Role of Advanced Glycation End Products as New Biomarkers in Systemic Lupus Erythematosus.

Advanced glycation end-products (AGEs) may play a relevant role as inducers in the chronic inflammatory pathway present in immune-mediated diseases, such as systemic lupus erythematosus (SLE). AGEs concentrations have been associated, with discrepant results to date, with some parameters such as disease activity or accrual damage, suggesting their potential usefulness as biomarkers of the disease. Our objectives are to confirm differences in AGEs levels measured by cutaneous autofluorescence between SLE patients and healthy controls (HC) and to study their correlation with various disease parameters. Cross-sectional study, where AGEs levels were measured by skin autofluorescence, and SLE patients' data were compared with those of sex- and age-matched HC in a 1:3 proportion through a multiple linear regression model. Associations of AGEs levels with demographic and clinical data were analyzed through ANOVA tests. Both analyses were adjusted for confounders. AGEs levels in SLE patients were significantly higher than in HC (p < 0.001). We found statistically significant positive associations with SLE disease activity index (SLEDAI) and damage index (SDI), physician and patient global assessment, C-reactive protein, leukocyturia, complement C4, IL-6 and oral ulcers. We also found a negative statistically significant association with current positivity of anti-nuclear and anti-Ro60 antibodies. AGEs seem to have a contribution in LES pathophysiology, being associated with activity and damage and having a role as a new management and prognosis biomarker in this disease. The association with specific antibodies and disease manifestations may indicate a specific clinical phenotype related to higher or lower AGEs levels.

B- and T-lymphocyte attenuator could be a new player in accelerated atherosclerosis associated with chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), cardiovascular morbi-mortality is higher than in general population. Atherosclerotic cardiovascular disease is accelerated in CKD, but specific CKD-related risk factors for atherosclerosis are unknown. METHODS: CKD patients from the NEFRONA study were used. We performed mRNA array from blood of patients free from atheroma plaque at baseline, with (n=10) and without (n=10) de novo atherosclerotic plaque development 2 years later. Selected mRNA candidates were validated in a bigger sample (n=148). Validated candidates were investigated in vivo in an experimental model of CKD-accelerated atherosclerosis, and in vitro in murine macrophages. RESULTS: mRNA array analysis showed 92 up-regulated and 67 down-regulated mRNAs in samples from CKD patients with de novo plaque development. The functional analysis pointed to a paramount role of the immune response. The validation in a bigger sample confirmed that B- and T-lymphocyte co-inhibitory molecule (BTLA) down-regulation was associated with de novo plaque presence after 2 years. However, BTLA down-regulation was not found to be associated with atherosclerotic progression in patients with plaque already present at baseline. In a model of CKD-accelerated atherosclerosis, mRNA and protein expression levels of BTLA were significantly decreased in blood samples and atheroma plaques. Plaques from animals with CKD were bigger, had more infiltration of inflammatory cells, higher expression of IL6 and IL17 and less presence of collagen than plaques from control animals. Incubation of macrophages with rat uremic serum decreased BTLA expression. CONCLUSIONS: BTLA could be a potential biomarker or therapeutic target for atherosclerosis incidence in CKD patients.

CYP24A1 and KL polymorphisms are associated with the extent of vascular calcification but do not improve prediction of cardiovascular events.

