heart disease (CHD) and LVH predict congestive heart failure, which is often the ultimate cause of death in patients with cardiac ischemia or LVH. A history of long-standing hypertension is associated with ischemic heart disease both in cross-sectional and prospective studies in ESRD. Atrial fibrillation and ventricular arrhythmias are highly prevalent in dialysis patients and are implicated in mortality and sudden death in this population. Despite the lack of evidence from randomized controlled trials, it appears reasonable that interventions aimed at curbing the high CV mortality of ESRD should be targeted to both hypertension and LVH.

Abstract:

Abstract: Patients with end-stage renal disease (ESRD) are at high risk from potentially devastating cardiovascular sequelae due to the unique clustering of risk factors in these patients. Inflammation is believed to play a key role in the pathogenesis of these cardiovascular lesions. Both pro- and anti-inflammatory cytokines produced from monocytes, and also from adipocytes, have been studied in this regard. Pro-inflammatory cytokines, although cytoprotective acutely, correlate with increased risk of cardiovascular disease (CVD) in chronic situations. Conversely, elevated levels of anti-inflammatory mediators are associated with increased patient survival times. Statistical modelling, calculation of relative risk and cost considerations indicate that determination of serum C-reactive protein levels may be a useful predictor of CVD in ESRD patients. Adipocytes are a rich source of many of the same cytokines produced by monocytes, including interleukin-6, tumour necrosis factor-alpha, as well as adipocyte-specific proteins, leptin and adiponectin (ADPN). ADPN, which is produced in much greater quantities than leptin, is inversely related to body mass index and to insulin resistance, suggesting a possible role in type 2 diabetes. Additionally, ADPN has been shown to modulate the endothelial inflammatory response in vitro. Plasma ADPN levels are an inverse predictor of cardiovascular outcomes among patients with ESRD. Furthermore, ADPN is related to several metabolic risk factors in a manner consistent with the hypothesis that this protein acts as a protective factor for the cardiovascular system.

Abstract: Continuing medical education is an essential element of state-of-the-art medical practice. Continuing medical education as structured today in most countries, must be able to guarantee the quality of continuing medical education and its independence. There should, therefore, be an independent professional body at national level responsible for assessing and guaranteeing both quality and independence. This body will also have the power to oversee the participation of medical specialists in continuing medical education. A system of credits should was developed to express the professional value of continuing medical education activities. Each activity is credited with a certain score, which can be awarded to the participating specialist. Continuing medical education should remain an ethical obligation subject to the disciplinary authority of the profession itself. Continuing medical education should be both an individual and also a collective obligation of the profession; in order to promote and make it effective, each member state must provide the means of making continuing medical education available to all physicians. For the above reason the CME is a strategic way to improve the quality of the health system. In Italy new way to obtain CME credits are going to be issue in the near future.

Abstract: The dipstick test is the most sensitive test for microhematuria screening. In the general population asymptomatic microhematuria is not rare. In terms of clinical presentation hematuria can be classified in a double temporal dimension, i.e. according to the age of the patients and to its time course (resolution vs. persistence). In isolated microhematuria, red cells morphology is useful to establish the site of hematuria (glomerular vs. non glomerular). This is important mostly because in older patients this alteration may underlie a genito-urinary cancer. Microhematuria is probably one of the most sought for clinical signs of urinary diseases. It is fundamental that this clinical sign be always interpreted in a context considering other symptoms and clinical data.

Abstract: BACKGROUND: Mild to moderate renal insufficiency in individuals with essential hypertension is currently considered the expression of a renal microvasculopathy characterized by preglomerular arteriolar involvement and tubulo-interstitial changes. Whether endothelial dysfunction plays a role in this alteration is still undefined. METHODS AND RESULTS: We investigated the relationship between endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm) and renal function in 500 patients with uncomplicated, never-treated, essential hypertension and serum creatinine within the normal range (ie, < or =1.5 mg/dL). Serum creatinine, creatinine clearance, and estimated glomerular filtration rate (GFR, by the Modification of Diet in Renal Disease formula) were related to the forearm blood flow response to ACh (all P< or =0.003), and these relationships held true in multiple regression analyses that included age, gender, systolic pressure, serum cholesterol and glucose, smoking, and body mass index. Accordingly, on multiple logistic regression analysis, the risk of moderate renal dysfunction (ie, an estimated GFR <60 mL x min(-1) x 1.73 m(-2)) was 64% lower (OR 0.36, 95% CI 0.18 to 0.70) in patients in the third ACh tertile (ie, those showing the higher vasodilatory response) than in those in the first tertile (ie, showing the lower response). C-reactive protein was related directly to serum creatinine and inversely to GFR and vasodilatory response to ACh, which suggests that endothelial dysfunction is a possible mechanism linking inflammation and impaired renal function in essential hypertension. CONCLUSIONS: An impaired vasodilatory response to ACh appears to be associated with renal function loss in patients with essential hypertension. This association suggests that systemic endothelial dysfunction is involved in mild to moderate renal insufficiency in patients with uncomplicated essential hypertension.

Abstract: Primary aldosteronism is a disorder characterized by hypertension and hypokalemia due to aldosterone secretion out of renin-angiotensin control. It is generally caused by aldosterone-producing adenoma or adrenocortical hyperplasia but, in some cases, it is due to genetic alterations. Familial type I hyperaldosteronism is the result of anomalous regulation of aldosterone secretion from ACTH (which normally regulates cortisol synthesis). Aldosterone hypersecretion can be suppressed by exogenous glucocortcoids such as dexamethasone. This autosomal dominant disorder is caused by unequal cross-over between two genes with wide sequence homology: CYP11B1 and CYP11B2. The hybrid gene is the product of fusion between the ACTH-responsive regulatory portion of the 11b-hydroxylase gene (CYP11B1) and the coding region of the aldosterone synthase gene (CYP11B2). Familial type I hyperaldosteronism is a disease with incomplete penetration and variable expressivity, especially in relation to hypertension. The marked variability in hypertension severity can mirror an interaction between the hybrid gene and other hereditary factors involved in the regulation of blood pressure. Familial type II hyperaldosteronism is another autosomal dominant form of hyperaldosteronism due to aldosterone hyper-secretion not suppressible by dexamethasone. This disorder is unrelated to mutation of the hybrid gene. The genetic cause of type II hyperaldosteronism is presently unknown, but a genome-wide search has revealed that the disorder is linked with a locus on chromosome 7 in a region that corresponds to cytogenetic band 7p22.

