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Chronic inflammation and proteinuria is a risk factor for cardiovascular disease (CVD) in patients with chronic kidney diseases and rheumatologic disorders. Our aim was to investigate the CVD events (CVDEs) and survival between the patients with FMF-related AA amyloidosis and glomerulonephropathies (GN) to define possible predictors for CVDEs. A prospective follow-up study with FMF-amyloidosis and glomerulonephropathy (GN) was performed and patients were followed for CVDEs. Flow-mediated dilatation (FMD), FGF-23, serum lipid, hsCRP levels, BMI and HOMA were assessed. A Cox regression analysis was performed to evaluate the risk factors for CVDEs. There were 107 patients in the FMF-amyloidosis group and 126 patients with GN group. Forty-seven CVDEs were observed during the 4.2-years follow up; all 28 patients in the FMF-amyloidosis group and 14/19 patients with GN developed CVDEs before the age of 40 (p = 0.002). CVD mortality was 2.8 times higher (95% CI 1.02–7.76) in patients with FMF-amyloidosis. Across both groups, FMD and FGF23 (p

Background:While the pathophysiology of chronic disorders varies there are three basic mechanisms - inflammation, oxidative stress and endothelial dysfunction – that are common in many chronic diseases. These mechanisms, which have a dynamic structure, are key to homeostasis. However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases.Objectives:To evaluate the effect of anti-atherosclerotic liquid (AAL), anti-inflammatory capsules (AIC) and anti-oxidant liquid (AOL) supplementation on the flow-mediated dilatation (FMD), inflammatory, oxidative stress and endothelial dysfunction markers in patients with selected chronic diseasesMethods:We analyzed data of 178 patients from cohorts with selected chronic diseases (Rheumatoid arthritis, familial Mediterranean fever, DM type-2, Hypertension, Multiple sclerosis, Chronic obstructive pulmonary disease, Alzheimer disease and Cancer) in this quasi-experimental study. Endothelial dysfunction was determined by FMD and serum asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (AAL, 3 ml once per day), omega-3 (AIC, 3 capsules once per day) and extract with Alaskan blueberry and 21 different red purple fruit vegetables (AOL, 30 ml once per day). Stepwise multivariate regression analysis evaluated the association of FMD with clinical and serologic parameters.Results:Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased and CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. FMD was negatively correlated with serum ADMA, MDA, PTX3, hsCRP levels, SBP and DBP and positively correlated to CuZn-SOD and eGFR levels both at baseline and after the 12-weeks treatment period. Multivariate regression analysis revealed that ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies (Table 1, Figure 1).Conclusion:Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. Short-term AAL, AIC and AOL therapies significantly improves FMD and normalizes ADMA, PTX3, hsCRP and MDA. This may have implications for adjunctive therapy in a number of chronic disorders.References:[1] Yilmaz MI, Saglam M, Caglar K, Cakir E, Sonmez A, Ozgurtas T et al. The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine. Am J Kidney Dis. 2006;47(1):42-50. doi:10.1053/j.ajkd.2005.09.029.Disclosure of Interests:None declared

While the pathophysiology of chronic disorders varies there are three basic mechanisms - inflammation, oxidative stress and endothelial dysfunction – that are common in many chronic diseases. However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases. We analyzed data of 178 patients from cohorts with selected chronic diseases in this quasi-experimental study. Endothelial dysfunction was determined by flow-mediated dilatation (FMD) and asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (anti-atherosclerotic liquid- AAL), omega-3 (anti-inflammatory capsules- AIC) and extract with Alaskan blueberry (anti-oxidant liquid- AOL). Stepwise multivariate regression analysis was used to evaluate the association of FMD with clinical and serologic parameters. Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased while CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. The FMD was negatively correlated with serum ADMA, MDA, PTX3, and hsCRP levels and positively correlated with CuZn-SOD and eGFR levels. ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies. Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. In addition, short-term AAL, AIC and AOL therapies significantly improves a number of parameters in our cohort and can normalize ADMA, PTX3, hsCRP and MDA levels.

Obesity increases hepatocellular carcinoma (HCC) risks via unknown mediators. We report that hepatic unconventional prefoldin RPB5 interactor (URI) couples nutrient surpluses to inflammation and non-alcoholic steatohepatitis (NASH), a common cause of HCC. URI-induced DNA damage in hepatocytes triggers inflammation via T helper 17 (Th17) lymphocytes and interleukin 17A (IL-17A). This induces white adipose tissue neutrophil infiltration mediating insulin resistance (IR) and fatty acid release, stored in liver as triglycerides, causing NASH. NASH and subsequently HCC are prevented by pharmacological suppression of Th17 cell differentiation, IL-17A blocking antibodies, and genetic ablation of the IL-17A receptor in myeloid cells. Human hepatitis, fatty liver, and viral hepatitis-associated HCC exhibit increased IL-17A correlating positively with steatosis. IL-17A blockers may prevent IR, NASH, and HCC in high-risk patients.

Abnormalities of thyroid function are commonly seen in chronic kidney disease (CKD) patients. They are associated with adverse clinical conditions such as atherosclerosis, endothelial dysfunction, inflammation and abnormal blood pressure variability. We investigated the association between thyroid disorders and endothelial function, assessed by flow-mediated dilatation (FMD) and carotid intima-media thickness (CIMT), and cardiovascular events (CVE) in CKD patients. This observational cohort study included 305 CKD (stages 1–5) patients. Routine biochemistry, including free T3, free T4 and thyroid stimulating hormone, fibroblast growth factor-23 (FGF-23) and FMD, CIMT were measured. We divided patients into four groups according to thyroid hormone status: euthyroidism, subclinical hyperthyroidism, subclinical hypothyroidism, and euthyroid sick syndrome. Fatal and composite CVE were recorded for a median 29 months. Patients with subclinical hypothyroidism had a higher prevalence of hypertension and diabetes and also were more likely to have higher values of systolic CIMT, phosphorus, intact parathormone (iPTH), FGF-23, homeostasis model assessment-insulin resistance and lower levels of FMD than euthyroid patients. In the unadjusted survival analysis, subclinical hypothyroidism and euthyroid sick syndrome were associated with an increased risk for the outcome as compared with euthyroidism [hazard ratio 30.63 (95 % confidence interval 12.27–76.48) and 12.17 (3.70–39.98), respectively]. The effects of subclinical hypothyroidism and euthyroid sick syndrome were maintained even in fully adjusted models. We demonstrated that subclinical hypothyroidism and euthyroid sick syndrome are associated with increased CVE in CKD patients. Further studies are needed to explore these issues.

Vascular injury and dysfunction contribute to cardiovascular disease, the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG) is a soluble member of the tumor necrosis factor receptor superfamily that has been linked to atherogenesis and endothelial dysfunction. Elevated circulating OPG levels predict future cardiovascular events (CVE). Our aim was to evaluate the determinants of circulating OPG levels, to investigate the relationship between OPG and markers of vascular damage and to test whether OPG improves risk stratification for future CVE beyond traditional and renal-specific risk factors in a CKD population. 291 patients with CKD stage 1-5 not on dialysis were included in the study. In the multivariate analysis, OPG was a significant predictor for flow-mediated dilatation, but not for carotid intima media thickness levels. During follow-up (median 36 months, IQR = 32-42 months), 87 patients had CVE. In the Cox survival analysis, OPG levels were independently associated with CVE even after adjustment for traditional and renal-specific cardiovascular risk factors. The addition of OPG to a model based on commonly used cardiovascular factors significantly improved the reclassification abilities of the model for predicting CVE. We show for the first time that OPG improves risk stratification for CVE in a non-dialysis CKD population, above and beyond a model with established traditional and renal-specific cardiovascular risk factors, including estimated glomerular filtration rate and fibroblast growth factor 23.