BACKGROUND: Novel ways of determining cardiovascular risk are needed as a consequence of population ageing and the increased prevalence of chronic kidney disease (CKD), both of which favour vascular calcification. Since the formation of arterial calcium deposits has a genetic component, single nucleotide polymorphisms (SNPs) could predict cardiovascular events. METHODS: A selection of 1927 CKD patients and controls recruited by the NEFRONA study were genotyped for 60 SNPs from 22 candidate genes. A calcium score was calculated from the echogenicity of arterial atherosclerotic plaques and the presence of cardiovascular events during a 4-year period was recorded. Association of SNPs with the calcium score was identified by multiple linear regression models and their capacity to predict events was assessed by means of Cox proportional hazards regression and receiver operating characteristics curves. RESULTS: Two variants, rs2296241 of CYP24A1 and rs495392 of KL, were associated with the calcium score. Despite this, only heterozygotes for rs495392 had a lower risk of suffering an event compared with homozygotes for the major allele {hazard ratio (HR) 0.67 [95% confidence interval (CI) 0.48-0.93]}. Of note, the calcium score was associated with an increased risk of cardiovascular events [HR 1.71 (95% CI 1.35-2.17)]. The addition of the rs495392 genotype to classical cardiovascular risk factors did not increase the predictive power [area under the curve (AUC) 71.3 (95% CI 61.1-85.5) versus 71.4 (61.5-81.4)]. CONCLUSIONS: Polymorphisms of CYP24A1 and KL are associated with the extent of calcification but do not predict cardiovascular events. However, the echogenic determination of the extent of calcium deposits seems a promising non-irradiating method for the scoring of calcification in high-risk populations.

Cardiovascular risk factors and the impact on prognosis in patients with chronic kidney disease secondary to autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary renal disease. There is an increased rate of cardiovascular disease (CVD) in ADPKD. In this study, we evaluate the prevalence of cardiovascular risk factors, the achievement rates for treatment goals and cardiovascular events (CVE) in ADPKD and their relations with asymptomatic CVD in CKD from other etiologies (CKDoe) and controls. METHODS: We evaluated 2445 CKD patients (2010-2012). The information collected was: clinical, anthropometric and analytical parameters, treatments and CVD evaluation (intima-media thickness (IMT), atheromatous plaque presence and ankle-brachial index (ABI)). Laboratory, vital status, CVE and hospitalizations were collected for 4 years. RESULTS: ADPKD patients had a worse renal function and worst achievement of blood pressure, higher parathormone levels but lower proteinuria compared to CKDoe. ADPKD patients presented lower IMT values than other groups, however, an intermediate rate of pathologic ABI and atheromatous plaque was present. More than half of the patients received statins, achieving LDL-c levels < 100 only in 50 and 39.8% of them (ADPKD and CKDoe respectively). The number of CVE during the follow-up period was low. In adjusted Cox regression model, ADPDK had the lowest occurrence of CVE of all three groups (HR:0.422, 95%CI 0.221-0.808, p = 0.009). CONCLUSION: ADPKD patients show intermediate control rates of CVD. A better control of CVD risk seems to be related with a lower load of CVD compared to other groups, which may lead in the long term to a better prognosis. Further investigation is necessary to determine cardiovascular prognosis in ADPKD.

TRAF3 Modulation: Novel Mechanism for the Anti-inflammatory Effects of the Vitamin D Receptor Agonist Paricalcitol in Renal Disease.

BACKGROUND: CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood. METHODS: Modulation of the noncanonical NF-κB2 pathway and its component TNF receptor-associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models. RESULTS: In PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-κB2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-κB2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA's effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-κB2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-κB2-dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol. CONCLUSIONS: These data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-κB2 pathway, identifying a novel mechanism for VDRA's effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.

Circulating ADAMs are associated with renal and cardiovascular outcomes in chronic kidney disease patients.

