Serum visfatin concentration and endothelial dysfunction in chronic kidney disease.

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.     

Effect of renin–angiotensin–aldosterone system (RAAS) blockade on visfatin levels in diabetic nephropathy

Aim: Plasma visfatin levels are elevated in diabetic nephropathy in parallel to the severity of proteinuria and glomerular filtration rate. The aim of this study was to find out whether the renin–angiotensin–aldosterone system (RAAS) blockage has any effect on the plasma visfatin levels. Methods: Thirty‐two patients with diabetic proteinuria (>500 mg/day) with a normal glomerular filtration rate (GFR) and 33 healthy subjects were enrolled. Patients were treated with ramipril 5 mg daily for 2 months. Proteinuria, GFR, high‐sensitivity C‐reactive protein (hsCRP), visfatin, flow‐mediated dilatation (FMD) and homeostasis model assessment of insulin resistance (HOMA‐IR) index measurements were performed both before and after the treatment. Results: The plasma visfatin, and hsCRP levels of the patients were significantly higher and the FMD was significantly lower (P < 0.001 for all). The visfatin levels were significantly correlated to FMD, systolic and diastolic blood pressures, proteinuria, eGFR, HOMA‐IR and hsCRP. Ramipril treatment resulted in a significant decrease in plasma visfatin, proteinuria, hsCRP, HOMA‐IR and increase in FMD (P < 0.001) in patients (P < 0.001 for all). Conclusion: The present study suggests that plasma visfatin levels are related to the endothelial functions, inflammation and the severity of proteinuria in diabetic nephropathy. Treatment with ramipril causes a significant decrease in visfatin levels along with the improvement of proteinuria, endothelial dysfunction and inflammatory state in diabetic nephropathy.     

Adiponectin level is reduced and inversely correlated with the degree of proteinuria in type 2 diabetic patients

AIMS: Adiponectin seems to be an important modulator for metabolic and vascular diseases. We aimed to measure plasma adiponectin levels in type 2 diabetic patients and investigate any association with the severity of proteinuria. METHODS: 80 patients (mean age, 46.9 +/- 5.1 years; body mass index (BMI), 25.8 +/- 1.98 kg/m2) and 47 healthy volunteers (mean age, 46.1 +/- 5.5 years; BMI 26.74 +/- 2.23 kg/m2) were included. Plasma adiponectin concentration, insulin levels, homeostasis model assessment (HOMA) indices, calculated glomerular filtration rate (GFR), high sensitive C reactive protein (hsCRP) and biochemistry panel were determined in all subjects. The association between adiponectin concentration and proteinuria was evaluated. Additionally, the relationship between adiponectin and hsCRP and calculated GFR were also investigated. RESULTS: Adiponectin levels in patients were significantly lower than those of controls (n = 80; 8.76 +/- 4.50 microg/ml for patients, n = 47; 24.27 +/- 5.59 microg/ml for controls, p < 0.001). Plasma adiponectin levels in patients with proteinuria were significantly lower than those without proteinuria (n = 43; 6.81 +/- 2.82 microg/ml for proteinuria, n = 37; 11.98 +/- 3.32 microg/ml for no proteinuria, p < 0.001). There was a significant negative correlation between plasma adiponectin concentrations and the degree of proteinuria (r = -0.433, p < 0.001). There were also significant negative correlations between adiponectin concentrations and insulin levels as well as HOMA index in the patient group (r = -0.322, p = 0.004; r = -0.301, p = 0.032). Additionally there was a significant negative correlation between adiponectin and hsCRP levels in the patient group (r = -0.872, p < 0.001). CONCLUSION: The results show that adiponectin is lower in patients with type 2 diabetes and the levels are negatively correlated with the severity of proteinuria.     

Normalization of endothelial dysfunction following renal transplantation is accompanied by a reduction of circulating visfatin/NAMPT. A novel marker of endothelial damage?