Both elevated serum uric acid and serum asymmetric dimethylarginine (ADMA) are risk factors for cardiovascular disease. We hypothesized that combined elevation of uric acid and ADMA amplifies the risk of all-cause mortality and/or cardiovascular events (CVE) in patients with chronic kidney disease (CKD).A total of 259 patients with CKD stages 1-5 were followed up in a time-to-event analysis for all-cause mortality and fatal and non-fatal CVE (including death, stroke, and myocardial infarction). Baseline measurements included serum uric acid and ADMA and endothelial function [ultrasound determined flow-mediated dilatation (FMD)].As a measure of endothelial function, log FMD value was positively associated with log eGFR, but negatively associated with log ADMA and log uric acid levels. During follow-up (median 38 months), 24 (9.3 %) deaths, 90 (34.7 %) CVE, and 95 (36.7 %) deaths and CVE (composite outcome) occurred. In the univariate Cox analysis, patients with both serum uric acid and ADMA levels above the median had an increased risk of all-cause mortality, CVE, and the composite outcome (HR 5.06, 95 % CI 2.01-12.76; HR 4.75, 95 % CI 2.98-7.59; and HR 4.13, 95 % CI 2.66-6.43, respectively). However, after adjustment for renal-specific risk factors (glomerular filtration rate, proteinuria, and hsCRP), this association was maintained only for CVE and the composite outcome. The addition of both biomarkers into a model with traditional and renal-specific risk factors did not increase the prediction abilities of the model for none of the three outcomes.Elevated serum uric acid and ADMA levels are associated with an increased cardiovascular risk, but their combination does not improve risk prediction. The effects are not additive, possibly because uric acid may lie in the causal pathway by which ADMA acts.

WOS: 000392937800028 PubMed ID: 28006774 Background/Aims: Fabry disease is a treatable cause of chronic kidney disease (CKD) characterized by a genetic deficiency of a-galactosidase A. European Renal Best Practice (ERBP) recommends screening for Fabry disease in CKD patients. However, this is based on expert opinion and there are no reports of the prevalence of Fabry disease in stage 1-5 CKD. Hence, we investigated the prevalence of Fabry disease in CKD patients not receiving renal replacement therapy. Methods: This prospective study assessed a-galactosidase activity in dried blood spots in 313 stage 1-5 CKD patients, 167 males, between ages of 18-70 years whose etiology of CKD was unknown and were not receiving renal replacement therapy. The diagnosis was confirmed by GLA gene mutation analysis. Results: Three (all males) of 313 CKD patients (0.95%) were diagnosed of Fabry disease, for a prevalence in males of 1.80%. Family screening identified 8 aditional Fabry patients with CKD. Of a total of 11 Fabry patients, 7 were male and started enzyme replacement therapy and 4 were female. The most frequent manifestations in male patients were fatigue (100%), tinnitus, vertigo, acroparesthesia, hypohidrosis, cornea verticillata and angiokeratoma (all 85%), heat intolerance (71%), and abdominal pain (57%). The most frequent manifestations in female patients were fatigue and cornea verticillata (50%), and tinnitus, vertigo and angiokeratoma (25%). Three patients had severe episodic abdominal pain attacks and proteinuria, and were misdiagnosed as familial Mediterranean fever. Conclusions: The prevalence of Fa bry disease in selected CKD patients is in the range found among renal replacement therapy patients, but the disease is diagnosed at an earlier, treatable stage. These data support the ERBP recommendation to screen for Fabry disease in patients with CKD of unknown origin. (C) 2016 The Author(s) Published by S. Karger AG, Basel Sanofi Genzyme Corporation; Intensificacion ISCIII and REDINREN [RD012/0021] We are indebted to our patients and their families for volunteering to contribute their medical information to the physicians who are dedicated to their care. This work was supported by grants from Sanofi Genzyme Corporation. The lead investigator had full access to all data in the study. All investigators take responsibility for the accuracy of the individual data that they entered in the system provided by FMF Arthritis Vasculitis and Orphan disease Research (FAVOR). AO was supported by Intensificacion ISCIII and REDINREN RD012/0021.

Cardiovascular events make up the primary cause of death in hemodialysis patients, and the risk for cardiovascular mortality is significantly increased by vascular calcification, a condition observed frequently in this patient population. The mechanisms underlying the pathogenesis of vascular calcification are complex, and many factors facilitate or hinder the development of calcification. In this review, we first summarize the main factors contributing to the pathogenesis of vascular calcification in patients with end-stage renal disease. We then explore the role of calcification inhibitors in the calcification process, as well as their effect on vascular dysfunction and mortality in hemodialysis patients.

Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family best known as a novel and early marker of acute kidney injury (AKI). Recent data suggest that NGQueryAL is not only a marker of AKI, but also an important player in the vascular remodeling, atherosclerotic plaque stability and thrombus formation. We conducted this study to investigate the association of serum NGAL levels with fatal and composite (fatal and non-fatal) cardiovascular events (CVE) in a cohort of patients with stage 1–5 CKD. This was an observational cohort study in which serum NGAL was obtained from 298 CKD (stages 1–5) patients. Fatal and composite CVE were recorded for a median 41 months. We examined alteration of serum NGAL through CKD groups as well as association with inflammatory markers. We also performed a Cox regression analysis to determine the association of NGAL with predefined clinical outcomes. The median value of NGAL was 50.5 ng/mL (IR 47.6–54.9 ng/mL), and higher NGAL values were recorded in diabetic patients. In a multiple linear regression model, including all univariate associates of NGAL, only log eGFR, log hs-CRP and log HDL cholesterol maintained an independent association with log NGAL. During the observational period, 30 patients died due to cardiovascular causes and 69 non-fatal CVE were registered. In the fully adjusted model, we observed a 2.08-fold increase in the risk of fatal CVE and a 1.50-fold increase in the risk of fatal and non-fatal CVE for each increment of 1 SD in log NGAL values. This is the first study that shows that serum NGAL is associated with cardiovascular events (fatal and non-fatal) in patients with CKD, independently of traditional risk factors, renal function and inflammation.

The role of reversibility of nontraditional risk factors, like inflammation and CKD-mineral bone disorder, in the reduction of cardiovascular risk after renal transplantation is still scarcely defined.The longitudinal relationship between C-reactive protein, CKD-mineral bone disorder biomarkers, and intima media thickness was investigated in a series of 178 patients (age=32±10 years) with stage 5 CKD maintained on chronic dialysis who underwent echo-color Doppler studies of the carotid arteries before and after renal transplantation. Smokers and patients with diabetes were excluded from the study. In all patients, immunosuppression was performed by a standard regimen on the basis of calcineurin inhibitors. Healthy controls were specifically selected to match the age and sex distribution of the patients. Biochemical and intima media thickness assessments were repeated 6 months after transplantation.Before transplantation, intima media thickness in patients with stage 5 CKD on dialysis (average=0.9±0.2 mm) was higher (P0.001) than in well matched healthy controls (0.6±0.1 mm) and reduced substantially (-22%; 95% confidence interval, -24% to -20%) after transplantation (P=0.001). GFR (multivariable-adjusted β=0.23; P0.001), C-reactive protein (β=0.15; P0.001), and fibroblast growth factor 23 (β=0.28; P0.001) were the strongest independent correlates of intima media thickness before transplantation. Similarly, longitudinal changes in the same biomarkers were the sole independent correlates of simultaneous changes in intima media thickness (C-reactive protein: β=0.25; fibroblast growth factor 23: β=0.26; P0.001 for both) after renal transplantation. The evolution of intima media thickness after transplantation was largely independent of classic risk factors, including BP, LDL cholesterol, and insulin resistance, as measured by homeostatic model assessment.Intima media thickness improves after renal transplantation. Such an improvement associates with parallel changes in serum C-reactive protein and fibroblast growth factor 23. These observations are in keeping with the hypothesis that the decline in cardiovascular risk after transplantation, in part, depends on partial resolution of nontraditional cardiovascular risk factors, like inflammation and CKD-mineral bone disorder.

Patients with hypogonadism have poor cardiovascular and metabolic outcomes, and the effect of testosterone replacement therapy (TRT) is not clear. We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects. A total of 60 patients with CHH (mean age 21.82±2.22 years) and 70 healthy control subjects (mean age 21.32±1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT. The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p

Background: Atrial electromechanical delay (AEMD) times were considered independent predictors of cardiovascular morbidity among the general population. We aimed at evaluating AEMD times and other risk factors associated with 2-year combined cardiovascular (CV) events in HD patients. Material and Methods: Sixty hemodialysis (HD) and 44 healthy individuals were enrolled in this prospective study. Echocardiography was performed before the mid-week dialysis session for HD patients. Data were expressed as mean ± SD. Spearman test was used to assess linear associations. Survival was examined with the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the predictors of combined CV events in this cohort. Results: At the beginning of the study, left intra-atrial-AEMD times were significantly longer in HD patients compared to the left intra-atrial-AEMD times in healthy individuals. After 24 months, 41 patients were still on HD treatment and 19 (31.6%) had died. Serum triglyceride, total cholesterol and albumin were found to be higher and C-reactive protein (CRP) levels, left intra-atrial EMD time (LIAT) and interatrial EMD times were found to be lower in survived HD patients. With the cut-off median values of 3.5 g/dl for albumin, 0.87 mg/dl for CRP, 157 mg/dl for total cholesterol and 151 mg/dl for triglyceride, the Kaplan-Meier curves demonstrated significant differences in terms of all-cause mortality. We also demonstrated the Kaplan-Meier survival curves of HD patients according to tertile values of LIAT. Cox regression analysis revealed that increased CRP and higher LIAT were found to be independent predictors of combined CV events. Conclusions: Increased LIAT and inflammation were found to be closely associated with 2 years combined CV events and all-cause mortality in HD patients.

