Introduction.Hypertension and additional non-traditional risk factors can damage the kidney directly and by promoting atherogenesis.Evidence indicates that increased oxidative stress and inflammation may mediate a large part of the effects of risk factors on the kidney.We hypothesized that in hypertensive patients (HT) oxidative stress, measured by 8-ISO Prostaglandin F2alpha (8-ISO), should raise in parallel with decreasing renal function, and should correlate with estimated glomerular filtration rate (eGFR).Methods.In 626 consecutive HT having renal function ranging from stage 1 to 5, plasma levels of 8-ISO, high sensitivity C-reactive protein (CRP), Transforming Growth Factor-beta (TGF-beta), and endothelin-1(ET-1) were measured.GFR was estimated by Modification of Diet in Renal Disease Study equation.Results.Plasma concentrations of all the studied molecules showed a progressive and significant increase from stage 1 to stage 5.The multiple regression analysis, considering eGFR as dependent variable, showed that in HT plasma levels of 8-ISO (beta -0.361, p<0.000001),ET-1 (beta -0.197, p<0.0001), and TGF-beta (beta -0.170, p<0.0004) correlated independently to eGFR.All biomarkers were good predictors of eGFR < 60ml/min (receiver-operator-curve [ROC] areas).ET-1 showed to be the best predictor with a ROC area = 0.938; with a threshold of 4 pg/ml, a 91% sensitivity and a 85% specificity was observed, whereas 8-ISO had a ROC area =0.931 and for a threshold of 329 pg/ml, sensitivity and specificity were 89%, respectively.On the contrary, CRP showed the lower predictive value with a ROC area = 0.917, with a threshold of 2.52 mg/L an 87% sensitivity and an 83% specificity were obtained.Conclusions.Our findings are a clear-cut demonstration of a strong and negative relationship of both oxidative stress and ET-1 with renal function stages in hypertensive patients.

AIMS Left ventricular hypertrophy (LVH) is a predictor for cardiovascular mortality, and it is considered to be a surrogate marker of preclinical cardiovascular disease. This study aimed at evaluating whether fetuin-A plasma levels are decreased in patients with moderate chronic kidney disease (CKD) and their linkage to plasma concentrations of hs-C-reactive protein (CRP), cardiotrophyn-1 (CT-1), tumor necrosis factor-ac (TNF-alpha), propeptide of collagen Type I (PIP) and to LVH. MATERIAL AND METHODS We enrolled 64 moderate CKD and 55 essential hypertensives (EH) with normal renal function as controls. All the patients underwent an echocardiographic examination; plasma samples were obtained to measure routine clinical parameters and the molecules listed above (measured by ELISA). RESULTS Among CKD there were 30/64 patients with LVH, and in EH group 14/55 subjects had LVH. Fetuin A was reduced in CKD when compared with EH (p < 0.0001). The comparison between CKD having LVH with those without LVH showed significant differences in plasma levels of fetuin-A (p < 0.002), TNF-alpha (p < 0.01) and hs-CRP (p < 0.001), CT-1 and PIP (p < 0.002). CKD with LVH had lower values of fetuin-A (p < 0.001), and higher values of hs-CRP (p < 0.001) TNF-alpha (p < 0.001), CT-1 (p < 0.001) and PIP (p < 0.001) than EH with LVH. The multivariate analysis of correlation demonstrated that in CKD patients hs-CRP (beta 0.42, p < 0.00006), and systolic blood pressure (beta 0.29, p < 0.02) were independent predictors of LV mass index. The relationship between LV mass index and fetuin-A did not reach statistical significance. CONCLUSIONS For the first time in moderate CKD patients, we demonstrate that fetuin-A is decreased and relates to LVH depending on C-reactive protein.

