Anna Vadalà

Relationship between albumin excretion rate and aortic stiffness in untreated essential hypertensive patients.

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.

Endothelin-1 and F2-isoprostane relate to and predict renal dysfunction in hypertensive patients

BACKGROUND 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 as 8-ISO-prostaglandin F2alpha (8-ISO-PGF2alpha), should raise paralleling decreasing renal function and should correlate with estimated glomerular filtration rate (eGFR). METHODS In 626 HT with renal function ranging from stages 1 to 5 and 100 healthy controls, plasma levels of 8-ISO-PGF2alpha, high-sensitivity C-reactive protein (CRP), transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1) were measured. GFR was estimated by the Modification of Diet in Renal Disease study equation. RESULTS When HT were stratified according to renal function stages, 8-ISO-PGF2alpha, CRP, TGF-beta and ET-1 increased progressively and significantly with decreasing eGFR. The multiple regression analysis, considering eGFR as a dependent variable, showed that 8-ISO-PGF2alpha (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 with eGFR. All biomarkers were good predictors of eGFR <60 ml/min/1.73 m(2) [receiver-operator-curve (ROC) areas]. ET-1 was shown to be the best predictor with a ROC area = 0.938; with a threshold of 4 pg/ml, 91% sensitivity and 85% specificity were observed, whereas 8-ISO had a ROC area = 0.931, and for a threshold of 329 pg/ml, sensitivity and specificity were 89%, respectively. In contrast, 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 correlation of both oxidative stress and ET-1 with renal function stages in HT. ET-1 and 8-isoprostane are predictive of eGFR.

Association between biomarkers of inflammation and left ventricular hypertrophy in moderate chronic kidney disease

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.

Changes of Plasma Endothelin and Growth Factor Levels, and of Left Ventricular Mass, After Chronic AT1-Receptor Blockade in Human Hypertension

The stimulation of autocrine and paracrine factors such as basic fibroblast- (bFGF) and platelet-derived (PDGF) growth factors mediates many of the growth-promoting actions of angiotensin II. The aim of this study was to evaluate the effect of chronic AT1-receptor blockade on plasma endothelin-1 (ET-1) and growth factors levels, and on left ventricular mass, in essential hypertension (EH). The study population consisted of 16 patients with mild-moderate EH, and 25 normotensive controls. In the EH patients under basal conditions, and after 3 and 6 months of chronic therapy with Losartan 50 mg/day, we measured serum levels of ET-1, bFGF and PDGF, and tumor necrosis factor (TNF). At the same time, all patients underwent 24-h ambulatory blood pressure monitoring and an echocardiographic evaluation to measure the thickness of the posterior wall (PWT) of the left ventricle and of the interventricular septum (IVS). The healthy controls underwent the same analyses, under basal conditions, at baseline and after 3 and 6 months of observation. In the EH patients, after 3 months of AT1-receptor blockade bFGF was reduced from 13.6 +/- 0.7 to 10.9 +/- 0.7 pg/mL (P < .004), and both TNF and PDGF were significantly decreased (P < .006 and P < .007, respectively). After 6 months of therapy, ET-1 was significantly diminished in comparison with baseline (6.9 +/- 0.8 v 5.5 +/- 0.1 fmol/mL; P < .05), and the reduction in the levels of growth factors were even more significant than at 3 months of treatment. Both PWT and IVS were significantly changed after 6 months of therapy with losartan after basal evaluation (P < .05, respectively). Systolic and diastolic 24-h blood pressures declined significantly after 3 and 6 months of therapy with losartan (P < .01, respectively). It seems likely that the inhibition of the action of angiotensin II by the specific AT1-receptor blockade, by reducing circulating levels of ET-1 and those of some growth factors, may offer an advantage regarding the effect on hypertensive cardiovascular changes in human hypertension.

Microalbuminuria and early endothelial activation in essential hypertension

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.

