Raffaella Riccobene

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.

The Association of Microalbuminuria With Aortic Stiffness Is Independent of C-Reactive Protein in Essential Hypertension

BACKGROUND It has not been fully elucidated whether microalbuminuria (MAU) and high-sensitivity C-reactive protein (hsCRP) are associated with aortic distensibility independently of each other. Our study was aimed to evaluate the independent relationships of urinary albumin excretion rate (AER) and hsCRP with aortic stiffness in hypertensive patients. METHODS We enrolled 140 untreated nondiabetic essential hypertensives (mean age: 48 +/- 12 years). In all subjects, 24-hour AER and plasma levels of hsCRP were determined by immunoenzymatic assay. MAU was defined as an AER of 20-200 microg/min. Aortic stiffness was assessed by measurement of carotid-femoral pulse wave velocity (PWV). RESULTS Carotid-femoral PWV, adjusted for age and mean arterial pressure (MAP), was higher in subjects with MAU (n = 41) than in those without it (n = 99) (11.6 +/- 2.3 vs. 9.9 +/- 1.8 m/s; P < 0.001) and in subjects with hsCRP above the median value when compared to those with lower levels of hsCRP (10.8 +/- 2.1 vs. 10 +/- 2.1 m/s; P = 0.026). In multiple regression analysis, AER and hsCPR remained independent predictors of aortic stiffness (beta = 0.24; P < 0.001 and beta = 0.15; P = 0.03, respectively). CONCLUSIONS Our results suggest that in patients with essential hypertension, MAU and CRP are independently associated with an increased aortic stiffness.

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.

Influence of Vascular Load on Plasma Endothelin-1, Cytokines and Catecholamine Levels in Essential Hypertensives

In vitro studies demonstrated a relationship between ET-1 and basic Fibroblast Growth Factor (bFGF), and of bFGF with Platelet Derived Growth Factor (PDGF). The present study was carried out to investigate in vivo the behaviour after vascular stress of circulating ET-1, bFGF and PDGF, and catecholamines, and their relationship. In 12 healthy normotensives (NTs) and 15 essential hypertensives (Ehs) venous blood samples to determine circulating ET-1, bFGF and PDGF, and catecholamine (EPI and NE) levels were drawn before and at the third minute of a handgrip test. Blood pressures (BP) and heart rate were automatically recorded before starting, and at 1, 2, and 3 minutes during the test. The NTs showed, in basal condition, lower values than the EHs of all the examined parameters; later, the handgrip test induced significant increases in circulating levels of ET-1, bFGF and catecholamine. In the EHs at the third minute of the exercise significant increases in plasma ET-1 (p < 0.002), bFGF (p < 0.006), and EPI and NE (p < 0.0005) levels were observed. Systolic and diastolic BP significantly increased after handgrip test in NTs and EHs. Plasma ET-1 correlated with bFGF both before (p < 0.01) and at the acme (p < 0.05) of the isometric exercise. Our results show that in EHs plasma ET-1 and bFGF correlate each other, indicating that in human hypertension a linkage between ET-1 and bFGF exists.

FLOW MEDIATED DILATION, ENDOTHELIAL AND INFLAMMATORY BIOMARKERS IN HYPERTENSIVES WITH CHRONICH KIDNEY DISEASE: PP.6.227

Objectives: Hypertension is characterized by a synergy between oxidative stress, inflammation and endothelial dysfunction. Endothelial dysfunction plays an important role in the patho-physiology of high blood pressure, of atherosclerosis and cardiovascular diseases. In the last decade, a technique for non-invasive assessment of flow mediated vasodilation (FMD) of the brachial artery, an endothelium dependent function, which assesses endothelial function in vivo was developed. The purpose of our study was to analyze the relationship between endothelial dysfunction, assessed by FMD, and biomarkers of endothelial dysfunction (ET-1, ICAM-1, VCAM-1), and inflammation (TNF-α) in patients with hypertension having chronic renal failure (CRF). Methods: Have been enrolled 50 subjects with hypertension (HT), with various degrees of kidney function (CRF II-IV), and 50 healthy control subjects. In all subjects plasma concentrations of ET-1, ICAM-1, VCAM-1, E-SEL and TNF-á were determined. In hypertensive subjects the analysis of endothelial function was carried out by FMD. Results: Overall, the results showed in HT plasma levels of ET-1, ICAM-1, VCAM-1, E-SEL and TNF-α significantly higher (p < 0.001) than in control subjects. The average value of FMD% as assessed in the group of hypertensive subjects was of 4.57 ± 1.08. The linear correlation analysis showed in hypertensive subjects, negative correlations and statistically significant of FMD% with ET-1, ICAM-1, VCAM-1, E-SEL, and TNF-α (p < 0.05 respectively). The analysis of correlation between FMD% and glomerular filtrate rate, as estimated by the MDRD study equation at 4 variables, was not statistically significant. Conclusions: Our study confirms, in hypertensive patients with different degrees of renal function, the presence of endothelial activation characterized by increased serum concentrations of adhesion molecules and markers of inflammation. These results are associated with reduced endothelium-dependent vasodilatation, regardless of the degree of renal function.

The Relationship between an Oxidative Stress Biomarker and Plasma Haemoglobin in Patients with Chronic Kidney Disease

AbstractIntroduction: Evidence suggests that decreased haemoglobin plasma concentration may be a predictor of adverse cardiovascular events in patients with chronic kidney disease (CKD). We hypothesized that in CKD patients, oxidative stress could influence the development of cardiovascular damage via a relationship with haemoglobin levels. Methods: We assayed plasma levels of the biomarker of oxidative stress 8-ISO-prostaglandin F2α (8-ISO-PGF2α) and of haemoglobin in 193 stage 2–5 CKD patients, investigating their relationship. Eighty healthy subjects and 80 patients with primary hypertension having normal renal function were enrolled as controls. Results: The CKD group was divided according to 8-ISO-PGF2α quartiles, and decreasing levels of both haemoglobin and estimated glomerular filtration rate (eGFR) along with increasing quartiles were observed. In the 193 CKD patients, the linear analysis of correlation showed inverse correlations of 8-ISO-PGF2α with both haemoglobin and eGFR (r = −0.47; r = −0.81; p < 0.00001, respectively). In the control groups, no correlation between haemoglobin and 8-ISO-PGF2α was found. The multiple regression analysis carried out in CKD patients, by a model with 8-ISO-PGF2α as the dependent variable, and including haemoglobin and all confounding factors, confirmed the inverse relationship between haemoglobin and 8-ISO-PGF2α (β = −0.50; p < 0.00001). In this model, only when eGFR was added did the relationship between haemoglobin and 8-ISO-PGF2α lose statistical significance. In this final multivariate model, 8-ISO-PGF2α correlated independently with eGFR (β = −0.82; p < 0.0001). Conclusions: In CKD, haemoglobin plasma level is inversely related to oxidative stress, depending on GFR. It remains to be elucidated whether or not the biochemistry of nitric oxide and haemoglobin interaction has a role in causing this relationship.

Parathyroid hormone is inversely related to endothelin-1 in patients on haemodialysis

Aim:  Parathyroid hormone secretion is mainly influenced by hypocalcaemia, hyperphosphataemia and vitamin D deficiency. However, previous in vitro and in vivo studies showed that endothelin‐1 can influence parathyroid hormone secretion. This study was aimed at evaluating this relationship in vivo in uraemic patients.