We hypothesized that in essential hypertensive patients (EHs), plasma levels of pro-atherogenic adhesion molecules would be increased and related with urine albumin excretion (UAE). Thus, this study was aimed at evaluating biochemical markers of endothelial activation and their relationship with UAE in a group of patients with uncomplicated EH. In basal condition soluble forms of adhesion molecules intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, as well as 24-h UAE were assayed. One hundred patients with essential hypertension and no diabetes or ultrasonographic evidence of atherosclerosis were included in the study. Seventy normotensive healthy subjects served as controls. EHs were first studied overall, than were divided into two subgroups: those with UAE ⩾20 mcg/min MAUs and those with UAE <20 mcg/min (non-MAUs). ICAM-1 (P<0.001) and VCAM-1 (P<0.0001) plasma concentrations were higher in EHs than in controls. Microalbuminuric EHs had greater levels of adhesion molecules than non-MAUs (ICAM-1 P=0.04; VCAM-1 P=0.02, respectively). In EHs UAE was correlated with ICAM-1 (r=0.29, P=0.003), and VCAM-1 (r=0.30, P=0.002). These associations were confirmed in multiple regression models (P=0.02 for both ICAM-1 and VCAM-1) including, along with adhesion molecules, age, body mass index and blood pressures. Our findings show that in essential hypertension there is a very early activation of endothelial adhesion molecules favouring atherosclerosis.

INTRODUCTION:Several studies have shown that chronic renal failure (CRF) is characterized by "accelerated atherosclerosis". More recent studies emphasize that inflammation and oxidative stress play a central role in atherosclerosis, and it is well-established that C-reactive protein (CRP) is a cardiovascular risk marker in the general population, in end-stage renal disease (ESRD) patients and in allograft recipients. METHODS:We measured the serum concentration of high sensitivity CRP, TNFalpha, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha, an in vivo oxidative stress marker) in 15 CRF patients and in 15 transplant recipients. Exclusion criteria were age < 30 and > 65 years, smoking, diabetes mellitus and history of cardiovascular diseases. Immunosuppressive therapy was not withdrawn, and antihypertensive treatment was the same for both groups. Systolic (SBP) and diastolic blood pressure (DBP), serum creatinine (sCr) and estimated glomerular filtration rate (GFR) were also evaluated. 15 healthy subjects were enrolled as controls. RESULTS:The transplanted group showed significantly higher values than controls of CRP (p < 0.05), TNFalpha (p < 0.05), 8-iso-PGF2alpha (p < 0.05). The CRF group as well exhibited, in comparison with controls significantly higher concentrations of CRP (p < 0.05), TNFalpha (p < 0.05), and 8-iso-PGF2alpha (p < 0.05). SBP, DBP and sCr were not different between transplanted and CRF patients. CRP was higher in transplant recipients than in CRF patients (p < 0.05). No difference in TNFalpha levels between the 2 groups was found. 8-iso-PGF2alpha was significantly higher in CRF than in the transplanted group (p < 0.05). In this latter, 8-iso-PGF2alpha showed a positive correlation with TNFalpha (p < 0.001), sCr (p < 0.001), SBP (p < 0.05) and DBP (p < 0.05). In the same group both 8-iso-PGF2alpha and TNFalpha were negatively correlated with GFR (r = -0.873 and -0.912, respectively, p < 0.001 for both). CONCLUSION:Our data have shown the coexistence of an increased oxidative stress and an inflammatory state in long-term renal graft recipients.