Abstract: BACKGROUND AND OBJECTIVE: The adipose tissue cytokine leptin is suggested to interfere with bone turnover mechanisms because, in rats with leptin deficiency, intra-cerebroventricular administration of this cytokine causes a reduction in bone mass. We studied the relationship between plasma leptin and biochemical bone turnover indicators in 161 hemodialysis (HD) patients. RESULTS: Plasma leptin was sex-dependent, being significantly higher (p<0.001 ) in female dialysis patients than in male dialysis patients, and it related directly to body mass index (BMI). In males, plasma leptin related inversely to serum intact parathyroid (PTH) (partial r= -0.34), serum PTH(1-84) (r= -0.36), carboxyterminal PTH (C-PTH) fragment (r= -0.31) and serum PTH(1-84)/C-PTH fragment ratio (r= -0.22), while no such relationships were found in females. Of 93 male dialysis patients, 44 had a serum intact PTH <100 pg/mL and 14 had a serum PTH(1-84)/C-PTH fragment ratio <1. In a multiple logistic regression analysis in males, for each 1 ng/mL increase in plasma leptin there was an 11% excess risk of serum intact PTH <100 pg/mL (odds ratio (OR) 1.11, 95% confidence interval (95% CI): 1.02-1.20, p=0.01) and a similar OR was found when low bone turnover was defined based on a serum PTH(1-84)/C-PTH fragment ratio <1 (p=0.01). In addition, plasma leptin related inversely to skeletal alkaline phosphatase and again this relationship was found in male but not in female dialysis patients. CONCLUSIONS: Our data support the theory that leptin reduces bone turnover in male dialysis patients. Whether this link underlies a noxious or a protective mechanism, i.e. if it can serve to limit high bone turnover due to hyperparathyroidism, remains to be established in prospective studies based on solid outcome measures like the risk of fractures.

Abstract:

Abstract: Patients with end-stage renal disease face a particularly high risk of cardiovascular disease and total mortality. Part of their increased risk is due to a higher prevalence of established risk factors, such as arterial hypertension, diabetes, smoking, and anemia. Hypertension and diabetes have a very high prevalence in dialysis patients and play a major role in their high mortality and morbidity. Hyperparathyroidism, hyperhomocysteinemia and disordered lipid metabolism represent factors that are peculiarly altered by the uremic state. Inflammatory processes, high sympathetic activity, and the accumulation of an endogenous inhibitor of NO synthase (ADMA), have recently emerged as cardiovascular risk factors of paramount importance. Sleep apnea has been linked with nocturnal hypertension and could be implicated in the high prevalence of concentric hypertrophy of the left ventricle in these patients. Hypertension control, as well as appropriate treatment of anemia and cessation of smoking, constitutes a fundamental area of intervention in dialysis patients. It appears possible that, in the near future, control of chronic inflammatory processes of high sympathetic activity and endothelial dysfunction will further help to curb the exceedingly high cardiovascular mortality of patients on chronic dialysis treatment.

Abstract: OBJECTIVE: Neuropeptide Y (NPY) is released during sympathetic stimulation and mediates the central effects of the adipostatic hormone leptin. The plasma concentration of NPY and leptin is increased in patients with end stage renal disease (ESRD), but it is unknown whether these substances are related to biochemical markers of sympathetic activity and to alterations in left ventricular (LV) mass and function in these patients. DESIGN: We investigated the relationship between NPY, norepinephrine (NE), leptin and echocardiographic measurements in a cross-sectional study in 198 patients with ESRD. RESULTS: NPY was directly related to plasma NE and heart rate but it was largely independent of arterial pressure and of retention of metabolic waste products. NPY was significantly higher in patients with LV hypertrophy and in those with LV systolic dysfunction than in those without these alterations. Of note, NPY emerged as an independent correlate of LV mass index and of LV ejection fraction (LVEF) (both P <or= 0.002) in multiple linear regression analyses including a series of cardiovascular risk factors. Furthermore in a multiple logistic regression model patients in the top NPY tertile had a risk for LV concentric hypertrophy that was 18.10 (95% confidence interval: 5.87-55.83) times higher than in those in the first tertile (P < 0.001). Leptin was unrelated to NPY as well as to LV mass and to systolic function. CONCLUSIONS: Elevated NPY is independently associated with LV concentric hypertrophy and systolic dysfunction in ESRD. It remains to be seen whether these links contribute to the high cardiovascular mortality in these patients.

Abstract: BACKGROUND: We investigated the relationship between fibrinogen and echocardiographic measurements of left ventricular (LV) geometry and LV function in a group of 192 patients with end stage renal disease (ESRD). RESULTS: Patients in the third fibrinogen tertile had higher mean wall thickness (MWT), relative wall thickness (RWT) and left ventricular mass index (LVMI) and lower LV end diastolic diameter and LV ejection fraction than those in the other tertiles. On multivariate analysis fibrinogen resulted to be an independent correlate of MWT (P = 0.001) and RWT (P = 0.0001) and the first factor in rank explaining the variance in LV ejection fraction (P = 0.0001). Left ventricular concentric hypertrophy was more prevalent (P = 0.001) in patients in the third fibrinogen tertile (n = 35, 54%) than in those in the second (n = 24, 37%) and first (n = 13, 21%) tertiles. In a multiple logistic regression model patients in the third tertile of fibrinogen had a risk for left ventricular concentric hypertrophy that was 3.56 (95% CI: 1.56-8.14) fold higher than in those in the first tertile (P = 0.003). CONCLUSIONS: Elevated fibrinogen is independently associated with LV concentric hypertrophy and systolic dysfunction in ESRD patients. These relationships may contribute to the negative prognostic impact of elevated fibrinogen levels in ESRD.

Abstract: BACKGROUND: Adiponectin (ADPN), the gene product of apM1, is the most abundant secretory protein of the adipose tissue in human plasma. Altered regulation (reduced synthesis) of this substance may be relevant to endothelial dysfunction and cardiovascular complications in patients with ESRD. METHODS: We investigated the relationship between plasma ADPN, glomerular filtration rate (GFR) (plasma iohexol clearance), and metabolic risk factors in 16 patients with nephrotic syndrome, in 25 patients with chronic nephropathies without nephrotic syndrome, and in 31 healthy subjects. RESULTS: Plasma ADPN was much higher (P < 0.01) in patients with nephrotic syndrome (24.4 +/- 14.9 microg/mL) than in patients with chronic nephropathies without nephrotic syndrome (12.3 +/- 7.2 microg/mL) and healthy subjects (5.9 +/- 2.6 microg/mL). In the aggregate 24-hour, proteinuria (r = 0.53, P < 0.01) and serum cholesterol (r = 0.53, P < 0.01) were strong and direct correlates of plasma ADPN, while serum albumin correlated inversely (r = -0.46, P < 0.01) with this protein. Proteinuria appeared to be an important confounder of the relationship between ADPN and the GFR because in the whole patient population (with and without nephrotic syndrome), this relationship emerged only after data adjustment for 24-hour proteinuria (partial r = -0.31, P = 0.05), while no such relationship was demonstrable on crude data analysis (r = 0.03, P = 0.87). CONCLUSIONS: ADPN is markedly increased in patients with nephrotic syndrome, and proteinuria is strongly related to circulating ADPN in patients with nephrotic and non-nephrotic renal diseases. The relationships between plasma ADPN, serum cholesterol, and serum albumin suggest that this adipocyte protein may serve to mitigate endothelial damage triggered by dyslipidemia and other risk factors in patients with chronic renal diseases.

