Do genetically determined very high and very low LDL levels contribute to Lp(a) plasma concentration?

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for atherosclerotic cardiovascular disease (ASCVD). Few data are available on the distribution of Lp(a) levels among subjects at different cardiovascular risk and in subjects with monogenic and polygenic dyslipidemias (familial hypercholesterolemia, FH and familial hypobetalipoproteinemia type 1, FHBL1). The aim of this study was to investigate the distribution of Lp(a) plasma levels in subjects with high and low LDL-C levels (FH and FHBL1) and in the general population. METHODS AND RESULTS: The study cohorts included 356 hypercholesterolemic patients, 212 carrying a FH causative mutation, 144 with clinical FH (mutation negative - FHneg), 52 FHBL1 and 797 free-living subjects. Lp(a) levels were significantly higher in FH subjects (both FH and FHneg) (median 12.46 mg/dl and 14.0 mg/dl, respectively) compared with FHBL1 and free-living subjects (7.68 mg/dl and 7.18 mg/dl, respectively). More, Lp(a) levels were similar in FH subjects carrying LDLR defective and null mutations and FHneg. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels (median 10.68 mg/dl and 9.20 mg/dl, respectively) compared with low and moderate CV risk (median 5.72 mg/dl and 7.80 mg/dl, respectively) (p < 0.0008). CONCLUSIONS: FH subjects exhibit higher Lp(a) levels than FHBL1 and general population. Lp(a) slightly contribute to hypercholesterolemia in FH patients. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels compared with low and moderate CV risk. Combined evaluation of Lp(a) levels in FH subjects with other traditional risk factors could identify very high-risk individuals who may benefit from early aggressive treatments to avoid premature CV events.

Left ventricular hypertrophy in chronic kidney disease: A diagnostic criteria comparison.

BACKGROUND AND AIMS: CKD patients have a high prevalence of LVH and this leads to an increase of cardiovascular risk. The aim of this study was to assess the prevalence of left ventricular hypertrophy (LVH) and left ventricular geometry in a group of 293 hypertensive patients with stage 2-5 chronic kidney disease (CKD), compared with 289 essential hypertensive patients with normal renal function. METHODS AND RESULTS: All patients underwent echocardiographic examination. Patients on stage 1 CKD, dialysis treatment, or with cardiovascular diseases were excluded. LVH was observed in 62.8% of patients with CKD and in 51.9% of essential hypertensive patients (P < 0.0001). We found increasingly higher left ventricular diameters, thicknesses, and mass from stage 2-5 CKD. Distribution of concentric and eccentric LVH was not very different between the two groups. However, after introducing mixed hypertrophy, the difference between the two groups group was disclosed (P = 0.027). Multiple regression analysis confirmed that the association between renal function and left ventricular mass (ß -0.287; P < 0.0001) was independent by potential confounders. Diastolic function was significantly worse in patients with CKD, especially in more advanced stages. CONCLUSION: Our study confirms that LVH is highly prevalent in patients with CKD, especially by using the most recent cut off; in this population, LVH is often characterized by the simultaneous increase of wall thicknesses and diameters with negative effects on diastolic function.

The Relationship Between Aortic Root Size and Hypertension: An Unsolved Conundrum.

