Prospective study of neuropeptide y as an adverse cardiovascular risk factor in end-stage renal disease.

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.

Chlamydia pneumoniae, overall and cardiovascular mortality in end-stage renal disease (ESRD).

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.

Neuropeptide Y, left ventricular mass and function in patients with end stage renal disease.

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

Adiponectin is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors.

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.

Adiponectin in essential hypertension.

Adiponectin (ADPN), the gene product of apM1, is the most abundant secretory protein of adipose tissue in human plasma. Synthesis of this substance may be reduced in endothelial dysfunction and cardiovascular diseases in humans. We investigated the relationship between plasma ADPN, body mass index (BMI), fat mass (BIA) and renal function in 36 patients with uncomplicated essential hypertension. Plasma ADPN was higher in hypertensive patients than in normotensive subjects, but the difference just failed to reach statistical significance (P=0.06). Hypertensive men had significantly higher plasma ADPN than normotensive men (6.7+/-2.6 vs 4.8+/-2.0 microg/mL, 40%, P=0.01). By contrast, the difference between hypertensive (8.5+/-3.9 microg/mL) and normotensive women (7.1+/-2.6 microg/mL) was not significant (20%). In hypertensive patients, plasma ADPN was inversely related to creatinine clearance and tended to be inversely related to serum insulin (r= -0.27) and HOMA-R index (r= -0.24). The relationship between plasma ADPN and renal function was confirmed in a multiple regression analysis which showed that creatinine clearance was the only independent predictor of plasma ADPN. Plasma ADPN in essential hypertension is dependent on sex and renal function. High levels in essential hypertensives may be the expression of a counter-regulatory response aimed at mitigating endothelial damage and cardiovascular risk associated with high arterial pressure.

Diagnostic value of troponin T for alterations in left ventricular mass and function in dialysis patients.

BACKGROUND: Cardiac troponin T (cTnT) is related to left ventricular (LV) mass in patients with end-stage renal disease (ESRD). Furthermore, cTnT reflects the severity of systolic dysfunction in patients with heart diseases. We tested the diagnostic value of cTnT for left ventricular hypertrophy (LVH) and LV systolic dysfunction in a large group of clinically stable hemodialysis patients without heart failure. RESULTS: CTnT was significantly (P < 0.001) higher in patients with LVH than in those with normal LV mass. In a multiple logistic regression model, adjusting for potential confounders (including cardiac ischemia), systolic pressure and cTnT (both P = 0.003) were the strongest correlates of LVH. Similarly, cTnT was significantly higher (P = 0.005) in patients with systolic dysfunction than in those with normal LV function and in a multiple logistic regression model cTnT ranked as the second independent correlate of this alteration after male sex. Serum cTnT had a high positive prediction value for the diagnosis of LVH (87%) but its negative prediction value was relatively low (44%). The positive predictive value of cTnT for LV dysfunction was low (25%) while its negative predictive value was high (93%). A combined analysis including systolic pressure (for the diagnosis of LVH) and sex (for the diagnosis of LV systolic dysfunction) augmented the diagnostic estimates to an important extent (95% positive prediction value for LVH and 98% negative prediction value for LV systolic dysfunction). CONCLUSIONS: CTnT has a fairly good diagnostic potential for the identification of LVH and for the exclusion of LV systolic dysfunction in patients with ESRD without heart failure. This marker may be useful for the screening of alterations in LV mass and function in clinically stable hemodialysis patients.

Low parathyroid hormone and pentosidine in hemodialysis patients.

BACKGROUND: Accumulation of advanced glycation end products (AGEs) has been linked to the severity of osteoarticular and cardiovascular damage in patients with end-stage renal disease. METHODS: We studied the relationship between plasma pentosidine and parathyroid hormone (PTH) levels and bone turnover in a group of hemodialysis patients (n = 85) with minimal aluminum exposure. RESULTS: Plasma pentosidine levels were greater than the upper limit of normal range (cutoff value, 2.46 pmol/mg protein) in all dialysis patients. When patients were divided into three tertiles according to plasma pentosidine levels, serum PTH levels were approximately six times lower in patients in the third pentosidine tertile than in those in the first tertile (P = 0.008), and a similar association (P = 0.009) was found between pentosidine and bone alkaline phosphatase levels. Multivariate analysis confirmed that these relationships were independent of established risk factors for low bone turnover. Forty patients (47%) had serum PTH levels less than 125 pg/mL (13.2 pmol/L). Of note, in a multiple logistic regression model, the relative risk for low PTH level was 4.02 (95% confidence interval, 1.30 to 12.40; P = 0.02) times greater in patients in the third pentosidine tertile than in the first tertile. CONCLUSION: Pentosidine, a reliable indicator of AGEs, is related inversely to circulating PTH and bone alkaline phosphatase levels. These associations are in agreement with recent experimental data indicating that AGE accumulation may be a factor involved in low bone turnover in dialysis patients.

Norepinephrine and concentric hypertrophy in patients with end-stage renal disease.

We have recently observed that in patients with end-stage renal disease (ESRD) raised plasma norepinephrine (NE) is an independent predictor of incident cardiovascular events but that its prognostic power is reduced when this sympathetic marker is tested in statistical models including also left ventricular mass. Because left ventricular hypertrophy (LVH) may be a mechanism whereby NE contributes to the high rate of cardiovascular events in ESRD, we examined the relationship between plasma NE and echocardiographic parameters of left ventricle mass in a large group of ESRD patients. Mean wall thickness (MWT) was higher in patients in the third NE tertile than in the other 2 tertiles (P=0.001), and such an increase was paralleled by a rise in relative wall thickness (RWT) (P=0.006). Concentric LVH was more prevalent in patients in the third NE tertile (46%) than in the second (38%) and first (25%) NE tertiles. Multivariate regression analysis confirmed that the association of plasma NE with the muscular component of left ventricle (MWT) and with RWT was independent (P< 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.

Troponin is related to left ventricular mass and predicts all-cause and cardiovascular mortality in hemodialysis patients.

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.

Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease.

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.

Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease.

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.

Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis patients.

This study was designed to investigate the relationship among brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) and left ventricular mass (LVM), ejection fraction, and LV geometry in a large cohort of dialysis patients without heart failure (n = 246) and to test the prediction power of these peptides for total and cardiovascular mortality. In separate multivariate models of LVM, BNP and ANP were the strongest independent correlates of the LVM index. In these models, the predictive power of BNP was slightly stronger than that of ANP. Both natriuretic peptides also were the strongest independent predictors of ejection fraction, and again BNP was a slightly better predictor of ejection fraction than ANP. In separate multivariate Cox models, the relative risk of death was significantly higher in patients of the third tertile of the distribution of BNP and ANP than in those of the first tertile (BNP, 7.14 [95% confidence interval (CI), 2.83 to 18.01, P = 0.00001]; ANP, 4.22 [95% CI, 1.79 to 9.92, P = 0.001]), and a similar difference was found for cardiovascular death (BNP, 6.72 [95% CI, 2.44 to 18.54, P = 0.0002]; ANP, 3.80 [95% CI, 1.44 to 10.03, P = 0.007]). BNP but not ANP remained as an independent predictor of death in a Cox's model including LVM and ejection fraction. Cardiac natriuretic peptides are linked independently to LVM and function in dialysis patients and predict overall and cardiovascular mortality. The measurement of the plasma concentration of BNP and ANP may be useful for risk stratification in these patients.