BACKGROUND: A disintegrin and metalloproteinase (ADAM) 17, also known as tumour necrosis factor α-converting enzyme (TACE), is a metalloproteinase that releases the ectodomains of most growth factors, cytokines, receptors and enzymes and has been associated with the presence of chronic kidney disease (CKD) and cardiovascular (CV) disease. The role of circulating ADAMs in the progression of renal function and CV events in CKD patients is unknown. METHODS: A total of 2570 subjects from an observational and multicentre study with CKD Stages 3-5, CKD Stage 5D and controls without any history of CV disease were studied. Circulating ADAM activity was assessed using a fluorometric technique. Progression of renal disease was defined as a 30% increase in serum creatinine or dialysis requirement after 24 months of follow-up. CV outcomes were assessed after 48 months of follow-up. RESULTS: Patients with advanced CKD had higher ADAM activity as compared with patients with moderate CKD or controls. Male patients with progression of CKD had higher ADAM levels at baseline compared with patients with stable renal function {22.19 relative fluorescence units/µL/h [95% confidence interval (CI) 11.22-37.32] versus 12.15 (7.02-21.50)}. After multivariate adjustment, higher ADAM activity was identified as a risk factor for progression of CKD in male patients [30% increase in the creatinine odds ratio (OR) 2.72 (95% CI 1.58-4.68), P < 0.001; dialysis requirement OR 3.00 (95% CI 1.65-5.46), P < 0.001; dialysis requirement or 30% increase in the creatinine OR 3.15 (95% CI 2.06-4.81), P < 0.001]. ADAM activity was also identified as an independent risk factor for CV events [hazard ratio (HR) 1.68 (95% CI 1.20-2.36), P = 0.003]. CONCLUSIONS: High ADAMs activity levels are independently associated with CKD progression in males and with CV events in CKD patients.

Sex hormones and their influence on chronic kidney disease.

PURPOSE OF REVIEW: The majority of end-stage renal disease including dialysis and kidney transplant patients are men. In contrast, the incidence of chronic kidney disease (CKD) is higher in women compared with men. In this review, we dissect the sex hormone levels and its effects on experimental models and patients with CKD. RECENT FINDINGS: Sex hormones are clearly involved in CKD progression to end-stage renal disease (ESRD). A significant reduction in lipid peroxidation as a mechanism of renoprotection has been observed in kidneys of streptozotocin (STZ)-diabetic ovariectomized rats after estradiol administration. Furthermore, a G-protein-coupled estrogen receptor inhibits podocyte oxidative stress maintaining the integrity of the mitochondrial membrane. Sex hormone depletion has been shown to modulate RAS system and protect against kidney injury in the male STZ-diabetic model. In human primary proximal tubular epithelial cells, a proteomic study showed that dihydrotestosterone dysregulated metabolic, suggesting that the deleterious effect of androgens within the kidney maybe related to altered energy metabolism in renal tubules. SUMMARY: Male gender is associated with worse CKD progression and this fact may be ascribed to sex hormone. Although male hormones exert a deleterious effect in terms of increasing oxidative stress, activating RAS system, and worsening fibrosis within the damaged kidney, female hormones exert a renoprotective effect.

Subclinical atherosclerosis burden predicts cardiovascular events in individuals with diabetes and chronic kidney disease.

BACKGROUND: Individuals with diabetes have remarkably high rates of cardiovascular morbidity and mortality. However, the incremental cardiovascular risk in diabetes is heterogeneous and has often been related to renal involvement. The purpose of this study was to analyse the prognostic value of subclinical atherosclerosis in determining the incidence of first cardiovascular events (CVEs) in individuals with diabetes and chronic kidney disease (CKD) compared to CKD individuals without diabetes. METHODS: We included data from individuals with CKD with and without diabetes, free from pre-existing cardiovascular disease, from the NEFRONA cohort. Participants underwent baseline carotid and femoral ultrasound and were followed up for 4 years. All CVEs during follow-up were registered. Bivariate analysis and Fine-Gray competing risk models were used to perform the statistical analysis. RESULTS: During the mean follow-up time of 48 months, a total of 203 CVE was registered. 107 CVE occurred among participants without diabetes (19.58 per 1000 person-years) and 96 CVE occurred among participants with diabetes (44.44 per 1000 person-years). Following the competing risk analysis, the variables predicting CVEs in CKD individuals without diabetes were the number of territories with plaque at baseline (HR 1.862, 95% CI [1.432;2.240]), age (HR 1.026, 95% CI [1.003;1.049]) and serum concentrations of 25-OH vitamin D (HR 0.963, 95% CI [0.933;0.094]). The only variable predicting CVEs among CKD participants with diabetes was the number of territories with plaque at baseline (HR 1.782, 95% CI [1.393, 2.278]). For both models, concordance (C) index yielded was over 0.7. CONCLUSIONS: The burden of subclinical atherosclerosis is the strongest predictor of future CVEs in diabetic individuals with CKD. Early detection of subclinical atherosclerotic burden by multiterritorial vascular ultrasound could improve CVE prediction in this population.