Abstract: INTRODUCTION: Patients affected by end-stage renal disease (ESRD) experience an excess of morbidity and mortality due to cardiovascular disease (CVD), which cannot be fully explained by the classical CVD risk factors. Among emerging CVD risk factors, oxidative stress is currently being given emphasis. METHODS: We achieved a consensus on key points relating to oxidative stress in ESRD patients. RESULTS: ESRD patients are subjected to enhanced oxidative stress, as a result of reduced anti-oxidant systems (vitamin C and selenium deficiency, reduced intracellular levels of vitamin E, reduced activity of the glutathione system) and increased pro-oxidant activity (advanced age, high frequency of diabetes, chronic inflammatory state, uraemic syndrome, bio-incompatibility of dialysis membranes and solutions). Oxidative stress and inflammation are deeply inter-related, as different oxidant free radicals are generated by phagocytic cells in response to inflammatory stimuli: both are related to endothelial dysfunction, as the endothelium is a source and a target of oxidants and participates in the inflammatory response. There is growing evidence, from experimental and clinical studies, that oxidative stress may be implicated in the pathogenesis of atherosclerosis and other complications of ESRD, namely dialysis-related amyloidosis, malnutrition and anaemia. Given that free radicals have very short half-lives (seconds), the clinical assessment of oxidative stress is based on the measurement of different stable oxidized compounds (such as lipid peroxidation products, advanced glycation and oxidation lipid and protein products, nucleic acid oxidation derivatives) or antibodies directed against oxidized epitopes (such as anti-oxidized low-density lipoprotein antibodies). At the same time, both enzymatic anti-oxidants (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic anti-oxidants (glutathione, vitamin C, vitamin E, negative inflammatory proteins) can be evaluated. However, many laboratory methods assessing various oxidative stress components still have to be standardized. Moreover, it is still uncertain whether it is better measuring plasma and/or intracellular concentrations or activities of these components. The possibility of improving patient outcome by therapeutic interventions aimed at reducing oxidative stress, e.g. by vitamin C or vitamin E supplementation, currently is to the fore, but results so far have remained inconclusive. CONCLUSIONS: It is important to consider oxidative stress as a potentially important source of patient morbidity and mortality, although this knowledge is not yet immediately applicable in the clinical arena. Further well-designed, randomized controlled clinical trials with anti-oxidants (e.g. vitamin E, vitamin C, N-acetyl cysteine, L-arginine) are required to establish evidence-based recommendations for clinical practice.

Abstract: Atherosclerosis is a multifaceted process which may be initiated by various insults to vascular endothelium. Independently of the nature of the offending factor, the endothelial dysfunction that results from the initial insult is characterized by increased adhesiveness of the endothelium to leukocytes and platelets and by the synthesis of vasoactive molecules, cytokines and procoagulant factors. This defensive response is characterized by classical inflammatory changes and may lead to plaque formation, luminal obstruction and plaque rupture. Factors involved in arterial damage in end-stage renal disease (ESRD) span from classical risk factors to disease-peculiar factors (anemia, secondary hyperparathyroidism and exposure to bioincompatible dialysis membranes and/or contaminated dialysis fluid) and to emerging and novel risk factors such as hyperhomocysteinemia, infections and accumulation of the endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA). There is strong and consistent evidence that acute phase reactants like C-reactive protein and cytokines like IL-beta, TNF-alpha and IL-6 are independently associated with death and atherosclerosis in ESRD patients. The experimental and epidemiological data collected thus far coherently show that endothelial dysfunction resulting from inflammation may promote abnormal vascular behavior and thrombosis in ESRD. There are several possible therapeutic approaches for reducing the risk excess associated with inflammation in ESRD. These possibilities range from drugs interfering with the angiotensin system or with adrenergic activity to anti-inflammatory and antilipid agents to vitamins, antioxidants, to the amino acid precursor of nitric oxide, L-arginine, and perhaps to antibiotics. The intellectual framework is well delineated but very few controlled trials have been performed or are underway in patients with ESRD.

Abstract:

Abstract: Hepatocyte growth factor is a pleiotropic cytokine with cardioprotective properties. Its serum concentration is markedly raised in end-stage renal disease. This study assessed the relation of hepatocyte growth factor (HGF) with left ventricular mass and geometry in end-stage renal disease. Serum HGF measurements and echocardiographic studies were performed in 185 patients receiving hemodialysis. Patients with serum HGF above the median (1.85 ng/mL) had more frequent cardiovascular complications. This cytokine was directly related to mean left ventricular wall thickness (r=0.23, P=0.002) and relative wall thickness (r=0.25, P=0.0001); a multivariate analysis showed that this relation was independent of other risk factors. Accordingly, the prevalence of left ventricular concentric geometry (either concentric left ventricular hypertrophy or remodeling) was much higher (n=49, 53%) among patients with HGF values above the median that in those with values < or =1.85 ng/mL (n=31, 34%). Furthermore, the risk for left ventricular concentric geometry was higher in patients with HGF values above the median (odds ratio, 2.57; 95% CI, 1.33 to 4.98; P=0.005), and multiple logistic regression analysis confirmed that this association was independent of other risk factors. In patients receiving hemodialysis, elevated serum HGF is associated with concentric left ventricular geometry. This is consistent with reports that link this cytokine to arterial remodeling and survival in patients with end-stage renal disease and suggests that it is part of a counterregulatory response aimed at attenuating cardiovascular damage in this high-risk population.

Abstract:

Abstract: A 26-year-old patient with chronic renal failure presented a spinal cord infarction during haemodialysis. This is the first case of a patient with chronic renal failure maintained on chronic haemodialysis described in literature. In this case, the severity of vascular lesions documented by widespread vascular calcifications were particularly striking.

Abstract: Patients with end-stage renal disease face a particularly high risk of cardiovascular disease and total mortality. Part of their increased risk is due to higher prevalence of established risk factors such as arterial hypertension, diabetes, smoking and anemia. Hypertension and diabetes have a very high prevalence in dialysis patients and play a major role in their high mortality and morbidity. Hyperparathyroidism, hyperhomocis-teinemia and disordered lipid metabolism represent factors which are peculiarly altered by the uremic state. Inflammatory processes, high sympathetic activity and the accumulation of an endogenous inhibitor of NO synthase (ADMA) have recently emerged as cardiovascular risk factors of paramount importance. Sleep apnea has been linked with nocturnal hypertension and could be implicated in the high prevalence of concentric hypertrophy of the left ventricle in these patients. Hypertension control as well as appropriate treatment of anaemia and cessation of smoking constitute fundamental areas of intervention in dialysis patients. It is possible that in the near future control of chronic inflammatory processes, of high sympathetic activity and endothelial dysfunction will further contribute to curb the exceedingly high cardiovascular mortality of patients on chronic dialysis treatment.

