Subclinical atherosclerosis and fetuin-A plasma levels in essential hypertensive patients.

The intima-media thickness (IMT) is considered as a surrogate marker for atherosclerotic disease. The aim of this study was to analyze the relationship of carotid IMT with fetuin-A in patients with essential hypertension (EH) and normal renal function. The plasma levels of fetuin-A, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and the biomarker of oxidative stress 8-iso-PGF2alpha were assayed in samples from 105 untreated EH patients. Carotid IMT measurements were also performed. EH was studied overall and after dividing in EH with IMT ≥ and <0.9 mm. All of the biomarkers were significantly different between the two subgroups, in particular, the fetuin-A level was lower in the patients with an IMT ≥0.9 mm. In the overall group, the linear analysis of correlation demonstrated that the IMT was significantly inversely correlated with the fetuin-A level (r=-0.40, P<0.0001) and directly with TNF-α (r=0.39, P<0.0001), IL-6 (r=0.38, P<0.0001) and 8-iso-PGF2alpha (r=0.356, P<0.0003). The multiple regression analysis performed that assigned IMT as a dependent variable showed that fetuin-A (ß=-0.268, P<0.0001) was independently correlated with the IMT. Receiver-operator curves demonstrated that fetuin-A levels have a predictive power of IMT>0.9 mm (AUC (area under the curve) 0.738, P<0.0001). Our results suggest that in EH, fetuin-A is associated with the IMT independently of oxidative stress and renal function, thus predicting increases in the IMT.

Left ventricular mass in hypertensive patients with mild-to-moderate reduction of renal function.

AIM: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular (CV) morbidity and mortality. The aim of the present study was to evaluate the relationship between LV mass and mild-to-moderate renal dysfunction in a group of non-diabetic hypertensives, free of CV diseases, participating in the Renal Dysfunction in Hypertension (REDHY) study. METHODS: Patients with diabetes, a body mass index (BMI) of more than 35 kg/m(2), secondary hypertension, CV diseases and a glomerular filtration rate (GFR) of less than 30 mL/min per 1.73 m(2) were excluded. The final sample included 455 patients, who underwent echocardiographic examination and ambulatory blood pressure monitoring. RESULTS: There was a significant trend for a stepwise increase in LV mass, indexed by both body surface area (LVMI) and height elevated to 2.7 (LVMH(2.7)), with the declining renal function, that remained statistically significant after correction for potential confounders. The prevalence of LVH, defined either as LVMI of 125 g/m(2) or more or as LVMH(2.7) of 51 g/m(2.7) or more, was higher in subjects with lower values of GFR than in those with normal renal function (P < 0.001 in both cases). The multiple regression analysis confirmed that the inverse association between GFR and LVM was independent of confounding factors. CONCLUSION: The present study confirms the high prevalence of LVH in patients with mild or moderate renal dysfunction. In the patients studied (all with a GFR of 30 mL/min per 1.73 m(2)), the association between LVM and GFR was independent of potential confounders, including 24 h blood pressure load. Taking into account the negative prognostic impact of LVH, further studies focusing on a deeper comprehension of the mechanisms underlying the development of LVH in chronic kidney disease patients are needed.

Relationship of fetuin-A with glomerular filtration rate and endothelial dysfunction in moderate-severe chronic kidney disease.

BACKGROUND: In end-stage renal disease, fetuin-A has been demonstrated to be reduced and inversely related to cardiovascular mortality. This study had 2 distinct aims. The first was to verify if circulating concentration of fetuin-A may depend on renal function in patients with chronic kidney disease (CKD). Furthermore, we analyzed the correlation of fetuin-A with the biomarker of endothelial dysfunction endothelin-1 (ET-1), and with the inflammatory cytokine interleukin-6 (IL-6). METHODS: In 108 subjects with stage 3-5 CKD, plasma levels of fetuin-A, ET-1 and IL-6 were assayed. Patients were studied first as a whole group and then were divided according to stages of CKD and fetuin-A tertiles. RESULTS: Fetuin-A concentration decreased in parallel with the increase in ET-1 and IL-6 levels as renal function declined. Multiple regression analysis showed that fetuin-A was independently associated with estimated glomerular filtration rate (beta=0.386; p<0.001), IL-6 (beta=-0.393; p=0.001) and ET-1 (beta=-0.219; p=0.02), in a multivariate model including also sex, parathyroid hormone and the calcium x phosphorus product. CONCLUSIONS: These results seem to indicate that in CKD, even when not severe, inflammatory processes are increased and linked to endothelial dysfunction, worsening progressively with the decline of renal function.

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.

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. METHODS: Parathyroid hormone and endothelin-1 plasma concentrations were measured in 67 haemodialysed patients. Patients with history of cardiovascular diseases and those with parathyroid adenoma were excluded. RESULTS: Plasma levels of endothelin-1 were found to be inversely related to those of parathyroid hormone (P < 0.04) The multiple regression analysis, carried out considering parathyroid hormone as a dependent variable, and including age, sex, blood pressure, calcium x phosphorus product, and endothelin-1, demonstrated that the independent correlates of parathyroid hormone were endothelin-1 (beta = -0.276; P = 0.015), and calcium x phosphorus product (beta = 0.417; P < 0.0001). CONCLUSION: For the first time in vivo, we demonstrated an inverse independent relationship between endothelin-1 and parathyroid hormone in haemodialysed patients. Because both endothelin-1 and parathyroid hormone are endowed with well-known harmful actions on cardiovascular apparatus, whether such inverse relation may really influence the natural history of cardiovascular damage due to secondary hyperparathyroidism remains to be elucidated.