Background Profilin-1 is a ubiquitous, actin-binding protein that plays an important role in the regulation of actin polymerization and cytoskeleton remodeling thus contribute vascular dysfunction.We conducted this study to investigate the association of serum profilin-1 levels with fatal and non-fatal CVE in a cohort of patients with stage 1-5 CKD. Matherials and methods Serum concentrations of profilin-1 levels were determined by enzyme-linked immunosorbent assay. Endothelium-dependent vasodilatation (flow-mediated dilatation (FMD) and endothelium-independent vasodilatation (nitroglycerine mediated dilatation (NMD) of the brachial artery were assessed non-invasively, using high-resolution ultrasound. Results Both fatal and non-fatal CVE was significantly higher in patients with high profilin-1 levels. Kaplan–Meier survival curves showed that patients with profilin-1 below the median value (114 pg/ml) had higher cumulative survival compared with patients who had profilin-1 levels above the median value (log-rank test, P

The chronic kidney disease (CKD)-mineral and bone disorder (MBD) syndrome is an important contributor to the CKD-associated cardiovascular disease and high mortality rates. Sclerostin, a protein synthesized in osteocytes, is a potent downregulator of bone metabolism and a novel candidate for the bone-vascular axis in CKD patients. We tested whether serum sclerostin values are predictive for all-cause mortality and cardiovascular events (CVEs) in a CKD population.Serum sclerostin was obtained from 173 CKD (stage 3-5) and 47 control patients, and its concentration was correlated with estimated glomerular filtration rate and to mineral and vascular abnormalities that are present in the CKD evolution. All-cause mortality and CVEs were also analyzed in relation to serum sclerostin values.Patients with CKD showed higher sclerostin levels (median 63.5 pmol/L vs 52 pmol/L, P.001) than controls, with values progressively higher across the CKD stages. In univariate analysis, serum sclerostin concentrations were correlated with gender, estimated glomerular filtration rate, flow-mediated dilatation, and endothelium-independent vasodilatation as markers of endothelial dysfunction and with different serum CKD-MBD-associated parameters. However, in multivariate analysis, only gender, fibroblast growth factor-23, phosphate, flow-mediated dilatation, and cholesterol remained significantly associated with sclerostin levels. During the observational period, there were 19 deaths and 50 CVEs. In survival analysis, different sclerostin levels were associated with all-cause mortality and CVEs in these patients.This is the first study that shows that serum sclerostin values are associated, even after multiple adjustments, with fatal and nonfatal CVEs in a nondialyzed CKD population.

To determine the relationships between inflammatory mediators, mitral annular calcification (MAC), and osteocalcin in patients with chronic kidney disease (CKD).Echocardiographic data for 60 patients diagnosed as CKD were retrospectively evaluated. The patients were divided into 2 groups; patients with MAC (MAC+ group) and patients without MAC (MAC- group). The relationships between biochemical markers-including osteocalcin-and MAC were evaluated.The study included 19 female and 41 male patients. In all, 29 patients were MAC+ and 31 were MAC-. High-sensitive C-reactive protein (hsCRP) and osteocalcin levels were significantly higher in the MAC+ group (p 0.05). The eGFR was lower, serum calcitonin (we could not obtain calcitonin data for 15 patients), Ca, PO4, CaxPO4, the erythrocyte sedimentation rate, red cell distribution width, the neutrophil/Lymphocyte rate, and PTH were higher in the MAC+ group; however, the differences between the groups were not significant (p 0.05). The mitral E/A ratio, mitral peak Ea velocity, tricuspid E/A ratio, hsCRP, and the osteocalcin level were strongly correlated with MAC. Multivariate logistic regression analysis showed that only the osteocalcin level and mitral E/A ratio were independent variables, each with an independent effect on MAC.CKD patients in the MAC+ group had higher osteocalcin levels than those in the MAC- group, and left ventricular diastolic dysfunction was more common in the MAC+ group.

Objectives. Secondary amyloidosis is the most important complication of FMF and endothelial function is more severely impaired. Elevated asymmetric dimethyl arginine (ADMA) may mediate the excess cardiovascular disease (CVD) risk of this group. We aimed to compare endothelial function characteristics, including ADMA, in patients with FMF-related amyloidosis and primary glomerulopathies and to define risk factors for a CVD event. Methods. We undertook a cross-sectional study with prospective follow-up including consecutive patients with FMF-related amyloidosis (n = 98) or other non-diabetic glomerulopathies (n = 102). All patients had nephrotic-range proteinuria and normal glomerular filtration rate. Flow-mediated dilatation (FMD) was assessed and ADMA levels, CRP and pentraxin 3 (PTX3) were determined. Patients were followed for cardiovascular events. Results. Amyloidosis patients secondary to FMF showed higher levels of ADMA, CRP and PTX3 and lower FMD as compared with patients with other glomerulopathies. Cardiovascular events (n = 54) were registered during 3 years of follow-up. Increased ADMA levels and lower FMD were observed in patients with cardiovascular risk in both groups, but especially in individuals with amyloidosis. Conclusion. Patients with FMF-related amyloidosis have increased CVD event risk, probably related to the high ADMA levels, elevated inflammatory markers and decreased FMD measures observed in these patients.

Background Red cell distribution width (RDW) is a measure of erythrocyte size variability and has been shown as an independent predictor of mortality. The aim of this article was to evaluate the association of RDW with endothelial dysfunction in patients with chronic kidney disease (CKD). Methods Patients with 1 to 5 stages of CKD were included in the study. Endothelial function was assessed with flow-mediated dilatation (FMD). Estimated glomerular filtration rate (eGFR) and carotid intima media thickness (CIMT) were determined. Clinicode-mographic characteristics, biochemical values, complete blood counts, ferritin, C-reactive protein (CRP) and cholesterol levels were recorded. Spearman's correlation was used to determine correlates of RDW. Multivariate linear regression model was used to assess independent associates of FMD. Results Overall, 367 patients with CKD 1 to 5 were included in the study. RDW showed a significant increase from stage 1 to stage 5 CKD. Median RDW was 13.5. Patients with RDW values higher than median had significantly lower hemoglobin, eGFR and FMD values and higher CIMT and CRP values compared with patients who had RDW values below median. RDW showed a significant positive correlation with the presence of diabetes mellitus, CIMT and CRP, whereas a significant negative correlation with eGFR, ferritin and FMD. Multivariate analysis showed independent predictors of FMD as RDW, presence of diabetes, hemoglobin, eGFR, CRP, and serum albumin. Conclusions Multivariate regression model revealed RDW as a significant predictor of FMD independent of major confounding factors, such as diabetes, inflammation, anemia and kidney function in CKD.

Background/Aims: Ramipril attenuates renal Fibroblast growth factor-23 (FGF-23) expression, ameliorates proteinuria and normalizes serum phosphate in the diabetic Zucker rat with progressive renal disease suggesting that the renoprotective effect by this drug may be in part due to a FGF-23-lowering effect of angiotensin-converting enzyme (ACE) inhibition. Methods: In this nonrandomized study, we tested whether ACE-inhibition reduces circulating FGF-23 in type-2 diabetics with stage-1 chronic kidney disease (CKD) and proteinuria. Intact FGF-23, the eGFR, proteinuria and the endothelium-dependent flow-mediated (FMD) response to ischemia and other parameters were measured at baseline and after 12-weeks of treatment with ramipril (n = 68) or amlodipine (n = 32). Results: Blood Pressure (BP) fell to a similar extent (p < 0.001) in the two groups. However, 24 h proteinuria and the FMD improved more (both p < 0.01) in ramipril-treated patients than in amlodipine-treated patients. Changes in proteinuria (r = 0.47) and in FMD (r = -0.49) by ramipril were closely associated (p < 0.001) with simultaneous changes in FGF-23 and this link was confirmed in multiple regression analyses. In these analyses, the relationship between FMD and proteinuria changes attained statistical significance (p < 0.01) only in a model excluding FGF-23 suggesting that endothelial dysfunction and FGF-23 share a common pathway conducive to renal damage. Conclusion: Findings in this study contribute to generate the hypothesis that FGF-23 may be implicated in proteinuria and in endothelial dysfunction in diabetic nephropathy (clinicaltrials.gov (NCT01738945)).