Factors influencing pathological ankle-brachial index values along the chronic kidney disease spectrum: the NEFRONA study.

Background: The ankle-brachial index (ABI) is widely used to diagnose subclinical peripheral artery disease (PAD) in the general population, but data assessing its prevalence and related factors in different chronic kidney disease (CKD) stages are scarce. The aim of this study is to evaluate the prevalence and associated factors of pathological ABI values in CKD patients. Methods: NEFRONA is a multicentre prospective project that included 2445 CKD patients from 81 centres and 559 non-CKD subjects from 9 primary care centres across Spain. A trained team collected clinical and laboratory data, performed vascular ultrasounds and measured the ABI. Results: PAD prevalence was higher in CKD than in controls (28.0 versus 12.3%, P < 0.001). Prevalence increased in more advanced CKD stages, due to more patients with an ABI ≥1.4, rather than ≤0.9. Diabetes was the only factor predicting both pathological values in all CKD stages. Age, female sex, carotid plaques, higher carotid intima-media thickness, higher high-sensitivity C-reactive protein (hsCRP) and triglycerides, and lower 25-hydroxi-vitamin D were independently associated with an ABI ≤0.9. Higher phosphate and hsCRP, lower low-density lipoprotein (LDL)-cholesterol and dialysis were associated with an ABI ≥1.4. A stratified analysis showed different associated factors in each CKD stage, with phosphate being especially important in earlier CKD, and LDL-cholesterol being an independent predictor only in Sage 5D CKD. Conclusions: Asymptomatic PAD is very prevalent in all CKD stages, but factors related to a low or high pathological ABI differ, revealing different pathogenic pathways. Diabetes, dyslipidaemia, inflammation and mineral-bone disorders play a role in the appearance of PAD in CKD.

High Levels of Hemoglobin Promote Carotid Adventitial Vasa Vasorum Neoangiogenesis in Chronic Kidney Disease.

Chronic kidney disease (CKD) patients, characterized by traditional and nontraditional risk factors, are prone to develop atheromatosis and thus cardiovascular events and mortality. The angiogenesis of the adventitial vasa vasorum (aVV) surrounding the carotid has been described as the atheromatosis initiator. Therefore, the aim of the study was to (1) evaluate if the carotid aVV in CKD patients increases in comparison to its physiological value of healthy patients; (2) explore which traditional or nontraditional risk factor including inflammation, bone and mineral metabolism, and anemia could be related to the aVV angiogenesis. CKD patients without previous cardiovascular events (44, stages 3-4; 37, stage 5D) and 65 healthy subjects were compared. The carotid aVV and the intima-media thickness (cIMT) were evaluated by ultrasound. CKD patients at stages 3-4 showed higher aVV of the right carotid artery even after adjusting for age. Importantly, a multiple linear regression model showed hemoglobin levels > 12.5 g/dL as the factor for an estimated higher aVV of the right carotid artery. In conclusion, the association of hemoglobin with higher aVV could suggest the role of high hemoglobin in the higher incidence of adverse cardiovascular outcomes in CKD patients.

Hepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosis.