Abstract:  Endothelial dysfunction is strongly linked to cardiovascular disease and outcome of patients with chronic kidney disease. We hypothesized that decreased inflammatory activity and increased adiponectin following transplantation could be one mechanism for a better endothelial health. Fifty-eight living donor kidney transplant non-diabetic recipients, 31 (23 male, 29 ± 5 yr) on cyclosporine A and 27 (10 male, 26 ± 5 yr) on tacrolimus immunsupression, were studied longitudinally. Visfatin, adiponectin, high sensitive C-reactive protein (hsCRP) levels, brachial artery flow mediated dilatation (FMD) and nitroglycerine mediated dilatation were measured before transplantation and on the 30th and 90th day after transplantation. Pre-transplantation visfatin, adiponectin and FMD values of patients were significantly higher than those of the controls (p < 0.001 for all). All values decreased significantly 30 and 90 d post-transplantation. Plasma visfatin and adiponectin, correlated negatively with FMD levels 90 d both before and after kidney transplantation (p < 0.001 for both). Endothelial function improved during the first month after transplantation, and the degree of improvement correlated to reductions in circulating visfatin, adiponectin and hsCRP levels. Of interest, the intracellular enzyme visfatin was the strongest predictor of FMD both before and after kidney transplantation and may thus reflect endothelial cell damage directly.     

Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin

BACKGROUND: Vascular calcification is common among end-stage renal disease (ESRD) patients and a central characteristic of the atherosclerotic cardiovascular disease observed in dialysis patients. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In the present study, we evaluated the association between fetuin-A, clinical phenotype, and outcome, as well as the impact of fetuin gene (AHSG) polymorphisms on the protein product and outcome. METHODS: In a cohort of 258 (161 males) ESRD patients starting renal replacement therapy [glomerular filtration rate (GFR) 6.8 +/- 0.2 mL/min] aged 52 +/- 1 years the following parameters were studied: presence of malnutrition (subjective global assessment), comorbidity [diabetes mellitus and clinical manifest cardiovascular disease (CVD)], carotid plaques (N= 101), hs-CRP, fetuin-A, S-albumin, interleukin (IL)-6, and single nucleotide polymorphisms (SNPs) in the AHSG gene (N= 215) at amino acid positions Thr248Met (C-->T), Thr256Ser (C-->G), Asp276Asn (G-->A), and Arg317Cys (C-->T). RESULTS: Both all-cause (P < 0.001) and cardiovascular (P < 0.001) mortality were associated with low fetuin-A levels independently of age, smoking, diabetes, S-albumin, CVD, and inflammation (CRP > or =10 mg/L). Inflamed (0.199 vs. 0.247 g/L; P < 0.01) and malnourished (0.207 vs. 0.262 g/L; P < 0.05) patients had significantly lower median fetuin-A than noninflamed and well-nourished ESRD patients, respectively. In a logistic regression model (N= 101), fetuin-A was significantly (P < 0.05) associated with the presence of carotid plaques independently of age, CVD, diabetes, S-albumin, gender, and inflammation. Significant correlations were observed between fetuin-A and both S-albumin (Rho = 0.30; P < 0.0001) and IL-6 (Rho =-0.21; P < 0.01). Patients with the AHSG 256Ser allele had lower serum fetuin-A levels, and higher all-cause and cardiovascular mortality rate if they were inflamed. CONCLUSION: The present study shows that a low fetuin-A level is associated with malnutrition, inflammation, and atherosclerosis (carotid plaques), as well as with increased cardiovascular and all-cause mortality. Because the present study demonstrates an effect of variations in the AHSG gene on both circulating fetuin-A levels and outcome, this indicates that ESRD patients with the AHSG 256Ser allele are at risk of accelerated vascular calcification.     