Background In this study, we examined the relative usefulness of serum copeptin levels as a surrogate marker of vasopressin (AVP) in adult polycystic kidney disease (ADPKD) by correlating it with baseline and longitudinal changes in markers of both renal function and common CVD manifestations (hypertensive vascular disease, atherosclerosis and endothelial dysfunction) that accompany the progression of this disease. Methods We studied a cohort of young and otherwise healthy ADPKD patients (n = 235) and measured cardiovascular function using flow-mediation dilatation (FMD), carotid intima media thickness (cIMT) and pulse wave velocity (PWV), as well as serum copeptin (commercial ELISA, a stable marker of AVP activity). The same analyses were carried out at baseline and after 3 years of follow-up. Results At baseline, median eGFR was 69 mL/min./1.73 m2, mean FMD 6.9 ± 0.9%, cIMT 0.7 ± 0.1 mm, and PWV 8.1 ± 1.2 m/s. At follow-up, equivalent values were 65 (44–75) mL/min./1.73 m2, 5.8 ± 0.9%, 0.8 ± 0.1 mm. and 8.2 ± 1.3 m/s. with all changes statistically significant. Plasma copeptin also rose from 0.62 ± 0.12 to 0.94 ± 0.19 ng/mL and this change correlated with ΔeGFR (-0.33, p 0.76], and ΔPWV [cut-off:≤7.80]. Conclusions Vascular dysfunction as reflected by FMD and cIMT, but not PWV or an altered cardiac geometry, precede most other signs of disease in ADPKD but is predicted by elevated levels of the circulating AVP-marker copeptin.

Background Soluble TWEAK (sTWEAK) and asymmetric dimethyl arginine (ADMA) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). We tested the hypothesis that the improvement in endothelial function observed after renal transplantation is directly linked to the normalization of both sTWEAK and ADMA. Materials and methods One hundred and seventy-five kidney transplant recipients (71% men; 31·6 ± 9·4 years) were studied immediately before and on the 180th day post-transplantation. At each visit, blood samples were taken to assess circulating levels of sTWEAK and ADMA. Brachial artery endothelium-dependent vasodilatation (FMD) assessments were also performed. Results Renal transplantation was followed by an improvement in FMD. This improvement was paralleled by an increase in sTWEAK and a reduction in ADMA after transplantation (P

Increased inflammation is common in patients with chronic kidney disease (CKD) and is associated with increased adverse cardiovascular events (CVE). Neutrophil-to-lymphocyte ratio (NLR) was used to predict survival in patients with acute coronary syndrome. We aimed to evaluate predictive ability of NLR in CKD patients.225 subjects with stage 3-5 CKD were followed for a mean of 39 months. Fatal and nonfatal CVE were recorded during this period. NLR at baseline was determined from complete blood count differential. Endothelial dysfunction (flow-mediated dilation, FMD), hsCRP and insulin resistance were determined. We investigated if NLR could predict development of fatal and nonfatal CVE. We also looked at how NLR and its individual components change across CKD stages and whether NLR is related to CRP, insulin resistance and endothelial dysfunction.There were 70, 74 and 81 patients in groups of CKD stage-3, stage-4 and stage-5, respectively. Median NLR was 2.81. NLR showed a significant increase from stage 3 to stage 5. NLR was inversely associated with FMD independent of hsCRP. 14 fatal and 52 nonfatal CVE occurred during follow-up period. NLR could predict composite CVE independent of insulin resistance and hsCRP. Increased NLR over 2.81 was related to a significantly decreased survival time (log-rank Chi-square = 14.833, P0.0001). A cutoff value for NLR ≥3.76 could predict development of composite CVE with 80.3 % sensitivity and 91.8 % specificity.NLR is independently related to endothelial dysfunction and could predict composite cardiovascular endpoints independent of traditional confounding factors in patients with moderate to severe CKD.

PurposeThe major cause of morbidity in hemodialysis patients is arteriovenous fistula deficiency. The patient should have adequate knowledge to ensure arteriovenous fistula patency. Our aim is to investigate the knowledge and attitude of the patients undergoing hemodialysis treatment regarding arteriovenous fistula.MethodsThis study was conducted on 335 patients who met the study criteria. Data collection forms evaluating the “Socio-Demographic and Medical Characteristics” and “Knowledge and Attitudes about arteriovenous fistula” of the patients were developed following a literature review by the investigators.ResultsThe rules most known and implemented were “to not measure blood pressure” and “to not draw blood from arms with fistula”, while the least known and implemented were “to use blood vessels on the hands in arms without fistula for intravenous intervention” and “to know which situations cause hypotension”.ConclusionsHemodialysis patients with arteriovenous fistulas need to know that developing self-care behavior is a means to reconcile lifestyles with current health status. Accordingly, planned training in self-care should be provided to hemodialysis patients and their families, and nurses should repeat information to patients who demonstrate a lack of knowledge.

Background and aims Endostatin, generated from collagen XVIII, and endorepellin, possess dual activity as modifiers of both angiogenesis and endothelial cell autophagy. Plasma endostatin levels are elevated in a large number of diseases, and may reflect endothelial cell dysfunction. Few data on endostatins are available for patients with chronic kidney disease (CKD). We tested whether serum endostatin values are predictive for all-cause mortality and cardiovascular events (CVEs) in a CKD population. Materials and method A total of 519 CKD pre-dialysis patients were included. Baseline plasma endostatin levels were measured in all patients. All included patients were followed-up (time-to-event analysis) until occurrence of death, fatal or nonfatal CVEs. Fatal and nonfatal CVE including death, stroke, and myocardial infarction were recorded prospectively Results The mean age of the patients was 52.2 ± 12.3 years. There were 241 (46.4%) males, 111 (21.4%) had diabetes, 229 (44.1%) were smokers and 103 (19.8%) had a previous CVE. After a median follow-up of 46 months, 46 patients died and 172 had a new CVE. In the univariable Cox survival analysis, higher endostatin levels were associated with a higher risk for both outcomes. However, after adjusting for traditional (age, gender, smoking status, diabetes, systolic blood pressure, HDL and total cholesterol) and renal-specific (eGFR, proteinuria and hsCRP) risk factors, endostatin levels remained associated only with the CVE outcome (HR = 1.88, 95% CI 1.37–2.41 for a 1 SD increase in log endostatin values). Conclusion Endostatin levels are independently associated with incident CVE in CKD patients, but show limited prediction abilities for all-cause mortality and CVE above traditional and renal-specific risk factors.

Background: Plasma levels of estimated whole blood viscosity (eWBV) have been increased by endothelial inflammation. Because there were no consistent data for assessing the eWBV levels for prediction of cardiovascular event (CVE) in patients with chronic kidney disease (CKD). We aimed to investigate the relationship between plasma eWBV levels and CVEs in patients with CKD. Materials and Methods: We conducted a prospective, cross-sectional, long-term follow-up study, assessing the relationship between plasma eWBV levels and CVE (either fatal or nonfatal) in patients with newly diagnosed CKD. We also evaluated estimated glomerular filtration rate (eGFR), pentraxin 3 (PTX3), high-sensitivity C-reactive protein (hsCRP), and flow-mediated dilatation (FMD). Results: Study patients were divided into 2 groups: patients with CVE and patients without CVE. The eWBV levels were higher in patients with CVE. Additionally, PTX3 and hsCRP were higher, and FMD and eGFR were lower in patients with CVE compared to those without CVE. According to the Cox regression analysis, WBV, plasma asymmetric dimethylarginine levels, FMD, hsCRP, eGFR, systolic blood pressure, calcium, and history of diabetes were independent predictors of CVEs in patients with CKD. Kaplan Meier survival curves were generated to establish the impact of the WBV on the cumulative survival of the cohort. Patients with eWBV values higher than 5.2 centipoise (cP) had lower survival rates when compared to patients with eWBV values lower than 5.2 cP (log rank = 4.49 df = 1 P = .034). Conclusion: In conclusion, plasma eWBV levels may increase the presence of lower eGFR and affect CVE in patients with CKD independent of classical and unconventional risk factors.