Background: C-reactive protein (CRP) predicts cardiovascular outcome. Oxidative stress is considered to be involved in endothelial alteration. We hypothesized that in essential hypertension (EH), oxidative stress, as measured by 8-iso-prostaglandin-F-2 alpha (8-iso-PGF(2 alpha)), should be associated with increased CRP and endothelial activation, as evaluated by soluble intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) plasma levels.Methods: In 83 subjects with mild EH and in 50 healthy control subjects we measured, in basal conditions, plasma levels of hs-CRP, 8-iso-PGF(2 alpha), ICAM-1 and VCAM-1, and tumor necrosis factor-alpha (TNF-alpha).Results: Subjects with EH had higher levels of 8-iso-PGF(2 alpha) (P <.0001), CRP (P <.001), ICAM-1 and VCAM-I (P <.001), and TNF-alpha (P <.001) than did control subjects. We divided successively EH according to CRP values (<1, 1-3, >3 mg/L), and we observed increasing and significantly different levels of the endothelial parameters and of TNF-alpha along with increasing CRP. Linear analysis of correlation pointed out significant correlation of CRP with 8-iso-PGF(2 alpha) (r = 0.730, P <.001), ICAM-1 and VCAM-1 (r = 0.642 and 0.468, P <.001 respectively), and TNF-alpha (r = 0.609, P <.001).Multiple regression analysis using CRP as a dependent variable confirmed the relationship of CRP with systolic blood pressure (beta 0.216, P = 0.039) and with 8-iso-PGF(2 alpha) (beta 0.602, P =.0001).Conclusions: Our data demonstrate that in EH, inflammatory molecules such as CRP and TNF-alpha are increased and related to both oxidative stress and endothelial activation.

To investigate and compare the degree of endothelial activation, and its relationship with glucose metabolism in hypertensive patients without- (EHs) and with Metabolic Syndrome (MSHs) as defined by ATP III. In 197 consecutive hypertensives of whom 91 EHs and 106 MSHs, and in 70 healthy controls, we measured Adhesion Molecules (ICAM,VCAM, E-Selectin), von Willebrand factor (vWF), insulin and glucose plasma levels, and microalbuminuria (MAU). Controls showed significantly (p< 0.0001) lower values of endothelial markers than EHs. The comparison between EHs and MSHs showed significant differences in endothelial markers (p<0.00006) and serum glucose and insulin levels (p<0.0001), MAU (p<0.01), BMI (p<0.00002). No differences in blood pressures (BP) were found. In MSHs serum glucose significantly correlated with Adhesion Molecules (p<0.001), vWf (r 0.434, p<0.001), and BMI (p<0.05). Serum insulin levels were correlated with BMI (p<0.001), and weakly with ICAM and MAU (p<0.05). MAU correlated with BMI (p<0.01) but not with metabolic parameters. Systolic BP correlated with ICAM (p<0.001), VCAM (p<0.01), E-Selectin (p<0.001), and vWf (p<0.01). Diastolic BP correlated with ICAM (p<0.001), and vWf (p<0.05). In EHs adhesion molecules and vWf correlated significantly with BPs and MAU but not with metabolic parameters. Our data suggest that Metabolic Syndrome is associated with a marked endothelial activation in which blood pressure seems to have a major role than insulin resistance.

Oxidative stress is known to turn into endothelial stress, thus contributing to the development of the vascular complications of hypertensive disease.The aim of this study was to quantify oxidative stress by analysing its index in vivo, the 8-iso-prostaglandin F2a (8-iso-PGF2a), as well as to evaluate any interaction with two indexes of endothelial disfunction: von Willerbrand factor (vWf) and E-selectin (E-Sel). Plasma concentrations of Nitric Oxide (NO) were also measured.Therefore, they were assaied in basal conditions in on 30 never treated essential hypertensive patients (EH) (average BP 158±18/98±8 mmHg), and in 30 healthy controls normotensive (C).EH showed significantly higher plasma of 8-iso-PGF2a (p<0.001), vWf (p< 0.001) and E-Sel (p<0.01) than C. On the contrary, NO plasma concentrations showed to be lower in EH than C (p<0.001). The linear analysis of correlation pointed out positive and highly significant correlations of 8-iso-PGF2a with vWf (r 0.912, p<0.001) and with E-Sel (r 0.937 p<0.001). As expected, 8-iso-PGF2a was inversely correlated with NO plasma levels (p<0.01). Systo-diastolic levels were significantly correlated with 8-iso-PGF2a plasma concentrations (SBP r 0.89, DBP r 0.70, p<0.001 respectively). Our results suggest that an increase in peroxidation of Arachidonic Acid, producing F2 isoprostanes biologically active as 8-iso-PGF2a having vasoconstrictor function, may represent a linking mechanism between hypertension and endothelial alterations.