Sympathetic Overactivity and 24-Hour Blood Pressure Pattern in Hypertensives with Chronic Renal Failure

In order to assess the activity of the sympathetic system and to evaluate the 24-h blood pressure pattern in hypertensives with chronic renal failure (CRF), 12 CRF patients and 16 essential hypertensives (EHs) were studied. In all subjects, plasma samples for catecholamines and renin activity were obtained both in the basal condition and after standing, and 24-h blood pressure monitoring (ABPM) was performed. The 24-h mean blood pressure results were quite similar between CRFs and EHs. In 50% of the CRFs, ABPM showed a nighttime decrease in diastolic BP (DBP) greater than 10%, while in the remaining 50% the ABPM indicated a nondipper blood pressure pattern. Of the 16 EHs, 4 had a nighttime decrease in DBP < 10%, that is, nondippers. The study of circulating catecholamines showed no significant differences in plasma epinephrine between CRFs and EHs, while plasma norepinephrine (NE) was significantly higher in hypertensives with CRF than in EHs, both at rest and after standing (p < 0.05 and 0.02, respectively). Among dipper hypertensives, subjects with CRF showed greater values of basal plasma NE than EHs (535 +/- 67 vs. 412 +/- 24.5 pg/mL, p < 0.05); the comparison between dipper and nondipper CRFs showed no differences in circulating NE levels (535 vs. 516 pg/mL). The present study shows that CRFs are characterized by higher values of plasma NE than EHs, and that there are no differences in sympathetic activity between dipper and nondipper hypertensives with CRF.

C-reactive protein and intercellular adhesion molecule-1 are stronger predictors of oxidant stress than blood pressure in established hypertension.

Background Oxidant stress is implicated in the pathogenesis of atherosclerosis in cardiovascular diseases. Our aim was to test oxidative stress, as 8-iso-prostaglandin F2α (8-iso-PGF2α), and its relationship with inflammation markers C-reactive protein (CRP) and tumour necrosis factor-α (TNFα), and endothelial activation assayed as soluble intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in essential hypertension. Methods In 216 essential hypertensive patients and 55 healthy control individuals, plasma levels of high-sensitivity CRP and TNFα, 8-iso-PGF2α, ICAM-1 and VCAM-1 were measured in basal conditions. Moreover, basal and 24-h ambulatory blood pressure monitoring measurements were obtained. Results Essential hypertensive patients showed higher levels of 8-iso-PGF2α (P < 0.0001), high-sensitivity CRP, TNFα, ICAM-1 and VCAM-1 (P < 0.001, respectively) than control individuals. In control individuals, 8-iso-PGF2α correlated only with high-sensitivity CRP (P < 0.001). In essential hypertensive patients, 8-iso-PGF2α correlated with high-sensitivity CRP (P < 0.000001), TNFα (P < 0.0001), ICAM-1 (P < 0.000001), VCAM-1 (P < 0.0001) and blood pressure. The multiple regression analysis considering 8-iso-PGF2α as the dependent variable showed that in essential hypertensive patients the independent predictors of 8-iso-PGF2α were ICAM-1, high-sensitivity CRP (P < 0.00001, respectively), and TNFα (P = 0.028). Conclusion Our findings demonstrate that oxidant stress is increased in essential hypertension, and relates to inflammation and endothelial activation. Factors other than blood pressure are stronger predictors of oxidant stress.