Abstract: Adipose tissue is a necessary survival characteristic of species that do not have constant access to food. TNF-alpha is a very fundamental "internal regulator" (intra-system) of adipose tissue metabolism, and IL-6 and IL-1 beta are relevant control factors, as well. Leptin and IL-6, but not TNF-alpha, appear to be the major signals linking adipose tissue to the systemic immunologic response. In ESRD, it has been coherently observed that acute-phase reactants like CRP and serum amyloid A are independently associated to atherosclerosis, death, and cardiovascular complications. Leptin is inversely related with plasma creatinine, suggesting that reduced renal clearance is a primary factor responsible for hyperleptinemia in ESRD. On the other hand, this adipose tissue hormone behaves as an inverse acute-phase reactant (i.e., it decreases during spontaneous episodes of the acute-phase response). Dialysis patients with hyperleptinemia have more severe degrees of insulin resistance but further studies are required to see whether leptin plays a role in insulin resistance in these patients. The most abundant protein synthesized in the adipose tissue, adiponectin, is inversely related to metabolic risk factors like glucose, triglycerides, insulin, and HDL cholesterol in uremic patients, suggesting that this cytokine is a protective factor for the cardiovascular system. Accordingly, plasma adiponectin is an independent, inverse predictor of incident cardiovascular events in dialysis patients.

Abstract:

Abstract:

Abstract: BACKGROUND: A reduction in salivary and lacrimal secretion has been described in several diseases. However, such alterations have not been investigated fully in patients with chronic renal failure. The aim of the present study is to estimate the frequency of alterations in salivary and lacrimal secretion in long-term hemodialysis patients. METHODS: Sixty-three hemodialysis patients and 23 healthy control subjects were studied. In all of them, we tested salivary secretion (Saxon's test), lacrimal secretion (Shirmer's test), and the presence of xerostomia and xerophthalmia symptoms. In a subgroup of patients, we performed other tests to evaluate evidence of ocular lesions and tissue damage to salivary glands. We also tested the relationship between salivary and lacrimal secretion and autonomic nervous system function. RESULTS: On average, salivary and lacrimal secretion were markedly reduced in uremic patients compared with healthy controls, and alterations in salivary gland function were related strongly to salivary gland fibrosis and atrophy. Xerophthalmia often was asymptomatic, but frequently was associated with corneal lesions. Xerostomia and xerophthalmia were unrelated to autonomic dysfunction and hepatitis C virus infection. CONCLUSION: A reduction in lacrimal and salivary secretion is frequent in long-term dialysis patients. Such alterations often are asymptomatic and could be the expression of acceleration of an age-dependent decline in glandular function and attendant fibrosis and atrophy.

Abstract: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. By competitively displacing L-arginine from the substrate binding site of NO synthase, ADMA interferes with many of the physiological functions of NO, like endothelium-dependent vasodilation and leukocyte adhesion. ADMA, like its biologically inactive regioisomer, symmetric dimethylarginine (SDMA), can be found in human plasma and urine in low concentrations. The concentrations of both dimethylarginines are increased in patients with end-stage renal disease, which may explain at least in part endothelial dysfunction and cardiovascular complications in this patient population. In addition, the metabolism of ADMA, but not SDMA, occurs via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Data from experimental studies suggest that ADMA inhibits vascular NO elaboration at concentrations that can be measured in plasma of patients with renal disease. Interestingly, ADMA and SDMA are poorly eliminated during hemodialysis. This is probably due to a high level of binding of both molecules to plasma proteins. High ADMA concentrations in patients with end-stage renal disease may contribute to their excess cardiovascular event rate, as in clinical studies a relationship between ADMA and carotid artery intimal thickening was found. Moreover, in a prospective study we demonstrated recently that determination of ADMA plasma concentration is useful to predict future cardiovascular event rate and total mortality in this patient population. As other researchers reported observations that are in line with our findings, there is evidence that ADMA may be a novel cardiovascular risk factor.

Abstract: The majority of patients with chronic kidney disease are followed-up in pre-dialysis clinics for a varying length of time, often for several years. The renal-team (physicians, nurses, dieticians, social assistants) intervenes on renal disease progression and educates the patient regarding the adjustments of his or her life-style to the limitations imposed by the disease. Pre-dialysis clinics are often overburdened and it is uncertain whether renal care should be based exclusively on renal teams, a difficult and costly option, or if it could be efficaciously organized by involving other health professionals. The Journal of Nephrology will maintain strong attention on these crucial issues for the future of nephrology.

Abstract: BACKGROUND: Cross-sectional and retrospective studies suggest that Chlamydia pneumoniae infection may contribute importantly to the high cardiovascular risk of patients with end-stage renal disease (ESRD). METHODS: We investigated the relationship between C. pneumoniae serology and survival and incident fatal cardiovascular events in a cohort of 227 ESRD patients (follow-up of 39 +/- 20 months). RESULTS: On univariate Cox regression analysis patients with anti-C. pneumoniae immunogloblulin A (IgA) titer > or = 1:16 had a significantly higher risk of all-cause and cardiovascular mortality when compared to patients without IgA antibodies. However, after data adjustment for age and smoking, the hazard ratio (HR) decreased substantially and became largely nonsignificant. Adjustments for traditional and nontraditional risk factors further decreased the independent association of IgA anti-C. pneumoniae and these outcomes (all-cause mortality HR, 1.08; 95% CI, 0.68 to 1.72; P = 0.74; cardiovascular mortality HR, 1.07; 95% CI, 0.60 to 1.89; P = 0.83). A similar loss of prognostic power was observed for IgG anti-C. pneumoniae so that in fully adjusted models the HRs were very close to those observed for IgA anti-C. pneumoniae (all-cause mortality HR, 1.13; 95% CI, 0.68 to 1.86, P = 0.64; cardiovascular mortality HR, 1.10; 95% CI, 0.60 to 2.00; P = 0.77). CONCLUSION: C. pneumoniae seropositivity is associated to shorter survival and incident fatal cardiovascular events in patients with ESRD but these associations are in large part attributable to the link between C. pneumoniae and well-established, traditional risk factors. It is highly unlikely that C. pneumoniae infection is a major risk factor in patients with ESRD.