BACKGROUND & AIMS: The pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD) is still incompletely understood. Several nuclear receptors play a role in liver lipid metabolism and can promote hepatosteatosis, but the possible role of vitamin D receptor (VDR) in NAFLD has not been investigated. METHODS: The expression of liver VDR was investigated in apolipoprotein E knockout (apoE(-/-)) mice on a high fat diet, in wild-type mice on methionine and choline deficient diet and in NAFLD patients with hepatosteatosis and non-alcoholic steatohepatitis. The relevance of VDR was assessed in apoE(-/-) mice by deletion of VDR or paricalcitol treatment and in human HepG2 cells by VDR transfection or silencing. The role of VDR in fibrosis was also determined in VDR knockout mice (VDR(-/-)) treated with thioacetamide. RESULTS: Expression of liver VDR was markedly induced in two mouse models of NAFLD, as well as in patients with hepatosteatosis, but decreased in non-alcoholic steatohepatitis. VDR deletion in high fat diet-fed apoE(-/-) mice protected against fatty liver, dyslipidemia and insulin resistance, and caused a decrease in taurine-conjugated bile acids, but did not influence fibrosis by thioacetamide. apoE(-/-)VDR(-/-) mouse livers showed decreased gene expression of CD36, DGAT2, C/EBPα and FGF21, and increased expression of PNPLA2, LIPIN1 and PGC1α. Treatment of apoE(-/-) mice on high fat diet with paricalcitol had modest opposite effects on steatosis and gene expression. Finally, this set of genes showed concordant responses when VDR was overexpressed or silenced in HepG2 cells. CONCLUSIONS: Induced hepatocyte VDR in NAFLD regulates key hepatic lipid metabolism genes and promotes high fat diet-associated liver steatosis. Therapeutic inhibition of liver VDR may reverse steatosis in early NAFLD. LAY SUMMARY: The amount of vitamin D receptor is induced early in the livers of mice and humans when they develop non-alcoholic fatty liver disease. If the gene for the vitamin D receptor is deleted, hepatic lipid metabolism changes and mice do not accumulate fat in the liver. We conclude that the vitamin D receptor can contribute to the fatty liver disease promoted by a high fat diet.

Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease.

BACKGROUND: Patients with cardiovascular (CV) disease have an increased circulating angiotensin-converting enzyme 2 (ACE2) activity, but there is little information about changes in ACE2 in chronic kidney disease (CKD) patients without history of CV disease. We examined circulating ACE2 activity in CKD patients at stages 3-5 (CKD3-5) and in dialysis (CKD5D) without any history of CV disease. METHODS: Circulating ACE2 activity was measured in human ethylenediamine-tetraacetic acid (EDTA)-plasma samples from the NEFRONA study (n = 2572): control group (CONT) (n = 568), CKD3-5 (n = 1458) and CKD5D (n = 546). Different clinical and analytical variables such as gender; age; history of diabetes mellitus (DM), dyslipidemia and hypertension; glycaemic, renal, lipid and anaemia profiles; vitamin D analogues treatment and antihypertensive treatments (angiotensin-converting enzyme inhibitor and angiotensin receptor blockade) were analysed. Circulating ACE2 and ACE activities were measured using modified fluorimetric assay for EDTA-plasma samples, where zinc chloride was added to recover enzymatic activity. RESULTS: In CKD3-5 and CKD5D, significant decrease in circulating ACE2 activity was observed when compared with CONT, but no differences were found between CKD3-5 and CKD5 when performing paired case-control studies. By multivariate linear regression analysis, male gender and advanced age were identified as independent predictors of ACE2 activity in all groups. Diabetes was identified as independent predictor of ACE2 activity in CKD3-5. Significant increase in the activity of circulating ACE was found in CKD3-5 and CKD5D when compared with CONT and in CKD5D when compared with CKD3-5. By multiple regression analysis, female gender and younger age were identified as independent predictors of ACE activity in CONT and CKD3-5. Diabetes was also identified as an independent predictor of ACE activity in CKD3-5 patients. CONCLUSIONS: Circulating ACE2 and ACE activities can be measured in human EDTA-plasma samples with zinc added to recover enzymatic activity. In a CKD population without previous history of CV disease, ACE2 activity from human EDTA-plasma samples directly correlated with the classical CV risk factors namely older age, diabetes and male gender. Our data suggest that circulating ACE2 is altered in CKD patients at risk for CV event.

The active form of vitamin D, calcitriol, induces a complex dual upregulation of endothelin and nitric oxide in cultured endothelial cells.