Inflammation and endothelial activation are linked to renal function in long‐term kidney transplantation

The aim of this study was to investigate the relationships between inflammation and adhesion molecules in long‐term kidney transplantation. We measured serum concentrations of tumor necrosis factor‐alpha (TNFα) and intercellular and vascular cell adhesion molecules (ICAM‐1 and VCAM‐1) in 35 renal transplant recipients (mean age of transplantation 5 ± 3 years) and in 35 chronic renal insufficiency (CRI) patients; twenty‐six healthy subjects were enrolled as controls. Transplanted showed higher values than controls of TNFα (P < 0.0001), ICAM‐1 (P < 0.0001), and VCAM‐1 (P < 0.0001). CRI group as well exhibited higher concentrations than controls of TNFα (P < 0.0001), ICAM‐1 (P < 0.0001), and VCAM‐1 (P < 0.0001). Transplanted and CRI patients had similar blood pressure and renal function levels, and TNFα, ICAM‐1, and VCAM‐1 were not significantly different in the two groups. In transplanted group ICAM‐1, VCAM‐1, and TNFα correlated negatively and independently with glomerular filtration rate (GFR) –P < 0.00001 for all. TNFα as well correlated with ICAM‐1 and VCAM‐1 (P < 0.001, respectively). In CRI group, TNFα correlated with serum creatinine, ICAM‐1, and VCAM‐1 (P = 0.01 for all). In conclusion, in long‐term renal transplantation, the level of kidney function and both inflammation and endothelial activation are closely related. In fact, the multiple regression analysis demonstrated that the level of kidney insufficiency and the levels of the studied molecules were independently associated.

Comparison of tumour necrosis factor and endothelin-1 between essential and renal hypertensive patients

The present study was performed to compare circulating levels of tumour necrosis factor-α (TNFα) and plasma endothelin 1 (ET-1), of hypertensive patients with or without renal failure and with those of normotensive healthy subjects. The study population consisted of 21 healthy normotensive subjects and 22 hypertensive patients, 11 with essential hypertension, and 11 with hypertension and chronic renal failure (CRF). Plasma ET-1 levels, serum TNFα and creatinine, creatinine clearance, 24-h urinary albumin excretion (UAE) were assayed, and 24-h blood pressure monitoring was obtained in all subjects. Office blood pressure was similar between hypertensive patients with and without CRF. However, 24-h blood pressure was greater in patients with CRF than in those with essential hypertension and normal renal function. Patients with hypertension manifested greater ET-1 levels than normotensive subjects (P < 0.01). serum tnfα and et-1 levels were higher in hypertensive patients with crf than in patients with essential hypertension and normotensive subjects. in the 22 hypertensive patients, tnfα levels were negatively correlated with serum creatinine (r = 0.60; P < 0.01), and et-1 levels were positively correlated with uae (r = 0.47, P < 0.05). the present study has shown that hypertensive patients, and particularly those with renal insufficiency, manifest abnormal blood levels of et-1 and tnfα. these factors could contribute to both cardiovascular and renal damage.

Endothelium-derived factors in microalbuminuric and nonmicroalbuminuric essential hypertensives

Previous evidence has demonstrated a relationship between growth factors and cardiovascular diseases. This study was aimed at evaluating levels of some endothelium-derived growth factors, and their relationship with microalbuminuria (MAU), in essential hypertension. Ninety-nine mild-moderate essential hypertensives (EH) and 25 healthy controls were studied. All patients underwent 24-h blood pressure monitoring, serum endothelin-1 (ET-1), basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF), and 24-h MAU assays. Later, EH were divided into two subsets consisting of microalbuminurics (MAU >11 microg/min) and nonmicroalbuminurics (MAU <11 microg/min). In microalbuminuric EH, circulating ET-1, bFGF, and PDGF were significantly higher than in nonmicroalbuminurics (P < .0001, P < .0001, P < .005, respectively) or in controls. In the group of 99 EH, significant positive correlations of MAU with both ET-1 and bFGF (r = 0.35, P < .001, and r = 0.34, P < .001, respectively) were found. ET-1 and bFGF correlated significantly (r = 0.31, P < .002). Circulating bFGF also correlated significantly with MAU in the microalbuminuric EH subset (r = 0.49, P < .01). Our results show that in microalbuminuric EH circulating levels of certain growth factors are increased. In human essential hypertension these factors are linked with MAU, an early cardiovascular and renal damage marker.