Increasing evidence suggests that inflammation and increased macrophage activity have a central role in pathogenesis of atherosclerosis. It is shown that chitotriosidase (CHIT-1) is a marker of macrophage activity in atherosclerotic plaque, and is found associated with severity of atherosclerotic lesion. There is no data about CHIT-1 activity of hemodialysis patients in the literature. Thus, we hypothesized that in hemodialysis patients, CHIT-1 levels might be a novel biomarker in early atherosclerosis.Forty-five hemodialysis patients were included in the study (age: 61.93 ± 13.34). Intima media thickness (IMT) was evaluated with high-resolution B-mode ultrasonography. Biomarker levels were measured in serum of patients.We found positive correlation among IMT, age (R: 0.426, P: 0.004) and, CHIT-1 value (R: 0.462, P: 0.001) in spearman correlation analysis. When age, CRP, creatinine, P, Alb, CHIT-1 were chosen as measures that can effect IMT in multiple regression model, IMT level was related with CHIT-1 (Beta: 0,396, P: 0.012) and age (Beta: 0,313 P: 0,048) independently.In conclusion, this is the first report showing that serum CHIT-1 level was related independently with carotid IMT in hemodialysis patients. This biomarker might have an unknown role in the development of atherosclerosis during uremia.

Patients with hypogonadism are at increased risk of cardiac and metabolic diseases and osteoporosis. Vitamin D and Fibroblast growth factor-23 (FGF-23) play role in the regulation of bone mineral metabolism and endothelial functions. Low vitamin D levels are reported in hypogonadism, while there is no data about the effect of testosterone replacement therapy (TRT). We investigated the effect of TRT on vitamin D and FGF-23 levels along with endothelial functions and insulin resistance in hypogonadal patients.Patients with congenital hypogonadotrophic hypogonadism (CHH) (n=32, age 20.6 ±1.58 years) were enrolled. TRT was implemented in transdermal form. The demographic parameters, FGF-23, 25(OH)D3, Asymmetric dimethylarginine (ADMA) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured both before and after TRT.After a follow-up period of 3.63±1.33 months, ADMA and FGF-23 levels were significantly increased (p=0.03 and p=0.005 respectively), while the 25(OH)D3 and HOMA-IR index were not significantly changed. The body mass index and waist circumference levels of the patients were also increased (p0.001 and p=0.02) along with a significant decrease in the HDL cholesterol levels (p=0.006).The results show that a short term TRT increases plasma FGF-23 and ADMA levels, in young, treatment naive patients with CHH. Whether this is an early implication of TRT related adverse effects in this very young and treatment naïve population of CHH is not clear. Future prospective studies are required to find out the long-term effects of TRT on cardio-metabolic morbidity and mortality in this specific population.

It is yet to be established which factors are responsible for differences among patients with the same degree of coronary artery disease in terms of coronary collateral development (CCD).Patients who had a greater than or equal to 95% stenosis in at least one epicardial coronary artery were classified into two groups according to their glomerular filtration rate (GFR) level. Afterwards, the degree of CCD was evaluated according to their plasma concentration of asymmetric dimethylarginine (ADMA) and GFR levels.Rentrop grade 2-3 was found more frequently in patients with GFR60 mL/min than in patients with GFR60 mL/min (68.6% vs 41.4%, p = 0.032). Then we divided patients into four groups according to their GFR levels and Rentrop grades; whereas we did not find any significant difference for L-arginine or ADMA levels (respectively p = 0.629 and p = 0.076), we did find a statistically significant difference between groups for L-arginine/ /ADMA ratio (p = 0.003) and this statistically significant difference was evident between patients with GFR60 mL/min and Rentrop 0-1 and patients with GFR60 mL/min and Rentrop 2-3 (1.23 vs 1.69, p0.001). Multivariate logistic regression analysis revealed that L-arginine/ADMA ratio was the only variable which had a significant effect on CCD (OR = 1.016; 95% CI 1.001-1.031, Wald = 4.565; p = 0.033).These results showed that CCD was poor in patients with GFR60 mL/min, presumably because of the adverse effect of decreased L-arginine/ADMA ratio on endothelial cells and angiogenesis.

Background: Magnesium is an essential ion for all living cells because over 300 enzymes require the presence of magnesium for their catalytic action. To date, no group has evaluated magnesium as a cardiovascular risk factor in chronic kidney disease (CKD) subjects, in which closely interrelated factors and potential confounders such as endothelial dysfunction, insulin resistance (the homeostasis model assessment (HOMA) index) and inflammation (expressed as serum C-reactive protein (CRP) levels) were also considered. Methods: Between March 2006 and December 2010, 283 CKD patients were followed up for time-to-event analysis until the occurrence of fatal or nonfatal cardiovascular events. Endothelium-dependent vasodilatation (flow-mediated dilatation; FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation) of the brachial artery were assessed noninvasively using high-resolution ultrasound. Results: From the univariate analysis of FMD, it appears that a higher magnesium level is associated with less endothelial dysfunction. When a multivariate analysis was performed, magnesium and estimated glomerular filtration rates (eGFR) maintained a strong positive correlation with FMD, supporting the hypothesis that higher levels of magnesium may protect against endothelial damage. In univariate Cox proportional hazards models, FMD, magnesium, high sensitivity CRP, the HOMA index, eGFR, comorbid diabetes, hypertension, smoking status, systolic blood pressure, serum phosphate and intact parathormone emerged as significant predictors for cardiovascular outcomes. Kaplan-Meier curves showed significantly higher cardiovascular mortality rates in CKD patients whose serum magnesium levels were below 2.05 mg/dl. Conclusions: This observational cohort study showed that magnesium may be an independent predictor of future cardiovascular outcomes and is the first study demonstrating such a role in etiologically diagnosed CKD patients, across different stages.

Orscelik, Ozcan/0000-0003-4349-9852; orscelik, ozcan/0000-0003-4349-9852; KOCYIGIT, ISMAIL/0000-0002-6654-4727 WOS: 000305812300002 PubMed: 22699414 Background/Aims: Cardiovascular disease is the main cause of morbidity and mortality in autosomal-dominant polycystic kidney disease (ADPKD) patients. To clarify temporal relationship between ADPKD, hypertension and the loss of renal function, we examined these factors in patients with early-stage ADPKD who did not yet have hypertension. Methods: Fifty patients with ADPKD (42% males, 36.6 +/- 8 9.9 years, no blood pressure medication) and 50 healthy controls (44% males, 35.4 +/- 8 6.4 years) were studied cross-sectionally. Pulse wave velocity (PWV), cardiac morphology and function, aortic elastic indexes, estimated glomerular filtration rate (eGFR), 24-hour ambulatory blood pressure, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and highly sensitive C-reactive protein (hs-CRP) were measured in all participants, using conventional methods. Results: Despite a normal blood pressure, aortic stiffness index and pulse wave velocity values were increased in patients compared to controls (6.8 +/- 4.7 vs. 5.1 +/- 3.3, p = 0.043 and 9.6 +/- 1.3 vs. 5.8 +/- 1.1 m/s, p < 0.001). In univariate analysis, IL-6, TNF-alpha, hs-CRP and eGFR were all significantly correlated with PWV. The independence of these correlations were analyzed in a regression model, and showed PWV to be significantly predicted by IL-6, TNF-alpha and hs-CRP. Conclusion: Increased arterial stiffness and pulse wave velocity are early manifestations of ADPKD appearing before hypertension or reduced eGFR. However, these vascular abnormalities are related to signs of systemic low grade inflammation, suggesting a common pathophysiological mechanism apparently present also in other vascular diseases but yet to be elucidated. Copyright (C) 2012 S. Karger AG, Basel

Background: Chronic kidney disease (CKD) is associated with increased risk for cardiovascular (CV) disease and is also associated with elevated uric acid, which is emerging as a nontraditional CV risk factor. We therefore evaluated uric acid as a risk factor for CV disease in subjects presenting to nephrologists with CKD who were not on medications known to alter endothelial function. Methods: 303 subjects with stage 3–5 CKD were followed for a mean of 39 months (range 6–46) and assessed for fatal and nonfatal CV events. Hyperuricemia was defined as uric acid >6.0 mg/dl for women and >7.0 mg/dl for men. In addition to other CV risk factors, endothelial function (flow-mediated dilatation), inflammatory markers (hsCRP), and insulin resistance (HOMA index and fasting insulin levels) were included in the analysis. We evaluated the association between uric acid and flow-mediated dilatation with linear regression. The impact of uric acid on composite CV events was assessed with Cox regression analysis. Results: Of a total of 303 patients, 89 had normouricemia and 214 had hyperuricemia. Both fatal (32 of 214 vs. 1 of 89 subjects) and combined fatal and nonfatal (100 of 214 vs. 13 of 89 subjects) CV events were more common in subjects with hyperuricemia compared with normal uric acid levels, and this was independent of estimated glomerular filtration rate, traditional CV risk factors including diabetes, hypertension and BMI, and nontraditional risk factors (hsCRP and endothelial function). The 46-month survival rate was 98.7% in the group with low uric acid compared to 85.8% in patients with high uric acid (p = 0.002). Conclusions: Hyperuricemia is an independent risk factor for CV events in subjects presenting with CKD who are not on medications known to alter endothelial function.