Despite the presence of vitamin D receptor (VDR) in endothelial cells, the effect of vitamin D on endothelial function is unknown. An unbalanced production of vasoactive endothelial factors such as nitric oxide (NO) or endothelin-1 (ET-1) results in endothelial dysfunction, which can alter the normal cardiovascular function. Present experiments were devoted to assess the effect of active vitamin D (calcitriol) on the synthesis of endothelial vasoactive factors. The results were that, in cells, calcitriol increased ET-1 and NO productions, which were measured by ELISA and fluorimetric assay, respectively. Calcitriol also increased endothelin-converting enzyme-1 (ECE-1) and endothelial-nitric oxide synthase (eNOS) activities, their mRNA (qPCR), their protein expressions (Western-blot), and their promoter activities (transfection assays). Calcitriol did not change prepro-ET-1 mRNA. The effect was specific to VDR activation because when VDR was silenced by siRNA, the observed effects disappeared. Mechanisms involved in each upregulation differed. ECE-1 upregulation depended on AP-1 activation, whereas eNOS upregulation depended directly on VDR activation. To evaluate the in vivo consequences of acute calcitriol treatment, normal Wistar rats were treated with a single ip injection of 400 ng/kg calcitriol and euthanized 24 h later. Results confirmed those observed in cells, that production and expression of both factors were increased by calcitriol. Besides, calcitriol-treated rats showed a slight rise in mean blood pressure, which decreased when pretreated with FR-901533, an ECE-1 antagonist. We conclude that calcitriol increases the synthesis of both ET-1 and NO in endothelial cells. However, the ET-1 upregulation seems to be biologically more relevant, as animals acutely treated with calcitriol show slight increases in blood pressure.

Prevalence of subclinical atheromatosis and associated risk factors in chronic kidney disease: the NEFRONA study.

BACKGROUND: The causes of the high cardiovascular mortality observed in chronic kidney disease (CKD) are unknown. Here, we report data on prevalence of subclinical atherosclerosis in the NEFRONA population and a stratified multivariate logistic analysis of factors associated with the presence of plaque. METHODS: We analysed 2445 patients with an estimated glomerular filtration rate (eGFR) <60 mL/min (CKD 3: 937; CKD 4-5: 820; CKD 5D: 688) and 559 non-CKD subjects (eGFR >60 mL/min), 18-75 years old, without previous cardiovascular events. An itinerant team of professionals performed carotid and femoral arterial ultrasound. RESULTS: The already high prevalence of plaques in CKD 3 is even higher in more severe CKD. Multivariate logistic analysis showed that, at any CKD stage, age and being male are independently associated with the presence of plaques. In CKD 3, there was a significant interaction of the smoking status and triglycerides levels which were independently associated with the presence of plaque. Furthermore, being diabetic was also associated with the presence of subclinical atherosclerosis. In stage 4-5 there was a significant association with smoking, high phosphate and hsCRP levels. In dialysis patients, being diabetic, having low levels of 25(OH)-vitamin D3 and smoking status also showed a significant association with the presence of plaque. Furthermore, the association of phosphate levels with the presence of subclinical atheromatosis showed a U-shaped curve. CONCLUSIONS: This analysis demonstrates the magnitude of subclinical atheromatous disease in a large CKD population. The patient characteristics associated with the presence of plaque differ in every CKD stage.

Observational multicenter study to evaluate the prevalence and prognosis of subclinical atheromatosis in a Spanish chronic kidney disease cohort: baseline data from the NEFRONA study.