Thoracic aortic aneurysms rupture and dissection are among the most devastating vascular diseases, being characterized by elevated mortality, despite improvements in diagnostic imaging and surgical techniques.An increased aortic root diameter (ARD) represents the main risk factor for thoracic aortic dissection and rupture and for aortic valve regurgitation.Even though arterial hypertension is commonly regarded as a predisposing condition for the development of thoracic aorta aneurysms, the role of blood pressure (BP) as determinant of aortic root enlargement is still controversial. The use of different methods for indexation of ARD may have in part contributed to the heterogeneous findings obtained in the investigations exploring the relationships between ARD and BP. Indeed, the best methods for ARD indexation, as well as the normal values of aortic root size, are still a matter of debate.Several non-hemodynamic factors influence ARD, including age, gender, and anthropometric variables, such as height, weight and their derivatives body surface area (BSA) and body mass index. Of these factors, anthropometric variables have the greatest impact.Several studies documented an association between ARD enlargement, assessed by echocardiography, and some indices of hypertensive target organ damage such as left ventricular hypertrophy, diastolic dysfunction, and carotid intima-media thickening. Recently, we found that ARD, expressed either as absolute values or normalized for BSA (ARD/BSA) or height (ARD/H), was significantly greater in hypertensive subjects with chronic kidney disease (CKD) when compared to their counterparts with normal renal function. Moreover, at univariate analyses estimated glomerular filtration rate (eGFR) showed significant inverse correlations with ARD not indexed and with ARD/BSA and ARD/H. Taking into account the effect of age, sex, duration of hypertension and other potentially confounding factors, in multiple regression analyses, only the association of GFR with ARD/H and that between GFR and ARD/BSA remained statistically significant. The receiver-operating characteristic curve analysis revealed that an estimated GFR of about 50 ml/min/1.73 m2 represents the better threshold to distinguish hypertensive patients with dilated aortic root from those with a normal one.Some population-based studies showed that an enlarged ARD might predict an adverse prognosis, even in absence of aneurysmatic alterations.In the Cardiovascular Health Study, a dilated aortic root was independently associated with an increased risk for stroke, cardiovascular and total mortality in both sexes and with incident congestive heart failure only in men. The relationship between ARD and heart failure has been observed also in the Framingham Heart Study. More recently, the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study demonstrated an independent relationship of ARD/H with incident cardiovascular morbidity and mortality.Although the relationship between BP and aortic root size is still a matter of debate, increasing evidence seems to support the notion that aortic root dilatation, even in absence of aneurysmatic alterations, may be regarded as an hypertensive organ damage paralleling other preclinical markers whose unfavourable prognostic significance is firmly established. Future studies are needed to assess whether or not antihypertensive therapy is able to reduce aortic root dimension and the increased risk associated with its enlargement.

Fecal calprotectin levels in patients with non-celiac wheat sensitivity: a proof of concept.

Some data suggest the existence of intestinal inflammation in patients with non-celiac wheat sensitivity (NCWS). We aimed to verify whether fecal calprotectin (FCP), a marker of intestinal inflammation, could be used to confirm this inflammatory status and to test its diagnostic performance in differentiating NCWS from irritable bowel syndrome/functional dyspepsia (IBS/FD). We conducted a multicenter study, comparing NCWS patients, diagnosed by a double-blind placebo-controlled wheat challenge, with IBS/FD subjects. In the retrospective phase, FCP values were analyzed to define the prevalence of its positivity and its role as a NCWS diagnostic biomarker. In the prospective phase we tested the effects of a strict 6-month wheat-free diet (WFD) on FCP values. 31.3% (n = 63/201) of NCWS patients had above normal FCP values (NCWS FCP +), whereas all IBS/FD patients proved negative (P = 0.0001). FCP using a cut-off value > 41 µg/g showed a 58.6% sensitivity and a 98.0% specificity (AUC 0.755, 95% C.I. 0.702-0.837) in distinguishing NCWS from IBS/FD patients. Of the 63 NCWS FCP+, 65.1% had negative FCP values after ≥ 6 months of WFD, with a significant reduction in FCP values (P < 0.0001). All NCWS FCP- subjects still preserved negative FCP values after ≥ 6 months of WFD. Our study showed that FCP can be a useful but supplementary diagnostic marker for differentiating between NCWS and IBS/FD. Strict WFD adherence reduced FCP values, normalizing them in 65.1% of NCWS FCP + subjects. These data suggest the existence of two NCWS subgroups: NCWS FCP + characterized by a probable predominantly inflammatory/immunologic pattern and NCWS FCP- featuring non-immuno-mediated etiopathogenetic mechanisms. (Registration number NCT01762579).

Statin-induced autoimmune myositis: a proposal of an "experience-based" diagnostic algorithm from the analysis of 69 patients.