Experimental data suggest that renal reperfusion induces a free radicals-mediated cell damage. This damage could cause the lack of survival of the transplanted kidney. This study was aimed at appraising oxidative stress in hypertensive patients with transplanted kidney (TPKs). Therefore, in 15 patients, undergoing immunosuppressive treatment, with serum creatinine (sCr) ranging from 0.8 to 3 mg/dL we assayed plasma levels of 8-ISO-PFG2alfa, a marker of oxidative stress, nitric oxide (NO) and TNFalfa. Moreover, 15 healthy controls were studied. Subsequently, the TPKs were divided into two subsets according to their sCr : > 1.4 > mg/dL. The two subsets showed significant differences in sCr (1.14±0.15 vs 1.95±0.7 mg/dL, p<0.04), whereas blood pressures did not differ. Plasma levels of 8-ISO-PFG2alfa and of TNFalfa were significantly (p<0.01, respectively) higher in TPKs than in controls, whereas NO was lower in TPKs (p<0.01). TPKs with sCr > 1.4 showed greater levels of plasma 8-ISO-PFG2alfa (p<0.0001) and TNFalfa (p<0.004) than patients with sCr < 1.4 mg/dL. On the other hand, plasma NO levels were lower (p<0.02) in TPKs with sCr > 1.4 than in the other group of TPKs. The linear analysis of correlation pointed out in the overall group of TPKs and both subsets a positive correlation of 8-ISO-PFG2alfa with sCr (overall: r 0.774, p< 0.001; sCr<1.4: r 0.92, p<0.01; sCr > 1.4: r 0.768, p< 0.01), and a negative correlation with NO (overall r 0.96,p<0.001). A weak but significant correlation (r 0.53, p< 0.05) of 8-ISO-PFG2alfa with systolic BP was shown in the overall group. Our results demonstrate that in transplanted hypertensive patients oxidative stress is augmented and correlated with declining renal function.

Objectives. To evaluate, in a group of nondiabetic essential hypertensive patients with normal renal function, the relationship between albumin excretion rate (AER) and carotid-femoral pulse wave velocity (PWV), as an index of aortic stiffness.Design. Cross-sectional study.Setting: Outpatient hypertension clinic.Subjects. Seventy patients with mild-to-moderate essential hypertension, aged 42 +/- 8 years, never pharmacologically treated. All subjects underwent routine laboratory tests, 24-h ambulatory blood pressure (BP) monitoring, measurement of carotid-femoral PWV, by means of a computerized method, and AER.Results. Microalbuminuric patients (AER greater than or equal to 20 mug min(-1); n = 19), when compared with normoalbuminuric subjects, showed more elevated 24-h BP (136/88 +/- 10/10 vs. 128/83 +/- 7/6 mmHg; P < 0.001 and P = 0.013, for systolic and diastolic BP respectively) and higher values of carotid-femoral PWV (10.4 +/- 2 m s(-1) vs. 9.2 +/- 1.3; P = 0.006). This latter difference remained statistically significant, even after correction by ancova for 24-h systolic and diastolic BP, and body mass index (BMI, P = 0.016). Univariate regression analysis disclosed a tight correlation between AER and carotid-femoral PWV (r = 0.42; P = 0.0003). This association was confirmed in a multiple regression model (beta = 0.35; P = 0.009) in which, as independent variables, besides PWV, 24-h BP, age, serum glucose values, smoking status, gender and BMI, were added.Conclusions. Our results seem to confirm that microalbuminuria may represent the early renal manifestation of a widespread vascular dysfunction, and therefore it is an integrated marker of cardiovascular risk.