Abstract: Chronic renal insufficiency is a situation characterized by high plasma concentration of neuropeptide Y (NPY). Because this neuropeptide interferes with cardiovascular (CV) function, it is possible that it is involved in the high CV-related morbidity and mortality of these patients. To test this hypothesis, a follow-up study was performed (average duration, 34 mo; range 0.2 to 52.0 mo) in a cohort of 277 patients with end-stage renal disease receiving chronic dialysis. Univariate analysis revealed that plasma NPY was directly related to plasma norepinephrine (r = 0.37, P < 0.001) and epinephrine (r = 0.17, P = 0.005), exceeding the upper limit of the normal range in the majority of patients with end-stage renal disease (170 of 277, 61%). One hundred thirteen patients had one or more fatal and nonfatal CV events; 112 patients died, 66 of them (59%) of CV causes. Plasma NPY failed to predict all-cause mortality but was an independent predictor of adverse CV outcomes (hazard ratio [10 pmol/L increase in plasma NPY], 1.32; 95% confidence interval, 1.09 to 1.60; P = 0.004) in a Cox proportional-hazard model that included a series of traditional and nontraditional CV risk factors. Plasma NPY maintained its predictive power for CV events in statistical model including plasma norepinephrine. Plasma NPY predicts incident CV complications in end-stage renal disease. Controlled trials are needed to establish whether interference with the sympathetic system, NPY, or both may reduce the high CV morbidity and mortality of dialysis patients.

Abstract: Before introducing a wrist device (NAIS-Matsushita) for blood pressure (BP) measurement in our Unit, we formally tested its validity. Since the wrist position is critical and BP in the clinical setting is often measured with patients lying in bed, we also estimated the error introduced by allowing the wrist to lay flat at the bed level. Ten normal subjects and 20 hypertensive patients took part in two consecutive studies. In the first study the subjects were sitting and the blood pressure was simultaneously taken with the auscultatory mercury sphygmomanometer on the left arm and with the NAIS on the right wrist. The wrist was kept at the heart level. In the second study two NAIS devices were used with the subjects lying in bed; the left wrist was allowed to stay at the bed level, while the right one was kept at the heart level. The diastolic BP was consistently underestimated (P< 0.001) by the wrist device (79 mmHg 95%CI: 75-83) as compared to the values obtained with the standard mercury sphygmomanometer (85 CI: 79-88). No significant difference was found in systolic BP (mercury: 135 CI: 127-143; wrist 134 CI: 126-141). In the second study the BP (systolic and diastolic) was markedly higher (P<0.001) when the wrist was kept at the bed level (systolic bed level: 144 CI: 135-152; systolic heart level: 135 CI:126-141; diastolic bed level: 83 CI:78-88; diastolic heart level: 76 CI:71-79).

Abstract: OBJECTIVE: Fibrinogen is an established predictor of cardiovascular events in the general population but the relationship between fibrinogen, mortality and incident cardiovascular complications has been very little investigated in patients with end-stage renal disease (ESRD). DESIGN AND SUBJECTS: We investigated the relationship between fibrinogen and all cause mortality and cardiovascular outcomes in a prospective cohort study in 192 patients on chronic haemodialysis treatment (follow-up: 34 +/- 16 months). RESULTS: Fibrinogen was significantly higher in patients who died during the follow-up than in those who survived. Similarly, fibrinogen was higher in patients who had fatal or nonfatal cardiovascular events than in event free patients. On multivariate Cox regression analysis fibrinogen was an independent predictor of survival [hazard ratio (1 g x L(-1) increase in plasma fibrinogen): 1.19, 95% confidence interval (CI): 1.05-1.35, P = 0.006] and a highly significant (P = 0.0008), independent predictor of fatal and nonfatal cardiovascular events [hazard ratio (1 g x L(-1) increase in plasma fibrinogen): 1.25, 95% CI: 1.10-1.43] in a model including traditional risk factors and serum C-reactive protein (CRP) and plasma homocysteine. CONCLUSIONS: Fibrinogen is as an independent risk factor for overall and cardiovascular mortality in patients with ESRD. Intervention studies are required to see whether reducing plasma fibrinogen may help to curb the exceedingly high cardiovascular risk of the uremic population.

Abstract:

Abstract: BACKGROUND: Diabetic nephropathy has become the major cause of end-stage renal disease (ESRD) in the western world and is forecast to become the most frequent cause of ESRD in the African continent and in developing countries in other areas. METHODS: A discussion to achieve a consensus on key points relating to diabetic nephropathy. RESULTS: Given the catastrophic consequences of diabetes not only for renal function but also for the cardiovascular system, major efforts should be aimed at prevention. The cornerstone of primary prevention (development of microalbuminuria) is a tight control of blood pressure and blood glucose. Although ACE inhibitors have proved effective in preventing the development of microalbuminuria in normotensive patients, this is not the case, in comparison with other classes of antihypertensive drugs, in those who are hypertensive but normoalbuminuric. Secondary prevention (transition to overt nephropathy) and tertiary prevention (progression of established nephropathy to ESRD) benefit from the use of inhibitors of the renin-angiotensin system, whilst the role of tight glycaemic control is more controversial at these stages. Therapeutic lifestyle changes are also important. They should include body weight control combined with regular physical exercise, cessation of smoking and reduced salt intake. The pathogenesis of diabetic nephropathy and its association with hypertension, accelerating renal damage, is complex. It involves genetic factors, altered renal sodium handling with sodium retention, metabolic disturbances and oxidative stress with the formation of advanced-glycation end products (AGEs) and reactive oxygen species. CONCLUSIONS: Although the awareness of the importance of normalizing blood pressure levels and tight glycaemic control have allowed improved survival of diabetic patients, the mortality excess remains unacceptably high in patients with diabetic nephropathy. New treatment strategies are under investigation, including inhibitors of AGE formation, protein kinase C inhibitors, antioxidants, glycosaminoglycans, PPAR-gamma agonists and COX-2 inhibitors.

Abstract:

Abstract: OBJECTIVE: To detect the association of single polymorphisms of the renin-angiotensin-aldosterone system (RAAS), or different combinations thereof, with hypertension. DESIGN AND METHODS: The GENIPER database is the result of a collaborative effort of 13 Italian research centres to collect genomic DNA in subjects well characterized in terms of blood pressure status. A total of 2461 subjects (normotensive = 611; hypertensive = 1850) were selected and genotyped for the angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensinogen (AGT) T/C704, angiotensin receptor type 1 (AT1) A/C1166 and aldosterone synthase (ALDO) T/C-344 genetic variants. RESULTS: Allele frequencies were homogeneous over the Italian territory, with the relevant exception of the ACE I/D, the D allele being significantly less frequent in the northern region (61%) than in the rest of the country (67%; P < 0.0001). When comparing allele and genotype distributions in normotensives and hypertensives, the latter presented a small but statistically significant increase of the C allele of AGT T/C704, the A allele of AT1 A/C1166 and the T allele of ALDO T/C-344 polymorphisms (P = 0.018, P = 0.037 and P = 0.015, respectively), with similar trends all over the country. A step-wise logistic regression analysis confirmed these findings, by entering in the model as independent predictors of blood pressure status of AGT T/C704 (P = 0.013), ALDO T/C-344 (P = 0.032) and AT1 A/C1166 polymorphisms (P = 0.075), but not ACE I/D (P = 0.996). We also found some evidence of an additive effect of individual genetic variants of the RAAS, modulating at different levels the same functional pathway, on the risk of developing hypertension, but no synergistic interaction was observed. CONCLUSIONS: Our results suggest that some allelic variants of RAAS genes carry a small but identifiable risk of developing arterial hypertension.