Statin-induced autoimmune myositis (SIAM) represents a rare clinical entity that can be triggered by prolonged statin treatment. Its pathogenetic substrate consists of an autoimmune-mediated mechanism, evidenced by the detection of antibodies directed against the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR Ab), the target enzyme of statin therapies. To facilitate the diagnosis of nuanced SIAM clinical cases, the present study proposes an "experience-based" diagnostic algorithm for SIAM. We have analyzed the clinical data of 69 patients diagnosed with SIAM. Sixty-seven patients have been collected from the 55 available and complete case records regarding SIAM in the literature; the other 2 patients represent our direct clinical experience and their case records have been detailed. From the analysis of the clinical features of 69 patients, we have constructed the diagnostic algorithm, which starts from the recognition of suggestive symptoms of SIAM. Further steps provide for CK values dosage, musculoskeletal MR, EMG/ENG of upper-lower limbs and, Anti-HMGCR Ab testing and, where possible, the muscle biopsy. A global evaluation of the collected clinical features may suggest a more severe disease in female patients. Atorvastatin proved to be the most used hypolipidemic therapy.

Efficacy and safety of lomitapide in familial chylomicronaemia syndrome.

BACKGROUND AND AIMS: Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder, resulting in elevated triglycerides (TGs), abdominal pain and pancreatitis. Treatment options are limited. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved for the treatment of homozygous familial hypercholesterolaemia. Whether its therapeutic use may be extended to FCS remains unknown. The aim of this study was to evaluate the efficacy and safety of lomitapide in adult patients with FCS. METHODS: The open-label, single-arm 'LOCHNES' study of lomitapide in FCS enrolled patients >18 years with genetically confirmed FCS, elevated fasting TG ≥ 750 mg/dL and history of pancreatitis. Patients were administered lomitapide to the maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26. RESULTS: Eighteen patients were enrolled with median baseline TG levels 1803.5 mg/dL (97.5% CI, 1452-2391 mg/dL). At Week 26, median fasting TGs were reduced to 305 mg/dL (97.5% CI 219-801 mg/dL; 70.5% reduction); median lomitapide dose was 35 mg/day; 13 patients achieved TGs ≤750 mg/dL. Adverse events were mild to moderate and mainly related to gastrointestinal tolerability. Liver imaging at baseline and Week 26 revealed hepatic fat increases from median 12.0%-32.5%, while median hepatic stiffness remained normal. No patient experienced acute pancreatitis or severe abdominal pain during lomitapide treatment. CONCLUSIONS: Lomitapide is effective and well tolerated in reducing TGs in FCS patients with a history of pancreatitis. Larger studies are warranted to determine lomitapide effectiveness in FCS.

Hyperalphalipoproteinemia and Beyond: The Role of HDL in Cardiovascular Diseases.

Hyperalphalipoproteinemia (HALP) is a lipid disorder characterized by elevated plasma high-density lipoprotein cholesterol (HDL-C) levels above the 90th percentile of the distribution of HDL-C values in the general population. Secondary non-genetic factors such as drugs, pregnancy, alcohol intake, and liver diseases might induce HDL increases. Primary forms of HALP are caused by mutations in the genes coding for cholesteryl ester transfer protein (CETP), hepatic lipase (HL), apolipoprotein C-III (apo C-III), scavenger receptor class B type I (SR-BI) and endothelial lipase (EL). However, in the last decades, genome-wide association studies (GWAS) have also suggested a polygenic inheritance of hyperalphalipoproteinemia. Epidemiological studies have suggested that HDL-C is inversely correlated with cardiovascular (CV) risk, but recent Mendelian randomization data have shown a lack of atheroprotective causal effects of HDL-C. This review will focus on primary forms of HALP, the role of polygenic inheritance on HDL-C, associated risk for cardiovascular diseases and possible treatment options.

Lipoprotein Abnormalities in Chronic Kidney Disease and Renal Transplantation.

Chronic kidney disease (CKD) is one of the most important risk factors for cardiovascular disease (CVD). Despite the kidney having no direct implications for lipoproteins metabolism, advanced CKD dyslipidemia is usually present in patients with CKD, and the frequent lipid and lipoprotein alterations occurring in these patients play a role of primary importance in the development of CVD. Although hypertriglyceridemia is the main disorder, a number of lipoprotein abnormalities occur in these patients. Different enzymes pathways and proteins involved in lipoprotein metabolism are impaired in CKD. In addition, treatment of uremia may modify the expression of lipoprotein pattern as well as determine acute changes. In renal transplantation recipients, the main lipid alteration is hypercholesterolemia, while hypertriglyceridemia is less pronounced. In this review we have analyzed lipid and lipoprotein disturbances in CKD and also their relationship with progression of renal disease. Hypolipidemic treatments may also change the natural history of CVD in CKD patients and may represent important strategies in the management of CKD patients.