Little is known about the relationships between microalbuminuria and large-artery stiffness. The aim of our study was to evaluate, in a group of non-diabetic essential hypertensive patients with normal renal function, the relationship between albumin excretion rate (AER) and carotid-femoral pulse wave velocity (PWV), as an index of aortic stiffness. We enrolled 70 subjects with mild-to-moderate essential hypertension, aged 42 ± 8 years, never pharmacologically treated. All patients underwent routine laboratory tests, 24-h ambulatory blood pressure monitoring, measurement of carotid-femoral PWV, by means of a computerized method, and AER. Subjects with AER above the median value (15.3 μg/min), when compared to patients with lower levels of albuminuria, showed more elevated 24-h systolic blood pressure (135 ± 8.7 vs 128 ± 7.3 mmHg; p = 0.001) and higher values of carotid-femoral PWV (10.2 ± 1.7 vs. 8.9 ± 1.4 m/sec; p = 0.002). This latter difference remained statistically significant, even after correction by ANCOVA for 24-h systolic BP, gender, age, glycaemia and HDL cholesterol (p = 0.01). Univariate regression analysis disclosed a tight correlation between AER e carotid-femoral PWV (r = 0.42; p = 0.0003). This association was confirmed in a multiple regression model (β= 0.35; p = 0.009) in which, as independent variables, besides PWV, were added: 24-h blood pressures, age, serum glucose values, smoking status, gender and body mass index. Our results seem to confirm that microalbuminuria may represent the early renal manifestation of a widespread vascular dysfunction, and therefore it may be considered as an integrated marker of cardiovascular risk. Am J Hypertens (2004) 17, 133A–133A; doi: 10.1016/j.amjhyper.2004.03.353

Many interventional trials demonstrated a greater efficacy of certain classes of drugs in treating target organ damage in essential hypertension and diabetic nephropathy. In order to evaluate if blood pressure control alone, inedependently of pharmacologic classes, influences endothelial activation positively, we studied 234 consecutive hypertensive outpatients coming to our clinic for the first time. All subjects underwent OGTT, renal function analysis,oral glucose tolerance test (OGTT), soluble forms of plasma ICAM-1, VCAM-1 and E-Selectin(E-Sel), plasma von Willabrand factor (vWf), and the assay of 24h microalbuminuria (MAU). We further studied 40 healthy normotensives.Out of the 234 subjects, 80 were untreated- and 92 were treated- (2–3 drugs) essential hypertensives (EH), whereas 62 were on antihypertensive therapy and resulted diabetics after OGTT. E-Selectin correlated significantly (p<0.001) with MAU in all groups of patients. Diabetic disease seems to induce a further endothelial acitvation when associated with hypertension. Antihypertensive therapy, when not selected to prevent organ damage, does not seem to influence endothelial activation in non-diabetic EH. Nonetheles, it is to consider a probably longer duration of hypertensive disease in treated patients than in untreated. (See Table) Results p < 0.01, p < 0.001 treated vs Diabetic hypertyensives. Results p < 0.01, p < 0.001 treated vs Diabetic hypertyensives.

BACKGROUND:Arterial hypertension and endothelial dysfunction have a role in the development of athero-sclerosis. This study assessed autocrine-paracrine endothelial function in patients with hypertension associated with renal failure.METHODS:Angiotensin II (Ang II), endothelin-1 ( ET-1), basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), soluble forms of adhesion molecules (ICAM-1, VCAM-1), E-selectin, von Willebrand factor (vWf) and nitric oxide (NO) were measured in 26 patients with hypertension and chronic renal failure (CRF), in 19 essential hypertensives (EH) and in 28 normotensive healthy subjects.RESULTS:Plasma concentrations of Ang-II, ET-1, ICAM-1, VCAM-1, E-selectin, bFGF and TGF-beta all were significantly higher in patients than in healthy subjects and EH. Furthermore, in CRF, serum creatinine correlated negatively with NO plasma levels (r = - 0.51; p < 0.0) and this relationship held true after adjusting the data for potential confounders. Plasma NO was inversely related with ET-1 and bFGF (P < 0.01).CONCLUSION:Hypertension in CRF is characterized by biochemical evidence of marked endothelial dysfunction, apparently more pronounced than in patients with EH. Amplified endothelial activation in CRF probably contributes to the high rate of atherosclerotic complications in CRF.