Diabetic nephropathy (DN) is a major manifestation of microangiopathy in patients with Diabetes Mellitus (DM). Inflammation is one of the major factors in the formation of endothelial dysfunction. Endothelial dysfunction is a major contributor to the complications of DM. The aim of the present study was to investigate the possible relationship between inflammation, endothelial dysfunction and proteinuria in patients with diabetic nephropathy.Plasma TNF-α and IL-6, pro-inflammatory cytokines, concentrations were measured in 25 patients with DN and in 30 diabetic control subjects. Also, we evaluated the markers of endothelial dysfunction such as flow mediated dilatation (FMD), nitrate-mediated dilatation (NMD) and carotid intima-media thickness (CIMT).TNF-α, IL-6 and high-sensitivity C-reactive protein concentrations were significantly higher (p = 0.012, p = 0.006 and p0.001, respectively) in the patients with DN than the controls. And, urinary protein concentrations were significantly higher (p0.001) but eGFR levels were significantly lower (p0.001) in the patients with DN. FMD was significantly lower in DN patients (p0.001). We have observed that FMD correlated negatively with body mass index (r = -0.424, p0.05). And there was also a positive correlation between TNF-α and urinary protein concentrations in the patients with DN (p0.05).TNF-α, IL-6, hsCRP and urinary protein concentrations are higher in the DN patients. There were no correlations among pro-inflammatory cytokines concentrations and markers of vascular endotelial disfunction. These findings did not show vascular endothelial dysfunction, but may indicate glomerular endothelial dysfunction.

Summary Background and objectives Deterioration of kidney function impairs testosterone production, with hypogonadism being common in men with chronic kidney disease (CKD). In nonrenal populations, testosterone is suggested to participate in the atherosclerotic process. In male dialysis patients, we showed that low testosterone increases the risk of mortality. We here studied plausible links among testosterone levels, vascular derangements, and cardiovascular events in nondialysis CKD men. Design, setting, participants, & methods This was a cross-sectional analysis in which flow-mediated dilation (FMD) was assessed in 239 CKD male patients (stages 1 to 5; mean age 52 ± 12 years), together with routine measurements, serum total and free testosterone, and follow-up for cardiovascular outcomes. Results Total and free testosterone levels decreased in parallel with the reduction of kidney function. Multiple regression analyses showed that total and free testosterone significantly and independently contributed to explain the variance of FMD. After a median follow-up of 31 months (range 8 to 35 months), 22 fatal and 50 nonfatal cardiovascular events occurred. In Cox analysis, the risk of cardiovascular events was reduced by 22% for each nanomole-per-liter increment of total testosterone. This reduced risk persisted after adjustment for age, renal function, diabetes mellitus, previous cardiovascular history, C-reactive protein, albumin, and FMD. The same was true for free testosterone concentrations. Conclusions The reduction in endogenous testosterone levels observed with progressive CKD was inversely associated with endothelial dysfunction and exacerbated the risk of future cardiovascular events in nondialysis male CKD patients.

Introduction. Systemic inflammation, endothelial dysfunction and arterial thickening contribute to the elevated cardiovascular risk of dialysis patients. However, the course of these derangements and their relative contribution to the cardiovascular risk of nondialysed chronic kidney disease (CKD) are scarcely investigated. Methods. Flow-mediated dilatation (FMD) and intimamedia thickness (IMT) were assessed in 304 nondialysed CKD patients Stages 1–5 (mean age 46 6 12 years, 158 men), together with routine biochemical measurements, C-reactive protein (CRP) and insulin resistance. Patients were then followed for time-to-event analysis of cardiovascular outcomes (fatal and nonfatal). Results. CRP and IMT increased, while FMD decreased in parallel with estimated glomerular filtration rate (eGFR) decline (P < 0.001 for all). CRP and intact parathormone, as well as eGFR, appeared as strong determinants of FMD and IMT in multivariate analyses. After a median follow-up of 41 (range 6–46) months, 30 fatal and 59 nonfatal cardiovascular events occurred. In univariate analysis, FMD, IMT and CRP were significant predictors of outcome. In a multivariate Cox model excluding IMT, both FMD [hazard ratios 0.52 (95% confidence intervals 0.37–0.73) per %] and CRP [1.07 (1.03–1.11) per mg/L] predicted cardiovascular outcomes independently of confounders. In a model excluding FMD, only CRP (and not IMT) was a significant predictor. Conclusions. Endothelial dysfunction, arterial thickening and inflammation occur in parallel with the decline in eGFR, contributing to the increased cardiovascular risk of nondialysed CKD. Our results support the use of FMD over IMT measurements to monitor nondialysed CKD patients at risk.

Background: An elevated serum uric acid level is strongly associated with endothelial dysfunction and inflammation, both of which are common in chronic kidney disease (CKD). We hypothesized that endothelial dysfunction in subjects with CKD would correlate with uric acid levels. Materials and Methods: We evaluated the association between serum uric acid level and ultrasonographic flow-mediated dilatation (FMD) in 263 of 486 patients with recently diagnosed CKD (stage 3–5) (48% male, age 52 ± 12 years). To minimize confounding, 233 patients were excluded because they were diabetic, had established cardiovascular complications or were taking drugs (renin-angiotensin system blockers, statins) interfering with vascular function. Results: Serum uric acid level was significantly increased in all stages of CKD and strongly correlated with estimated glomerular filtration rate (eGFR-MDRD); FMD was inversely associated with serum uric acid (r = –0.49, p < 0.001). The association of serum uric acid with FMD remained after adjustment for age, gender, smoking, LDL cholesterol, eGFR, high-sensitivity C-reactive protein, systolic blood pressure, proteinuria, and homeostatic model assessment index (β = –0.27, p < 0.001). Conclusion: Increased serum uric acid is an independent predictor of endothelial dysfunction in subjects with CKD.

Studies in animals show that fibroblast growth factor (FGF)-23 interferes with vascular reactivity induced by the nitric oxide (NO) system. To investigate the relationship between circulating FGF-23 levels and the response of forearm blood flow to ischemia (flow-mediated vasodilatation, FMD) and nitroglycerin, we tested 183 patients with stage 3-4 chronic kidney disease (CKD). None of them had cardiovascular complications or were taking drugs interfering with vascular function. Patients with FGF-23 levels above the median had significantly lower glomerular filtration rate, FMD, and fetuin-A levels (an anti-inflammatory molecule and potent inhibitor of calcification). They also had higher proteinuria and phosphate levels when compared to patients whose FGF-23 levels were below the median. The response to nitroglycerin was not different between the two groups. Multiple regression analysis showed that the relationship between FGF-23 and FMD was only modestly sensitive to adjustment for classical risk factors, biomarkers of bone mineral metabolism, high-sensitivity C-reactive protein, and homeostatic model assessment index. Adjustment for asymmetrical dimethyl arginine (ADMA) weakened the strength of this link; however, it remained highly significant. There was no independent association between FGF-23 and nitroglycerin. Thus, attenuation of FMD by ADMA suggests that this endogenous inhibitor of NO synthase may, in part, mediate the vascular effects of FGF-23 in patients with CKD. © 2010 International Society of Nephrology.

Background and objectives: Soluble TNF-like weak inducer of apoptosis (sTWEAK) and long pentraxin-3 (PTX3) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). This study tested the hypothesis that the improvement in endothelial function after initiation of angiotensin II receptor blocker (valsartan), calcium channel blocker (amlodipine) therapy, or a combination of both is directly linked to the normalization of sTWEAK and PTX3. Design, setting, participants, & measurements: One-hundred-eight diabetic CKD stage I patients with hypertension (56% men, 46.7 ± 5.3 years) were allocated to a 12-week intervention with amlodipine (10 mg/d), valsartan (160 mg/d), or their combination. Plasma levels of sTWEAK, PTX3, and flow-mediated dilation (FMD) were studied during the interventions. Results: All treatment strategies effectively increased FMD and reduced proteinuria, confirming a more prone reduction with the combined therapy. These improvements were followed by significant PTX3 reductions. Valsartan alone and in combination with amlodipine achieved significant incremental raises in sTWEAK plasma levels. More importantly, the changes observed in sTWEAK (β = 0.25, P = 0.006) or PTX3 (β = −0.24, P = 0.007) plasma levels were independently associated with the improvement in ultrasonographically measured FMD. Conclusions: This study shows that treatment with antihypertensive drugs improves FMD and normalizes proteinuria, PTX3, and sTWEAK in diabetic CKD stage I patients with hypertension. The improvement in FMD was independently associated with PTX3 and sTWEAK normalization. Two surrogate biomarkers of endothelial function are therefore identified with potential as therapeutic targets. The study was registered in clinicaltrials.gov as NCT00921570.