Resistive index of ophthalmic artery as an imaging biomarker of hypertension-related vascular and kidney damage.

Aim: Resistive index of ophthalmic artery (RI-OA) is associated with atherosclerotic diseases. The aim of this study was to evaluate the association of RI-OA and hypertension-related vascular and kidney damage. Materials and methods: Two-hundred and eighty hypertensive patients underwent evaluation of RI-OA, carotid atherosclerosis and level of 24 h albuminuria. Results: Albuminuria and carotid atherosclerosis were positively associated with RI-OA independently of other cardiovascular risk factors. Receiver-operating characteristic curve analysis allowed us to calculate a cut-off value of RI-OA >0.625, which would be suspicious about the existence of atherosclerotic disease. Conclusion: The ophthalmic vascular circulation allows to study connections between macro- and microcirculation in vivo. RI-OA could be a useful marker for a better stratification of the risk of developing kidney and cardiovascular disease.

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.

Choroidal thickness is associated with renal hemodynamics in essential hypertension.

The choroid is the most vascularized structure of the eye and plays a central role in the development of the retinal vascular changes that occur in arterial hypertension. Changes of choroidal thickness (ChT) assessed by optical coherence tomography (OCT) technology could reflect the vascular complications of hypertension. Also, intrarenal hemodynamic damage, associated with endothelial dysfunction, demonstrated to be a good indicator of systemic morphofunctional arterial impairment. The aim of this study is to assess the relationship between ChT and renal hemodynamics in subjects with essential hypertension. Routine laboratory tests, clinical history, and physical examination, including blood pressure assessment, were performed in 90 subjects with essential hypertension. All patients underwent Doppler ultrasonographic evaluation of intra-renal hemodynamics and OCT imaging to assess ChT. When subjects were divided in two groups based on renal resistive index (RRI), group I (RRI ≥ 75% percentile) showed significantly lower values of ChT than group II (RRI < 75% percentile) (P < .001). When divided in two groups based on the ChT median values, patients with lower ChT had significantly higher RRI values than those with ChT above the median values (P < .05). In multivariate model including age, eGFR, and other variables as confounding factors, RRI ≥ 75% was independently associated with ChT. ChT was significantly correlated with renal resistive index in subjects with essential hypertension, confirmed in multivariate analyses. This result could be referred to changes in vascular elastic properties that occur in retinal and intrarenal vascular system probably due to oxidative stress and endothelial dysfunction commonly found in early complications of hypertension.

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.

Is echocardiography mandatory for patients with chronic kidney disease?

This study aims at evaluating the prevalence of left ventricular diastolic dysfunction in a group of 319 hypertensive patients with stage 3b-4-5 chronic kidney disease (according to Kidney Disease Improving Global Outcomes classification), compared with 216 patients with essential hypertension and normal renal function. All patients underwent echocardiographic examination. Patients on stage 1-2-3a chronic kidney disease, dialysis treatment, or with previous manifestations of heart failure or other cardiovascular diseases were excluded. Patients with renal disease had significantly worse diastolic function (both considering trans-mitral flow and tissue Doppler imaging parameters). Diastolic dysfunction is found in 70.5% of the CKD group and in 41.6% of hypertensive patients (p < 0.0001). Multiple regression analysis shows an association between renal function and diastolic function (ß 0.223; p < 0.0001), independent of potential confounders. Our study shows that diastolic dysfunction is highly prevalent in patients with advanced chronic kidney disease; we posit that in this population, the risk of diastolic heart failure is very high. We think that patients with a marked decrease of glomerular filtration rate (GFR) must be considered at high risk for diastolic heart failure and should have an echocardiographic examination performed, even if asymptomatic and in the absence of evident cardiovascular disease.

Renal haemodynamics and coronary atherosclerotic burden are associated in patients with hypertension and mild coronary artery disease.