BACKGROUND: Cardiovascular events (CVE) are more prevalent in chronic kidney disease (CKD) than in general population, being the main cause of morbimortality. Specific risk factors related to CKD have been suggested, because traditional factors do not fully explain this increase in cardiovascular disease rates. However, the role of atheromatosis, its pathogenesis and evolution are still unclear. The potential use of diagnostic tests to detect subclinical atheromatosis has to be determined. METHODS: NEFRONA is a prospective multicenter cohort study. 2445 CKD subjects were enrolled from 81 Spanish hospitals and dialysis clinics, from 2010 to 2012. Eligibility criteria included: 18 to 74 years old, CKD stage 3 or higher, and no previous CVE. 559 non-CKD controls were also recruited. Demographical, clinical and analytical data were collected. Carotid and femoral ultrasounds were performed by a single trained team to measure carotid intima-media thickness (cIMT) and detect atheromatous plaques. Ankle-brachial index (ABI) was measured. RESULTS: Differences in age, sex and prevalence and control of cardiovascular risk factors were found between controls and CKD patients. These differences are similar to those described in epidemiological studies.No difference was found regarding cIMT between controls and CKD (when subjects with plaques in common carotid arteries were omitted); earlier CKD stages had higher values. CKD patients had a higher rate of atheromatous plaques, with no difference between stages in the unadjusted analysis. A group of patients had plaques in femoral arteries but were plaque-free in carotid arteries, and would have gone underdiagnosed without the femoral study. The percentage of pathologic ABI was higher in CKD, with higher prevalence in more advanced stages, and a higher rate of ABI >1.4 than <0.9, suggesting more vascular calcification. CONCLUSIONS: NEFRONA is the first large study describing the actual prevalence of subclinical atheromatosis across different CKD stages. There is a very high rate of atheromatous plaques and pathologic ABI in CKD. Prospective data will add important information to the pathogenesis and evolution of atheromatosis in CKD, compared to non-CKD subjects.

Influence of nonalcoholic fatty liver disease severity on carotid adventitial vasa vasorum.

Introduction: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the world's population and encompasses a spectrum of liver conditions, from non-alcoholic steatohepatitis (NASH) to inflammation and fibrosis. In addition, NAFLD also links to extrahepatic conditions like diabetes or obesity. However, it remains unclear if NAFLD independently correlates with the onset and progression of atherosclerosis. Material and methods: This cross-sectional study aimed to explore the relationship between NAFLD severity, assessed via liver biopsy, and early atherosclerosis using adventitial vasa vasorum (VV) density. It included 44 patients with obesity (33 with steatosis, 11 with NASH) undergoing bariatric surgery. Results: Results revealed no significant differences in adventitial VV density between steatosis and NASH groups, neither in the mean values [0.759 ± 0.104 vs. 0.780 ± 0.043, P=0.702] nor left-right sides. Similarly, carotid intima-media thickness (cIMT) did not vary between these groups. Additionally, no linear correlation existed between VV density and cIMT. Only gender showed an association with VV density. Conclusion: These findings suggest that NASH severity doesn't independently drive early atherosclerosis or affects cIMT. Gender might play a role in early atherosclerotic disease in NAFLD, impacting VV density and cIMT. This highlights the need to consider other risk factors when evaluating cardiovascular risk in NAFLD patients.

Association between adherence to the mediterranean diet, physical activity, and sleep apnea-hypopnea syndrome (SAHS) in a middle-aged population with cardiovascular risk: Insights from the ILERVAS cohort.

INTRODUCTION: Sleep Apnea-Hypopnea Syndrome (SAHS) is a common sleep disorder influenced by factors like age, gender, and obesity. The Mediterranean Diet (MedDiet) and physical activity have shown health benefits in lung diseases, but their effects on SAHS remain underexplored. METHODS: In a cross-sectional analysis of 678 middle-aged individuals with low-to-moderate cardiovascular risk from the ILERVAS cohort, we assessed adherence to the MedDiet and physical activity levels using validated tools. Sleep parameters, SAHS severity, and excessive daytime sleepiness were evaluated through non-attended cardiorespiratory polygraphy and the Epworth Sleepiness Scale. Multinomial logistic regression models were employed to assess the relationship between MedDiet adherence, physical activity, and SAHS severity. RESULTS: The prevalence of severe, moderate, and mild SAHS was 15.5%, 23.2% and 36.1%, respectively. We found no significant associations between adherence to the MedDiet, physical activity levels, and the presence or severity of SAHS. However, we noted a significant interaction between MedDiet and physical activity with minimum SpO2 values (p = 0.049). Notably, consuming more than one serving of red meat per day was independently associated with a higher risk of moderate SAHS [OR = 2.65 (1.29-5.44), p = 0.008]. CONCLUSION: Individually, MedDiet adherence and physical activity did not show independent correlations with SAHS. However, when considered together, a minimal but significant effect on minimum SpO2 was observed. Additionally, red meat consumption was associated with a moderate risk of SAHS. Further research is necessary to comprehend the intricate connections between lifestyle factors and sleep-breathing disorders, with a focus on personalized approaches for high-risk populations.