Abstract: The concept of dialysis adequacy has to be widened to include medium size and large molecule removal in addition to urea kinetics. The HEMO study found a non-significant trend toward a beneficial effect on mortality of high-flux dialysis compared with low-flux dialysis. In that study, the beneficial effect of convection could have been attenuated by the fact that 'internal filtration' in high-flux haemodialysis (HD) is lower than that expected by convection in haemofiltration (HF) or haemodiafiltration (HDF). To explore the putative beneficial effect of convection, this Italian multicentre study was planned, comparing on-line convective treatments (HF and HDF) with standard, low-flux HD. The enrolled patients will be evaluated prospectively on their usual treatment for 2 months (baseline period) and subsequently randomized to continue either with low-flux HD (50%) or to start on-line convective treatment (50%), HF or HDF according to a 1:1 ratio. The primary end point of the study will be cardiovascular stability and blood pressure control. As secondary aims of the study, the impact on symptoms, morbidity and mortality will be assessed. Feasibility and patient compliance during HF and HDF treatments will also be evaluated. The experimental phase of the study, of at least 2 years, is divided into a 3-month adaptation period and a subsequent evaluation period. A recruitment period of 1 year is planned. The study design has adequate power to detect an absolute reduction of 3% hypotensive episodes with the experimental convective treatments compared with standard low-flux HD.

Abstract: BACKGROUND: Sympathetic tone is consistently raised in patients with end-stage renal disease (ESRD). We therefore tested the hypothesis that sympathetic activation is associated with mortality and cardiovascular events in a cohort of 228 patients undergoing chronic hemodialysis who did not have congestive heart failure at baseline and who had left ventricular ejection fraction >35%. METHODS AND RESULTS: The plasma concentration of norepinephrine (NE) was used as a measure of sympathetic activity. Plasma NE exceeded the upper limit of the normal range (cutoff 3.54 nmol/L) in 102 dialysis patients (45%). In a multivariate Cox regression model that included all univariate predictors of death as well as the use of sympathicoplegic agents and beta-blockers, plasma NE proved to be an independent predictor of this outcome (hazard ratio [1-nmol/L increase in plasma NE]: 1.07, 95% CI 1.01 to 1.14, P=0.03). Similarly, plasma NE emerged as an independent predictor of fatal and nonfatal cardiovascular events (hazard ratio [1-nmol/L increase in plasma NE] 1.08, 95% CI 1.02 to 1.15, P=0.01) in a model that included previous cardiovascular events, pulse pressure, age, diabetes, smoking, and use of sympathicoplegic agents and beta-blockers. The adjusted relative risk for cardiovascular complications in patients with plasma NE >75th percentile was 1.92 (95% CI 1.20 to 3.07) times higher than in those below this threshold (P=0.006). CONCLUSIONS: Sympathetic nerve overactivity is associated with mortality and cardiovascular outcomes in ESRD. Controlled trials with antiadrenergic drugs are needed to determine whether interference with the sympathetic system could reduce the high cardiovascular morbidity and mortality in dialysis patients.

Abstract:

Abstract: Nocturnal hypoxemia secondary to sleep apnea has long been implicated as a cardiovascular risk factor in renal failure, but to date there is no study that links nocturnal hypoxemia to cardiovascular outcomes in end-stage renal disease. Fifty uremic patients on regular dialysis treatment without primary sleep apnea, pulmonary diseases, or other illnesses that may cause sleep apnea underwent pulse oximetry studies during night and were followed up for 32 mo. Average nocturnal SaO(2), minimal SaO(2), and the number of episodes of hypoxemia were similar in patients who died during the follow-up and in patients who survived, and none of these parameters predicted all-cause mortality. Average nocturnal SaO(2) was significantly lower (P = 0.006) in patients who had cardiovascular events during the follow-up (94.7 +/- 2.9%) than in event-free patients (97.1 +/- 1.3%). In a Cox model, average nocturnal SaO(2) was the second factor in rank explaining these outcomes. In this model a 1% decrease in average nocturnal SaO(2) was associated with a 33% increase in the incident risk of fatal and nonfatal cardiovascular events. Furthermore the risk of cardiovascular events was 5.05 times higher in patients with average nocturnal SaO(2) <95% (95% CI 1.61 to 15.86) than in those above this threshold (P = 0.005). This study adds weight to the hypothesis that nocturnal hypoxemia in dialysis patients represents an important cardiovascular risk factor.

Abstract: BACKGROUND: The endogenous inhibitor of nitric oxide (NO), asymmetric dimethylarginine (ADMA), is a strong predictor of adverse cardiovascular outcomes in patients with end-stage renal disease (ESRD). METHODS: Since arterial and cardiac remodeling is associated with altered endothelial microcirculatory responses to forearm ischemia (a NO-dependent response), interference of ADMA with the NO system may be important for the pathogenesis of left ventricular hypertrophy (LVH) in these patients. This study sought to identify the relationship between plasma ADMA and LV geometry and function in a cohort of 198 hemodialysis patients. RESULTS: Plasma ADMA was significantly higher (P = 0.008) in patients with LVH (median 3.00 micromol/L, inter-quartile range 1.73 to 3.97 micromol/L) than in those without this alteration (1.88 micromol/L, 1.15 to 3.56 micromol/L) and was significantly related to left ventricular (LV) mass (r = 0.26, P < 0.001). Interestingly, ADMA was much higher (P < 0.001) in patients with concentric LVH (3.60 micromol/L, 2.90 to 4.33 micromol/L) than in patients with eccentric LVH (2.17 micromol/L, 1.47 to 3.24 micromol/L) or normal LV mass (1.76 micromol/L, 1.13 to 2.65 micromol/L). Furthermore, plasma ADMA was higher (P = 0.02) in patients with systolic dysfunction (3.52 micromol/L, 2.08 to 5.87 micromol/L) than in those with normal LV function (2.58 micromol/L, 1.53 to 3.84 micromol/L) and inversely related to ejection fraction (EF; r = -0.25, P < 0.001). The link between ADMA and LV mass and EF was confirmed by multivariate analysis (ADMA vs. LVMI, beta = 0.17, P = 0.006; ADMA vs. EF, beta = -0.24, P < 0.001). CONCLUSIONS: Overall, this study indicates that raised plasma concentration of ADMA is associated to concentric LVH and LV dysfunction. Intervention studies are needed to see whether the link between ADMA and concentric LVH remodeling and LV dysfunction is a causal one.