Oxidative stress, inflammation and cardiovascular disease in chronic renal failure.

Traditional risk factors such as hypertension, diabetes, dyslipidemia, obesity and metabolic syndrome, as well as additional nontraditional risk factors, can damage the kidney directly and by promoting intrarenal atherogenesis. Evidence indicates that increased oxidative stress and inflammation may mediate most of the effects of risk factors on the kidney. Clinical studies have demonstrated a relationship between oxidative stress and inflammatory biomarkers, and a few studies indicate an inverse correlation of oxidative stress biomarkers with estimated glomerular filtration rate (eGFR). Further, surrogate indexes of atherosclerosis such as intima-media thickness and aortic pulse wave velocity have been demonstrated to be related to plasma concentrations of markers of endothelial activation, inflammation and fibrosis in patients with different stages of chronic kidney disease (CKD). Moreover, plasma concentrations of high-sensitivity C-reactive protein have been shown to be increased and related to left ventricular mass in CKD individuals having left ventricular hypertrophy. In contrast, in these patients, decreases in fetuin-A plasma levels have been reported. Considering the complex background of the pathophysiological changes characterizing CKD patients, we can consider cardiovascular disease a multifactorial complication of CKD.

Relationship of transforming growth factor-beta(1) with tumour necrosis factor-alpha and endothelial activation in patients with stable renal transplantation.

AIM: To evaluate whether or not transforming growth factor-beta(1) is related to inflammation markers and to intercellular and vascular cell adhesion molecules in patients with stable renal transplantation. METHODS: Serum concentrations of transforming growth factor-beta(1), tumour necrosis factor-alpha, C-reactive protein and adhesion molecules were analysed in 33 renal transplanted patients, 33 patients with chronic renal insufficiency (matched to the transplanted group for level of renal function), and 33 hypertensives with normal renal function. anova, Student's t-test and simple regression analysis were used to analyse the data. RESULTS: Transplanted patients showed higher values than hypertensives of transforming growth factor-beta(1), tumour necrosis factor-alpha, C-reactive protein and adhesion molecules (P < 0.0001 for all). Renal insufficiency group exhibited higher concentrations of transforming growth factor-beta(1), tumour necrosis factor-alpha, C-reactive protein and adhesion molecules than hypertensives (P < 0.0001 for all). Transplanted and renal insufficiency patients had similar blood pressure and renal function levels, and transforming growth factor-beta(1), tumour necrosis factor-alpha, C-reactive protein and adhesion molecules were not significantly different. In transplanted and in renal insufficiency groups transforming growth factor-beta(1), adhesion molecules and tumour necrosis factor-alpha correlated significantly each other and with glomerular filtration rate (P < 0.001 for all). CONCLUSION: In long-term renal transplantation inflammation and endothelial activation biomarkers, the pro-fibrotic cytokine transforming growth factor-beta(1) and kidney function are interrelated. Because of the relevant role that inflammation, organ fibrosis and graft dysfunction may play against renal and cardiovascular survival of graft recipients, a better comprehension of the interactions between these variables is needed.

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 F2alpha (8-iso-PGF2alpha), and its relationship with inflammation markers C-reactive protein (CRP) and tumour necrosis factor-alpha (TNFalpha), 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 TNFalpha, 8-iso-PGF2alpha, 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-PGF2alpha (P < 0.0001), high-sensitivity CRP, TNFalpha, ICAM-1 and VCAM-1 (P < 0.001, respectively) than control individuals. In control individuals, 8-iso-PGF2alpha correlated only with high-sensitivity CRP (P < 0.001). In essential hypertensive patients, 8-iso-PGF2alpha correlated with high-sensitivity CRP (P < 0.000001), TNFalpha (P < 0.0001), ICAM-1 (P < 0.000001), VCAM-1 (P < 0.0001) and blood pressure. The multiple regression analysis considering 8-iso-PGF2alpha as the dependent variable showed that in essential hypertensive patients the independent predictors of 8-iso-PGF2alpha were ICAM-1, high-sensitivity CRP (P < 0.00001, respectively), and TNFalpha (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 (TNFalpha) 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 TNFalpha (P < 0.0001), ICAM-1 (P < 0.0001), and VCAM-1 (P < 0.0001). CRI group as well exhibited higher concentrations than controls of TNFalpha (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 TNFalpha, ICAM-1, and VCAM-1 were not significantly different in the two groups. In transplanted group ICAM-1, VCAM-1, and TNFalpha correlated negatively and independently with glomerular filtration rate (GFR) -P < 0.00001 for all. TNFalpha as well correlated with ICAM-1 and VCAM-1 (P < 0.001, respectively). In CRI group, TNFalpha 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.

Relation of C-reactive protein to oxidative stress and to endothelial activation in essential hypertension.

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(2alpha) (8-iso-PGF(2alpha)), 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(2alpha), ICAM-1 and VCAM-1, and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Subjects with EH had higher levels of 8-iso-PGF(2alpha) (P < .0001), CRP (P < .001), ICAM-1 and VCAM-1 (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(2alpha) (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(2alpha) (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.