Both apelin and asymetric dymethyl arginine (ADMA) regulate blood pressures. Low apelin and high ADMA levels have been reported in several cardiometabolic disorders. However, there is no data about ADMA and apelin levels in essential hypertension and any relationship between them. We investigated a group of newly diagnosed and untreated 30 young hypertensive men and 30 healthy controls. Apelin levels were significantly lower and the ADMA levels were significantly higher in the patients (p = 0.04 for both). Both ADMA and apelin were related to the systolic blood pressures (SBP) (beta = -0.393, p = 0.003; beta = 0.285, p = 0.03, respectively). Future studies are necessary in order to clearly define the role of ADMA and apelin in the pathogenesis of essential hypertension.

Renin-angiotensin system (RAS) blockade improves proteinuria and the endothelial functions in diabetic nephropathy. Plasma asymmetric dimethylarginine (ADMA), abundant in the cell than in the plasma, is also improved by RAS blockage. We hypothesized that RAS blockade may reduce ADMA by reducing injurious cell death.In a hypothesis-generating study, we assessed circulating levels of apoptotic signalling peptides in incident chronic kidney disease (CKD) stage 1 patients (aged18 years with diabetes mellitus type 2 as the only cause of nephropathy) not previously prescribed statins or RAS blockade. Ninety-three (29 M, 47 ± 5 years) patients with CKD 1 diabetic nephropathy and 38 healthy subjects (20 M, 47 ± 5 years) were enrolled. Ramipril was given (5 mg daily for 12 weeks), and circulating ADMA, soluble Fas (sFas), myostatin and endothelial function [flow-mediated vasodilation (FMD); ultrasound)] were measured.After the study, ADMA, sFas, myostatin, insulin resistance, high-sensitive C-reactive protein (hsCRP), estimated glomerular filtration rate (eGFR), blood pressure and proteinuria levels were decreased, and FMD and serum albumin levels increased (P0.05 for all). ADMA and sFas levels were independently related to FMD levels both before (rho = -0.33; P0.005 and rho = -0.26; P0.02, respectively) and after (rho = -0.39; P0.001 and rho = -0.28; P0.002, respectively) ramipril treatment. Changes in sFas and ADMA were related to the change in FMD (-0.32; P0.004 and -0.31; P0.004, respectively).A reduction of proteinuria in CKD 1 diabetic kidney disease is accompanied by lower circulating sFas, myostatin and ADMA, suggesting that increased cell death may contribute to ADMA formation and endothelial dysfunction in diabetic CKD.

Background and objectives: Hemoglobin (Hb) is the main carrier and buffer of nitric oxide. Evidence has been produced that Hb concentration is inversely related with endothelial function in human diseases. Testing whether this association exists also in diabetic patients stage 1 to 2 chronic kidney disease (CKD) is important because anemia in these patients starts at an earlier stage than in other renal diseases. The relationship was investigated between Hb and flow-mediated dilation (FMD) levels of the patients with diabetic nephropathy in a cross-sectional design. Design, setting, participants, & measurements: Eighty-nine diabetics with mild to moderate proteinuria and normal to mildly reduced GFR who were normotensive, nondyslipidemic, and cardiovascular-events free were enrolled. None of the patients was taking metformin or renin-angiotensin system blockers. Results: FMD was inversely related with Hb levels. Furthermore, there was an inverse link between proteinuria and FMD. However, further analysis of this association showed that the FMD-proteinuria link was confined to patients with proteinuria exceeding 150 mg/d, while no such association existed in patients with proteinuria

Background and objectives: Recently, we showed that soluble TNF-like weak inducer of apoptosis (sTWEAK) plasma levels are diminished in hemodialysis patients and had additive effects with IL-6 on survival. Because sTWEAK plasma level has been associated with the presence of chronic kidney disease (CKD) and cardiovascular disease, we hypothesized that in patients with CKD, sTWEAK levels may relate to the increased prevalence of endothelial dysfunction that usually accompanies the decline of estimated GFR (eGFR). Design, setting, participants, & measurements: We studied 295 patients with different stages of nondiabetic CKD (52% male; age 47 ± 12 yr), testing the association between sTWEAK plasma levels and CKD stage and the relationship between flow-mediated dilation (FMD) and sTWEAK concentrations. Fifty-five healthy volunteers (51% male; age 47 ± 11 yr) served as matched control subjects. Results: A gradual decrease in FMD was observed as eGFR decreased. Compared with healthy control subjects, sTWEAK plasma levels were diminished in all stages of CKD and correlated strongly with eGFR. FMD levels were associated with sTWEAK concentrations in univariate analysis. This association persisted after multivariate adjustment for eGFR levels, high-sensitivity C-reactive protein, diastolic BP, and sTWEAK, all of which were found to be significant and independent contributors to FMD. Conclusions: A decline in eGFR is accompanied by gradual reductions in sTWEAK plasma levels. Because sTWEAK strongly and independently correlated with FMD, our study suggests novel links between sTWEAK and endothelial dysfunction in patients with CKD.

The microcirculation is regulated by oxygen gradients and by endothelial release of nitric oxide, which can react with hemoglobin to form S-nitroso derivatives. Here we induced flow-mediated dilatation of the brachial artery in response to ischemia in 141 non-diabetic patients with stage 3-4 chronic kidney disease who had no history of smoking, cardiovascular events or use of erythropoietin-based agents. Patients with hemoglobin concentrations above the cohort median of 11.6 g/dl were found to have significant reductions in flow-mediated dilatation compared to those below the median. This inverse relationship remained significant after adjustment for potential confounders, including insulin sensitivity, glomerular filtration rate, proteinuria, body mass index, serum urate, etiology of underlying renal disease, treatment with anti-hypertensive drugs, and traditional Framingham risk factors. Given that hemoglobin can act as an important nitric oxide carrier and buffer, our studies suggest that the mechanism by which hemoglobin influences the endothelium-dependent microcirculation requires its nitrosylation; however, more direct studies need to be performed.

Adipose tissue appears to be a modulator of vascular injury and systemic inflammation. The aim of this study was to establish the relationship between plasma adiponectin concentration and severity of proteinuria in patients with proteinuria. We enrolled 77 patients with nephrotic and non-nephrotic proteinuria with normal renal function along with 38 matched controls in a cross-sectional study. These patients were divided into group 1 (n = 44, non-nephrotic proteinuria,3.5 g/day) and group 2 (n = 43, nephrotic proteinuria,3.5 g/day) by severity of proteinuria. Circulating adiponectin and high-sensitivity C-reactive protein (hsCRP) levels were measured using commercial ELISA. HOMA index and hsCRP levels were all significantly higher in proteinuric patients than in control subjects, while plasma adiponectin levels were significantly lower (p0.001). When compared to patients with non-nephrotic proteinuria, patients with nephrotic proteinuria had significantly higher plasma hsCRP and HOMA index (p0.001). According to the multiple regression analysis, proteinuria levels were independently related to adiponectin levels. Decreases in adiponectin levels were more prominent in patients with nephrotic proteinuria than in patients with non-nephrotic proteinuria. These results show that the reduction of plasma adiponectin concentrations depend on insulin resistance and inflammation rather than directly severity of proteinuria in patients with proteinuria.

Background: Defective endothelial function, an initial step in the development of atherosclerotic plaque, is prevalent in moderate to advanced chronic kidney disease (CKD). In this study, the investigators hypothesized that fetuin-A, a calcification inhibitor, is a novel risk factor for the development of endothelial dysfunction in patients. Methods: 198 nondiabetic patients with a mean age of 44.0 ± 12.4 years and with different stages of CKD were studied. In addition to a detailed metabolic panel, flow-mediated dilatation assessed by high-resolution brachial ultrasonography was performed to determine endothelial dysfunction. Carotid intima-media thickness was also estimated by ultrasonography. Serum fetuin-A concentrations were determined by using a human ELISA method. Results: Endothelial dysfunction was observed in all stages (1–5) of CKD and worsened in parallel to the reduction in estimated glomerular filtration rate. Serum fetuin-A concentrations were also found to be decreased in all but stage 1 CKD. On multiple regression analysis, endothelial dysfunction was independently associated with fetuin-A (β = 0.745, p < 0.001) and intact parathyroid hormone concentrations (β = –0.216, p < 0.001). Conclusion: These data in a selected cohort of CKD patients indicate that fetuin-A may be one of the contributing factors for the development of endothelial dysfunction in CKD patients.