Abstract:

Abstract: Its is well established that sleep apnea (SA) is a health problem of paramount importance because it disrupts sleep and quality of life and may induce serious neuroendocrine and cardiovascular complications. There is little doubt that chronic renal failure is an independent cause of SA. The hypothesis that SA may depend on the accumulation of endogenous opioids still remains to be tested. Cytokines, particularly TNF-alpha and IL-6 which are much elevated in end-stage renal disease (ESRD), may also be implicated in the pathogenesis of SA. Nocturnal hypoxemia is an independent predictor of cardiovascular events in ESRD and the prediction power of this parameter remains strong and substantially unmodified after statistical adjustment for established cardiovascular risk factors in the dialysis population. Left ventricular hypertrophy and dysautonomia appear to be most likely intermediate mechanisms mediating the adverse cardiovascular effects of SA in ESRD.

Abstract: Cardiac troponin T (cTnT) predicts death and cardiovascular outcomes in clinically stable patients with end-stage renal disease. Because this protein is synthesized exclusively in myocardial cells, its predictive power for these outcomes may be because it reflects, besides cardiac ischemia, left ventricular (LV) mass, which is a strong predictor of cardiovascular death in this population per se. We tested the relationship between cTnT level and LV mass and the predictive power of this cardiac protein for all-cause and cardiovascular mortality in a cohort of hemodialysis patients (n = 199) without acute coronary syndrome and heart failure followed up for an average of 35 months (range, 0.8 to 52 months). cTnT was measured by means of a third-generation electrochemiluminescence immunoassay. cTnT level was related directly to interventricular septum (r = 0.36; P < 0.001) and posterior wall thickness (r = 0.40; P < 0.001), as well as LV mass (r = 0.45; P < 0.001). On multivariate analysis, after age, LV mass was the strongest independent predictor of cTnT level (beta = 0.28; P < 0.001). Serum cTnT level was significantly related to all-cause and cardiovascular mortality on univariate analysis (P < 0.001). On multivariate Cox regression analysis, the adjusted risk for all-cause death was 2.39 times (95% confidence interval [CI], 1.13 to 5.06; P = 0.02) greater in patients in the third cTnT tertile than the first tertile, and a similar pattern emerged for cardiovascular mortality (hazard ratio, 2.35; 95% CI, 1.01 to 5.49; P = 0.048). In hemodialysis patients, plasma cTnT level is independently related to LV mass and predicts all-cause and cardiovascular mortality. These data support the hypothesis that this marker can be usefully applied for risk stratification in clinically stable dialysis patients.

Abstract: Adiponectin (ADPN), which is a secretory protein of adipose tissue, attenuates endothelial inflammatory responses in vitro. Among human subjects, plasma ADPN concentrations are reduced among patients with atherosclerotic complications but are substantially increased among patients with advanced renal failure. The clinical and biochemical correlates of plasma ADPN levels were investigated and the predictive power of ADPN levels with respect to survival rates and cardiovascular events was prospectively tested in a cohort of 227 hemodialysis patients, who were monitored for 31 +/- 13 mo. Plasma ADPN levels were 2.5 times higher (P < 0.0001) among dialysis patients (15.0 +/- 7.7 microg/ml) than among healthy subjects (6.3 +/- 2.0 microg/ml), were independent of age, and were higher (P = 0.03) among women (15.2 +/- 7.9 microg/ml) than among men (14.0 +/- 7.4 microg/ml). For both genders, plasma ADPN levels were inversely related to body mass index values, plasma leptin levels, insulin levels, serum triglyceride levels, and homeostatic model assessment index values. Furthermore, plasma ADPN levels were directly related to HDL cholesterol levels and inversely related to von Willebrand factor levels. Plasma ADPN levels were lower (P < 0.05) among patients who experienced new cardiovascular events (13.7 +/- 7.3 microg/ml) than among event-free patients (15.8 +/- 7.8 microg/ml). There was a 3% risk reduction for each 1 microg/ml increase in plasma ADPN levels, and the relative risk of adverse cardiovascular events was 1.56 times (95% confidence interval, 1.12 to 1.99 times) higher among patients in the first ADPN tertile, compared with those in the third tertile. Plasma ADPN levels are an inverse predictor of cardiovascular outcomes among patients with end-stage renal disease. Furthermore, ADPN is related to several metabolic risk factors in a manner consistent with the hypothesis that this protein acts as a protective factor for the cardiovascular system.

Abstract: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase that has been linked to endothelial dysfunction and atherosclerosis in the general population. ADMA is also elevated in end-stage renal disease and may contribute to the high cardiovascular risk in patients with chronic renal failure. A prospective cohort study was performed to investigate the relationship between plasma ADMA, C-reactive protein (CRP), and intima-media thickness (IMT) in 90 patients undergoing hemodialysis. In the baseline study, plasma ADMA was directly related to IMT both on univariate analysis (r = 0.32, P = 0.002) and on multiple regression analysis (beta = 0.23, P = 0.01). In the follow-up study (15 mo) IMT changes were significantly related to ADMA (r = 0.51, P = 0.02) and serum CRP (r = 0.53, P = 0.01) in patients with initially normal IMT. In these patients, ADMA and CRP were strongly interrelated (r = 0.64, P = 0.002), and on multiple regression analysis the interaction between ADMA and CRP emerged as the sole independent predictor of the progression of intimal lesions. Independently of other risk factors, plasma ADMA in patients on hemodialysis is significantly related to IMT. Furthermore, in patients with initially normal IMT, ADMA and CRP are interacting factors in the progression of carotid intimal lesions. These data support the hypothesis that accumulation of this endogenous inhibitor of NO synthase is an important risk factor for cardiovascular disease in chronic renal failure and suggest a possible link between ADMA and inflammation.

Abstract: BACKGROUND: We prospectively tested the prediction power of homocysteinemia for all-cause and cardiovascular outcomes in a cohort of 175 hemodialysis patients followed for 29 +/- 12 months. METHODS: Survival analysis was performed by the Cox's proportional hazard model and data were expressed as hazard ratio and 95% confidence interval (CI). RESULTS: During the follow-up period 51 patients died, 31 of them (61%) of cardiovascular causes and 16 patients developed non-fatal atherothrombotic complications. Plasma total homocysteine was an independent predictor of cardiovascular mortality (P=0.01). Combined analysis of fatal and non-fatal atherothrombotic events showed that homocysteine was a strong and independent predictor of these outcomes because the risk of these events was 8.2 times higher (95% CI 1.9 to 32.2) in patients in the third homocysteine tertile than in those in the first tertile (P=0.005). CONCLUSIONS: There is a clear association between hyperhomocysteinemia and incident cardiovascular mortality and atherothrombotic events in hemodialysis patients. Intervention studies are needed to determine whether the accumulation of this substance has a causal role in the pathogenesis of cardiovascular damage in patients undergoing hemodialysis.