Intrarenal hemodynamic alterations are independent predictors of cardiovascular events in different populations. It has been hypothesized that there is an association between renal hemodynamics and coronary atherosclerotic burden in patients with hypertension. Therefore, the present study examined the associations between renal hemodynamics, coronary atherosclerotic burden and carotid atherosclerotic disease. A total of 130 patients with hypertension aged between 30-80 years who had been referred for an elective coronary angiography were enrolled in the present study. A duplex ultrasound of the intrarenal vasculature was performed to evaluate the resistive index (RI), pulsatility index (PI) and acceleration time (AT). The carotid intima-media thickness was additionally assessed. A coronary angiography was performed to detect the atherosclerotic burden using the Gensini Score (GS). Based on the GS values, subjects were divided into quintiles (I: ≤9; II: 9-17; III: 17-30; IV: 30-44; and V: GS >44) as well as in subjects with mild (GS ≤30) or severe coronary disease (GS >30). A weak significant difference in PI was identified among quintiles (P=0.041), whereas, RI and AT did not differ significantly. PI was associated with GS in the group with low coronary atherosclerotic burden (GS ≤30; P=0.047), whereas, no association was detected in subjects with GS >30. This association remained following adjustment for age and left ventricular ejection fraction (P=0.025). In conclusion, renal vascular alterations were associated with coronary atherosclerotic burden in patients with hypertension with mild coronary disease.

Plasma aldosterone and its relationships with left ventricular mass in essential hypertensive patients with the metabolic syndrome.

BACKGROUND: The association of aldosterone with the metabolic syndrome (MetS) has not been fully elucidated. The aim of our study was to evaluate the relationships of plasma aldosterone concentration (PAC) with MetS and left ventricular mass (LVM) in nondiabetic Caucasian patients with essential hypertension. METHODS: Measurements were taken with the patients off antihypertensive medications. The measurements included 24-h blood pressure (BP) readings, plasma renin activity (PRA) and aldosterone, and an echocardiogram. RESULTS: Subjects with MetS (n = 201) had higher age-adjusted PAC (10.2 +/- 5.8 vs. 11.6 +/- 5.9 ng/dl; P = 0.01) and greater age-adjusted LVM indexed for height2.7 (LVMH2.7) (56 +/- 19 vs. 62 +/- 20 g/m2; P = 0.001) than those without MetS (n = 249). The difference in respect of PAC between the two groups was independent of PRA and was attributable mainly to obesity. After adjusting for potential confounders, LVMH2.7 was associated with MetS as a whole (beta = 0.11; P = 0.02) and with body mass index (BMI) (beta = 0.19; P < 0.0001) in the overall population. The latter relationship was attenuated (beta = 0.15; P = 0.001) after further adjustment for PAC. In the MetS group the association of LVMH2.7 with PAC held (beta = 0.19; P = 0.007) in multivariate analyses. In subjects without MetS, this relationship had only borderline statistical significance. CONCLUSIONS: Our results suggest that the elevated PAC related to obesity may help to explain the increased LVM observed in association with MetS, and may contribute to enhancing the cardiovascular risk associated with MetS.

Inverse relationship between ambulatory arterial stiffness index and glomerular filtration rate in arterial hypertension.

BACKGROUND: Arterial stiffness and mild-to-moderate renal dysfunction are predictors of cardiovascular (CV) morbidity and mortality. Recently, the ambulatory arterial stiffness index (AASI) has been proposed as a surrogate index of arterial stiffness. It has been associated with an enhanced risk of stroke. The aim of our study was to assess the relationship between AASI and glomerular filtration rate (GFR) in a group of hypertensive patients with no CV complications. METHODS: A total of 143 untreated hypertensive subjects (mean age: 44 +/- 12 years; men 57%), with serum creatinine <1.5 mg/dl, were enrolled. AASI was calculated as one minus the regression slope of diastolic on systolic blood pressure (BP) obtained by individual 24-h BP recordings. GFR was computed from the scintigraphic determination of the technetium-99m diethylenetriaminepentaacetic acid uptake within the kidneys, by the Gates' method. RESULTS: Hypertensive patients with AASI above the median value (n = 71) had lower GFR than those with AASI below the median (n = 72) (98.3 +/- 31 vs. 122.4 +/- 32 ml/min/1.73 m(2); P < 0.001). This difference held even after adjustment for age and gender. The linear regression analysis disclosed a significant inverse correlation between GFR and AASI (r = -0.30; P < 0.001), that was replicated (beta = -0.19; P = 0.02) in a multiple regression model including, as independent variables (besides AASI), age, gender, high-density lipoprotein cholesterol, body mass index, 24-h pulse pressure (PP) and nocturnal reduction in BP. CONCLUSIONS: AASI is inversely related to GFR in arterial hypertension. This may help to explain the increased CV risk associated with mild-to-moderate renal dysfunction.