Cumulative tobacco consumption has a dose-dependent effect on atheromatosis burden and improves severe atheromatosis prediction in asymptomatic middle-aged individuals: The ILERVAS study.

BACKGROUND AND AIMS: Sex-specific impact of cumulative tobacco consumption (CTC) on atheromatosis extension and total plaque area remains unknown. We aimed to determine the impact of CTC in atheromatosis localization and burden. METHODS: We performed a cross-sectional analysis in 8330 asymptomatic middle-aged individuals. 12-territory vascular ultrasounds in carotid and femoral arteries were performed to detect atheromatous plaque presence and to measure total plaque area. Adjusted regressions and conditional predictions by smoking habit or CTC (stratified in terciles as low (≤13.53), medium (13.54-29.3), and high (>29.3 packs-year)) were calculated. Severe atheromatosis (SA, ≥3 territories with atheroma plaque) was predicted with the Systematic COronary Risk Evaluation 2 (SCORE2) model. The improvement of SA prediction after adding CTC was evaluated. RESULTS: CTC was associated with an increased risk of atheromatosis, stronger in femoral than in carotid artery, but similar in both sexes. A dose-dependent effect of CTC on the number of territories with atheroma plaque and total plaque area was observed. Addition of CTC to the SCORE2 showed a higher sensitivity, accuracy, and negative predictive value in males, and a higher specificity and positive predictive value in females. In both sexes, the new SCORE2-CTC model showed a significant increase in AUC (males: 0.033, females: 0.038), and in the integrated discrimination index (males: 0.072; females: 0.058, p < 0.001). Age and CTC were the most important clinical predictors of SA in both sexes. CONCLUSIONS: CTC shows a dose-dependent association with atheromatosis burden, impacts more strongly in femoral arteries, and improves SA prediction.

Antihypertensive Effects of an Optimized Aged Garlic Extract in Subjects with Grade I Hypertension and Antihypertensive Drug Therapy: A Randomized, Triple-Blind Controlled Trial.

The use of garlic (Allium sativum) for treating arterial hypertension has been recognized as effective for several decades. However, tolerance to treatment is low, and several technological modifications have been developed to improve its tolerability, such as the aging process at controlled temperature and humidity. This study aims to validate the antihypertensive effects of an optimized extract of aged black garlic with low doses of s-allyl-cysteine (SAC) in a Grade I hypertensive population with drug treatment. A randomized, triple-blind, placebo-controlled parallel trial was developed, where a daily supplementation with 0.25 mg/day of SAC for 12 weeks was performed. A reduction in systolic and diastolic blood pressure of 1.8 mmHg (0.7 to 4.1 95% CI) and 1.5 mmHg (0.3 to 3.0 95% CI), respectively, was observed. Similarly, an increase in blood nitric oxide (10.3 µM, 1.1 to 19.5 95% CI) and antioxidant capacity (7 × 10-3 µM TE/min, (1.2 to 13 × 10-3 95% CI) and a reduction in uric acid levels (-0.3 mg/dL, -0.5 to -0.001 95% CI) and ACE activity (-9.3 U/L; -18.4 to -0.4 95% CI) were observed. No changes in endothelial function and inflammatory cytokines were observed. It was concluded that low-dose SAC supplementation in an optimized black-garlic extract allows for an extra-significant reduction in blood pressure in a Grade I hypertensive population receiving drug treatment.