Asymmetric dimethyl-arginine (ADMA), a residue of the proteolysis of arginine-methylated proteins, is a potent inhibitor of nitric oxide synthesis. The increased protein turnover that accompanies proteinuric secondary amyloidosis may increase circulating levels of ADMA, and this may contribute to endothelial dysfunction. We performed a cross-sectional study of 121 nondiabetic proteinuric patients with normal GFR (including 39 patients with nephrotic-range proteinuria and secondary amyloidosis) and 50 age-, sex-, and BMI–matched healthy controls. The proteinuric patients had higher levels of serum ADMA, symmetric dimethyl-arginine (SDMA), high-sensitivity C-reactive protein (hsCRP), and insulin resistance (homeostasis model assessment index) than controls. Compared with controls, brachial artery flow-mediated dilatation (FMD), serum L-Arginine, and the L-Arginine/ADMA ratio were significantly lower among proteinuric patients, suggesting greater endothelial dysfunction. When patients with secondary amyloidosis were compared with patients with glomerulonephritis who had similar levels of proteinuria, those with amyloidosis had higher ADMA and SDMA levels and lower L-Arginine/ADMA ratios and FMD measurements (P < 0.001 for all). Finally, even after adjusting for confounders, ADMA level correlated with both proteinuria and the presence of secondary amyloidosis, and was an independent predictor of FMD. We propose that ADMA synthesis may be increased in chronic kidney disease, especially in secondary amyloidosis, and this may explain part of the mechanism by which proteinuria increases cardiovascular morbidity and mortality.

Summary Background: Pentraxin (PTX)-3, a new candidate marker for inflammation is expressed in a variety of cell types. Recently, we have shown that increase in PTX-3 level is associated with clinical outcome in incident CKD stage 5 patients at start of renal replacement therapy. However, no data are available on PTX-3 and its relationship with clinical outcome in prevalent dialysis patients. Methods: We analyzed plasma PTX-3 concentrations in relation to comorbidities (Davies score), protein-energy wasting (PEW) and inflammation markers in 200 prevalent hemodialysis (HD) patients, aged 64 14 years, who had been on HD treatment for a median period of 36 months. Survival (42 months) was analyzed in relation to PTX-3 levels (high PTX-3 tertile vs. low two tertiles). Results: Plasma PTX-3 correlated positively with C-reactive protein and interleukin-6, and negatively with s-albumin and fetuin-A. Patients with cardiovascular disease (CVD) and PEW had higher levels of PTX-3 than their counterparts and PTX-3 was associated with comorbidity score. In multiple logistic regression analysis, the high comorbidity score and PEW were the significant predictive variables of high PTX-3. In unadjusted analysis high PTX-3 was significantly associated with allcause mortality. After adjustment for sex, age, dialysis vintage, comorbidity score, PEW and CRP using the multivariate Cox regression analysis, death rate was still significantly higher in patients with high PTX-3 (HR 1.7; CI 1.1–2.7, P = 0.03). Conclusion: Markedly increased levels of PTX-3 were found in HD patients with signs of CVD and PEW. In addition, the concentration of PTX-3 was associated with inflammation markers and comorbidity score. Our data also shows that high PTX-3 level was independently associated with all-cause mortality.

Background: Vascular access thrombosis represents a major cause of morbidity in the hemodialysis population. The role of serum lipid profile in access thrombosis is not sufficiently established. The aim of this study was to investigate the association between serum lipid profile and native arteriovenous fistula (AVF) thrombosis. Methods: Clinical files of 99 maintenance hemodialysis patients were reviewed retrospectively for 3 years. Serum lipid profile, albumin and C-reactive protein (CRP) were measured. Catheter angiography was performed in patients with AVF dysfunction and AVF thrombosis. Results: Patients with AVF thrombosis and patent AVF had similar serum levels of total cholesterol and triglyceride levels. However, patients with AVF thrombosis had significantly lower low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and albumin and higher serum CRP levels than patients with patent AVFs. Conclusions: Serum levels of lipid subfractions are associated with AVF thrombosis in maintenance hemodialysis patients. Larger and prospective cohort studies are needed to confirm these observations.

BACKGROUND Endothelial dysfunction (ED) is common in patients with moderate to advanced chronic kidney disease (CKD). Recently, visfatin, a protein with insulin-mimetic properties, was shown to be associated with sVCAM-1. Thus, we hypothesised that visfatin may be a marker of ED in CKD. METHODS We studied 406 patients with different stages of non-diabetic CKD (50% males, 46 +/- 12 years), testing the relationship between flow-mediated dilatation (FMD), assessed by high resolution brachial ultrasonography, and plasma adiponectin and visfatin concentrations. Eighty healthy volunteers (50% males, 46 +/- 11 years) served as matched controls. RESULTS Compared to healthy controls, ED was observed in all stages of CKD (Stages 1-5) and correlated strongly with the reduction in estimated glomerular filtration rate (eGFR). Whereas visfatin concentrations were found to be increased in all but CKD stages 1 and 2, adiponectin levels were found to be increased in all patients but CKD stage 1. Visfatin and adiponectin levels were strongly correlated with eGFR (rho = -0.62 and rho = -0.72, respectively, P < 0.001 for both). FMD levels were negatively correlated with both visfatin and adiponectin levels (rho = -0.53 and, rho = -0.57, respectively, P < 0.001 for both). In a multiple regression model, eGFR levels (Beta = 0.74, P < 0.001), visfatin (Beta = -0.15, P < 0.001), age (Beta = 0.06, P < 0.01), adiponectin (Beta = 0.09, P < 0.05), HOMA-IR (Beta = 0.07, P < 0.05) and hsCRP (Beta = -0.08, P < 0.05) were all found to be significantly related to FMD. CONCLUSIONS We conclude that the circulating levels of visfatin and adiponectin are associated with ED in all stages of CKD, independently of inflammation and insulin resistance.

Visfatin, a new adipokine, facilitates adipogenesis and has insulin-mimetic properties. We aimed to investigate the plasma visfatin levels in patients with newly diagnosed and untreated type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT), who had no obesity or hypertension. Twenty-two patients with T2DM, 18 subjects with IGT and 40 healthy controls were enrolled. Visfatin levels were measured along with the BMI, blood pressure, lipids, glucose, insulin, adiponectin and hsCRP levels, and HOMA-IR indexes. Age, sex and BMI were similar in all groups. Visfatin levels were higher in the diabetic group than the controls (p = 0.01). There was no significant difference in the visfatin levels between the T2DM and IGT groups as well as IGT group and healthy controls. Plasma visfatin concentrations did not differ between men and women. Visfatin levels did not correlate with BMI, blood pressure, plasma adiponectin, insulin, hsCRP, glucose and lipid levels or HOMA-IR indexes in the three groups. These results indicate that hyperglycemia causes an increase in plasma visfatin levels and, as in people with T2DM but not with IGT, this increase gets more prominent as the glucose intolerance worsens.

SUMMARY: Aim: Plasma adiponectin levels are well associated with metabolic syndrome. However, the relationship between hypertension and plasma adiponectin levels is not clear. Also, there is not enough data about the effects of different antihypertensive regimens on plasma adiponectin levels. Methods: Ninety-six hypertensive patients (48 male, 48 female) who fulfil the diagnostic criteria of metabolic syndrome were enrolled. Patients were treated for 3 months with metoprolol (n = 18, 100 mg/day), amlodipine (n = 20, 10 mg/day), doxazosin (n = 18, 4 mg/day), ramipril (n = 20, 5 mg/day) and valsartan (n = 20, 80 mg/day). Blood biochemistry and plasma adiponectin concentrations were measured both before and after the study. Insulin resistance was measured by homeostasis assessment index (HOMA). Results: Plasma adiponectin levels were correlated with the total cholesterol (r = −0.244, P = 0.017), triglyceride (r = −0.306, P = 0.002), high-density lipoprotein-cholesterol (r = 0.286, P = 0.005), body mass index (r = −374, P