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Background and Methods: Smoking is associated with hyperparathyroidism in the elderly general population and nicotine, the main component of tobacco smoke, stimulates PTH release in experimental models. Although smoking is a persisting problem in patients with end-stage renal disease (ESRD), the association between smoking and PTH has never been specifically examined in these patients. We investigated the relationship between smoking and hyperparathyroidism in a well-characterized group of 161 nondiabetic dialysis patients., Results: Sixty-four patients (40%) were smokers. Heavy smokers had higher intact PTH (median: 280 pg/mL) and PTH1-84 (188 pg/mL) than light smokers (180 pg/mL and 95 pg/mL) and nonsmokers (169 pg/mL and 95 pg/mL). In a multiple regression analysis, smoking was independently associated with intact PTH (ß=0.29, p=0.002) and PTH1-84 (ß=0.29, p=0.002). Fifty-six of 161 patients (35%) were classified as having hyperparathyroidism. In a multiple logistic regression model the odds of hyperparathyroidism were about 4 times higher in heavy smokers (odds ratio 3.88, 95% CI 1.16-12.92, p=0.027) than in nonsmokers., Conclusion: In dialysis patients heavy smoking is independently associated with high levels of intact PTH and PTH1-84. Further observational, mechanistic and interventional studies are needed to assess the nature (causal or noncausal) of these links in ESRD.

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.

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.

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.

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.

Methods: We investigated the influence of salt intake on urinary and plasma endothelin-1 (ET-1) in 55 patients who entered a two-week double-blind, randomised, crossover study comparing a 50 mMol/day salt intake and 150 mMol/day. Twenty-four-hour ET-1 excretion and plasma ET-1 were measured by RIA on pre-extracted samples., Results: In the whole cohort (n=55), changes in urinary ET-1 were related to salt excretion (r=0.28, P=0.04) and urinary volume (r=0.47, P=0.0001). In a multivariable model, changes in PRA, plasma aldosterone, blood pressure and heart rate did not add any predictive power to salt excretion with regard to urinary ET-1 variations. The relationship between urinary volume and urinary ET-1 was stronger than that of urinary sodium with ET-1 excretion because sodium was excluded from the multivariable model when urinary volume was introduced. Changes in urinary ET-1 were unrelated to mean blood pressure changes (P=0.66). Changes in plasma ET-1 were unaffected by changes in salt intake (P=0.58) but were strongly related to those in PRA (r= -0.45, P=0.01) and plasma aldosterone (r= -0.53, P=0.002)., Conclusions: The renal excretion of ET-1 is influenced by changes in salt intake and appears largely independent of the blood pressure response to salt. Changes in urinary volume which accompany variations in salt excretion play an important role in this response. Since urinary ET-1 reflects its renal synthesis, our data support the notion that renal ET-1 plays a role in the regulation of sodium balance in patients with mild hypertension.

Aim: To investigate the relationship between carotid atherosclerosis and some major cardiovascular risk factors in uremic patients on chronic dialysis., Methods: A cross-sectional study was carried out in 119 unselected dialysis patients (89 on hemodialysis and 30 on chronic ambulatory peritoneal dialysis, CAPD). Fasting blood sampling for serum lipids, albumin, hemoglobin, and echo-colour-Doppler evaluation of common carotid arteries were performed in all patients (during the non-dialysis day in hemodialysis patients). In hemodialysis patients BP was measured before and after dialysis; in CAPD patients home BP values were recorded during the month before the study day., Results: Ninety-five patients had at least one plaque and 57 had at least four plaques. Thirty-eight had mild and eleven severe carotid stenosis. In multiple regression models, the mean internal diameter of carotid arteries was explained (R=0.52, P=0.0001) by systolic pressure (r=0.39), serum cholesterol (r=-0.28), age (r=0.27) and smoking (r=0.24) while the degree of carotid stenosis was predicted (R=0.39, P=0.0001) by age (r=0.36) and smoking (r=0.25). The number of atherosclerotic plaques was explained (R=0.51, P=0.0001) by age (r=0.36), smoking (r=0.25) and pulse pressure (r=0.20), serum albumin just failing to reach statistical significance (P = 0.06). However, serum albumin was a significant and independent predictor of the number of atherosclerotic plaques (r=-0.26) in hemodialysis patients (n=89). Sex, diabetes, Kt/V, duration of dialysis treatment, hemoglobin, serum calcium and phosphate did not add any predictive power to the models., Conclusions: In dialysis patients arterial pressure and smoking are associated with carotid atherosclerosis. Serum albumin appears to serve as an independent predictor of carotid atherosclerosis.