Hypertension, microalbuminuria and renal dysfunction: the Renal Dysfunction in Hypertension (REDHY) study.

AIMS: We assessed the prevalence of kidney dysfunction evaluated by different methods to estimate glomerular filtration rate (GFR) in a wide group of nondiabetic hypertensive patients, without cardiovascular (CV) complications and without known renal disease, participating in the Renal Dysfunction in Hypertension (REDHY) study. METHODS: A total of 1,856 hypertensive individuals (mean age 47 +/- 14 years; men 53%), free from diabetes mellitus and CV complications, and consecutively attending our outpatient hypertension center, were enrolled. Patients with a body mass index >35 (calculated as kg/m(2)) were excluded. The GFR was estimated by the creatinine clearance rate (CrCl), the simplified Modification of Diet in Renal Disease Study prediction equation (MDRD), the Cockcroft-Gault formula (CG) and the Mayo Clinic quadratic equation (Mayo). A 24-hour urine sample was collected to evaluate CrCl and albumin excretion rate (AER). Albuminuria was defined as an AER greater than 20 microg/min. RESULTS: The prevalence of albuminuria was 23.4% (22.7% microalbuminuria and 0.7% macroalbuminuria). Mild renal dysfunction (defined as 24-hour AER >20 microg/min in presence of eGFR > or =60 ml/min per 1.73 m(2)) was found in a proportion of patients ranging from 20.3% using CrCl, to 18.4% using the MDRD equation. The prevalence of overt renal insufficiency (estimated GFR <60 ml/min per 1.73 m(2)) was higher when CrCl (10.8%) or the MDRD equation (10%) was used to estimate the GFR, instead of the CG (7.4%) or Mayo equation (5.4%) (p<0.0001). CONCLUSIONS: Mild renal dysfunction and overt renal insufficiency are highly prevalent among subjects with nonmalignant arterial hypertension without CV complications. However, the prevalence of moderate-to-severe renal function impairment is strongly influenced by the method used to estimate the GFR.

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.

Para-perirenal distribution of body fat is associated with reduced glomerular filtration rate regardless of other indices of adiposity in hypertensive patients.

Obesity is a well-known risk factor for the development and progression of chronic kidney disease. Recently, para-perirenal ultrasonographic fat thickness (PUFT) has shown to correlate with both total and visceral fat better than body mass index (BMI), waist circumference (WC), and other indices of obesity. Moreover, a local paracrine and mechanical action of the PUFT on kidney has been described in recent studies. Aim of our study was to assess the relationship between glomerular filtration rate (GFR) and PUFT in comparison with other anthropometric and ultrasonographic indices of adiposity. Two hundred and ninety-six hypertensive patients were enrolled. PUFT, cutis-rectis thickness and rectis-aorta thickness were obtained by ultrasonography. Anthropometric measures of adiposity were also measured. Estimated GFR was calculated using the CKD-EPI equation. Higher PUFT values were observed in patients with impaired renal function (P < 0.001), whereas no differences in BMI and WC were shown between groups divided by GFR. PUFT significantly correlated with GFR in all patients (r = -0.284; P < 0.001), with no differences in groups divided by sex, diabetes, or BMI. This association held in multivariate analyses also after correction for confounding factors, including other adiposity indices (P < 0.001). When receiver operating characteristic curves were built to detect a eGFR < 60 mL/minutes per 1.73 m2 , a PUFT value ≤3.725 cm showed a negative predictive value of 94.0%, with the largest area under the curve (AUC: 0.700) among the variables considered. In conclusion, the relationship between PUFT and GFR seems to be more accurate and less influenced by the bias affecting traditional indices of adiposity.

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.