Abstract:

Abstract: To be appropriately labelled as a 'risk factor' any putative risk factor should increase the prediction power of standard statistical models based on 'traditional' (Framingham) risk factors. In end-stage renal disease (ESRD), Framingham risk factors do not fully explain the cardiovascular burden of these patients. Inflammation, hyperhomocysteinemia and anemia contribute to the high cardiovascular risk of ESRD, but knowledge is still incomplete. We suspected that asymmetric dimethylarginine (ADMA) is an important cardiovascular risk factor in dialysis patients. This substance inhibits nitric oxide synthase thus triggering a series of pathophysiological events leading to atherosclerosis. To test this hypothesis, we studied the relationship between ADMA and intima media thickness (IMT) in the carotid artery. ADMA was found to be strongly and independently related to IMT. More importantly we found that patients with relatively higher plasma ADMA had shorter survival and a higher rate of incident cardiovascular complications in comparison to those with a relatively lower plasma concentration. These data represent a sound basis for intervention studies aimed at modifying the plasma ADMA concentration in ESRD patients.

Abstract: For about three decades glomerular diseases have been the most intensively investigated research area in nephrology. The increasing proportion of patients with end-stage renal disease (ESRD) secondary to hypertension has now revived interest in hypertension. Prospective studies have firmly established that high blood pressure is associated with an increased risk of renal failure independent of other risk factors. Hypertension-related renal injury might be interpreted in a general context taking into account genes, intrauterine growth and environmental factors. Disturbed intrauterine growth (due to malnutrition or other factors) has a negative influence on the development of the cardiovascular system and favours the occurrence of hypertension, insulin resistance, hypercholesterolaemia and hyperuricaemia in adult life (Barker's hypothesis). Altered intrauterine growth has also been associated with a reduced number of nephrons at birth. Damage attributable to glomerular hyperperfusion in kidneys with a reduced number of nephrons is aggravated by vascular lesions in middle and small arterial vessels (secondary to hypertension, hyperlipidaemia and environmental risk factors such as smoking). The observation that subjects homozygous for the D allele of the ACE gene are predisposed to both cardiovascular complications and nephrosclerosis, suggests that genetic factors may interact with altered intrauterine growth in determining the risk of cardiovascular and renal diseases.

Abstract: Understanding and modifying the causes of the high cardiovascular morbidity and mortality associated with renal disease is the greatest challenge faced by renal physicians. About one person in 20 has a serum creatinine level above normal (> or =1.5 mg/dl in males and > or =1.4 mg/dl in females), signifying mild kidney disease. People with hypertension, hyperlipidaemia, and/or diabetes (approximately 350000 people per million in the general population) have the highest risk of renal failure. Anaemia, extracellular volume expansion, increased angiotensin II and aldosterone levels, high calcium-phosphate product, inflammation, hyperhomocysteinaemia, and impaired nitric oxide synthesis all amplify the risk of cardiovascular disease in patients with renal failure. These factors may adversely affect the cardiovascular system by influencing the generation of reactive oxygen species, thus contributing to high oxidative stress. Further research into optimal follow-up of patients with mild renal insufficiency is needed. Identification of 'problematic' and/or treatment-resistant patients should be a primary goal. Greater understanding of the genetic and environmental precursors of diseases associated with renal insufficiency would also be beneficial, particularly for younger patients. Observational studies aimed at linking these risk factors to well-defined and measured renal and cardiovascular outcomes should increase knowledge of renal disease progression and cardiovascular risk in these populations.

Abstract: 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< or =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.

Abstract: Atherosclerotic renal artery stenosis is the most common primary disease of the renal arteries, and it is associated with two major clinical syndromes, ischemic renal disease and hypertension. The prevalence of this disease in the population is undefined because there is no simple and reliable test that can be applied on a large scale. Renal artery involvement in patients with coronary heart disease and/or heart failure is frequent, and it may influence cardiovascular outcomes and survival in these patients. Suspecting renal arterial stenosis in patients with recurrent episodes of pulmonary edema is justified by observations showing that about one third of elderly patients with heart failure display atherosclerotic renal disease. Whether interventions aimed at restoring arterial patency may reduce the high mortality in patients with heart failure is still unclear because, to date, no prospective study has been carried out in these patients. Increased awareness of the need for cost containment has renewed the interest in clinical cues for suspecting renovascular hypertension. In this regard, the DRASTIC study constitutes an important attempt at validating clinical prediction rules. In this study, a clinical rule was derived that predicted renal artery stenosis as efficiently as renal scintigraphy (sensitivity: clinical rule, 65% versus scintigraphy, 72%; specificity: 87% versus 92%). When tested in a systematic and quantitative manner, clinical findings can perform as accurately as more complex tests in the detection of renal artery stenosis.

Abstract: BACKGROUND: A reduction in salivary and lachrymal secretion has been described in many pathologies; however, such alterations have not been described in patients with renal failure. This study was designed to estimate the frequency of alterations in salivary and lachrymal secretion in haemodialysed patients. PATIENTS ABD METHODS: We studied 63 haemodialysed patients and 23 healthy control subjects. In all of them we tested salivary secretion (Saxon test), lachrymal secretion (Shirmer test) as well as the presence of symptoms of xerostomia and xerophthalmia. In a subgroup of patients We investigated any evidence of ocular lesions and tissue damage of salivary glands (histopathology). We also tested the correlation between salivary and lachrymal secretion and autonomic nervous system function. Furthermore, we also studied the association between xerostomia and xerophthalmia and serum auto antibodies (anti nuclear, anti-Ro (SS-A), anti-La (SS-B)) and anti HCV antibodies. RESULTS: On average salivary and the lachrymal secretion was markedly reduced in uraemic patients compared with healthy controls. We found the alterations in salivary glands function to be strongly related to salivary glands fibrosis and atrophy and independent of amyloid accumulation. On the other hand, we observed that xerostomia and xerophthalmia were unrelated to autonomic dysfunction as well as to HCV infection and circulating auto antibodies. Moreover, xerophthalmia was frequently associated with evidence of corneal damage. CONCLUSIONS: Reduced salivary and lachrymal secretion is frequent in uraemic patients. Such alterations are often asymptomatic and could be an expression of the accelerated age-dependent decline in glandular function and the attendant fibrosis and atrophy.