Evaluation of serum fetuin-A relationships with biochemical parameters in patients on hemodialysis

Background Complications associated with atherosclerosis in dialysis patients are attracting attention. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In this study, the relation between serum fetuin-A concentration and biochemical parameters in patients on hemodialysis was investigated. Methods Forty hemodialysis patients, 22 men and 18 women, aged 57 ± 12 years; and 20 controls, 10 men and 10 women, aged 50 ± 10 years, participated in this study. We measured serum fetuin-A by enzyme-linked immunosorbent assay. The biochemical parameters of serum albumin, alkaline phosphatase, calcium, phosphate, intact parathyroid hormone, total cholesterol, triglyceride, lipoprotein (a), brain natriuretic peptide (BNP), highly sensitive C-reactive protein (hsCRP), hemoglobin, and hematocrit in whole blood were also measured before starting dialysis sessions. Other parameters included the cardio ankle vascular index, age, mean arterial pressure, total weekly urea clearance (Kt/V), smoking habit, body mass index (BMI), and duration of dialysis. These variables were included in simple regression analysis. Results Levels of serum fetuin-A in the hemodialysis patients (331 ± 55 μg/ml) were significantly lower than those in the healthy controls (361 ± 55 μg/ml; P < 0.05). There was a negative correlation between serum fetuin-A levels and duration of dialysis (r = −0.37, P < 0.01), BNP (r = −0.37, P < 0.001), and hsCRP (r = −0.40, P < 0.01), and a positive association with serum albumin (r = 0.31, P < 0.05). Conclusions These data suggest that a low fetuin-A level is a useful predictor of malnutrition and inflammation, as well as being a useful predictor of the cardiac failure caused by an increased ventricular load in hemodialysis patients.     

Plasma levels of Asymmetric Di Methyl Arginine and endothelial dysfunction in diabetic subjects with neuropathic foot ulcer

ObjectiveAsymmetric dimethyl arginine (ADMA) is an amino acid that acts as an endogenous competitive inhibitor of Nitric oxide synthase, leading to endothelial dysfunction (ED). The aim of this study was to evaluate the relationship between plasma ADMA (p-ADMA) level and ED in diabetic subjects with neuropathic foot ulcer (NFU), and the possible predictors of p-ADMA level.Materials and methods80 diabetic subjects of matched age, sex and BMI were included; 40 with NFU (G1), 20 with peripheral nerve dysfunction (PND) (G2) and 20 without PND (G3), plus 20 matched healthy subjects (G4). Flow-mediated-dilatation (FMD) of brachial artery and Carotid-intima-media-thickness (CIMT) were measured to evaluate ED and subclinical atherosclerosis, respectively.ResultsG1&2 had a significantly lower FMD than G3&4 [−5.09 (−22.5 to 22.92), 4.67 (−15 to 23.91) vs. 15.74 (8.33−36.59) and 20.1 (10.0–46.15)%, respectively] (p < 0.001), and higher CIMT [0.9 (0.6–1.5), 0.9 (0.6–1.3) vs. 0.6 (0.5−0.8) and 0.7 (0.5−0.9) cm, respectively] (p < 0.001, r = 0.237, p = 0.034, r = 0.330, p = 0.003, respectively), with no significant correlation with FMD (r = −0.176, p = 0.118). FMD was inversely and strongly related to CIMT (r = −0.520, p < 0.001). p-ADMA levels were significantly higher in uncontrolled hypertensive patients in comparison to controlled and normotensive subjects [717 (286−3611) vs. 648 (335−874) and 686 (526−857) ng/L, respectively] (p = 0.026). Metformin users and hypertensive subjects on ACEIs or ARBs had the lowest p-ADMA levels than the non-users (p < 0.001, p = 0.007, respectively).ConclusionThe remarkable ED in diabetic subjects with NFU is unlikely to be due to alteration in p-ADMA. Further studies are needed in order to conclude a causal association between p-ADMA and ED in this group of patients.     

Endothelial dysfunction and fetuin A levels before and after kidney transplantation

BACKGROUND: Endothelial dysfunction (ED) has a major role in the cardiovascular outcome of patients with chronic kidney disease (CKD). The aim of this study was to investigate the relation between fetuin A levels and ED in kidney transplant recipients. METHODS: Forty-two living donor kidney transplant recipients, 21 (11 male) on cyclosporine A and 21 (10 male) on tacrolimus-based regimes, were studied. Forty-two (21 male) healthy subjects were enrolled as controls. Fetuin A, highly sensitive C-reactive protein (hsCRP) levels, brachial artery endothelium-dependent vasodilatation (FMD), nitroglycerine mediated dilatation (NMD), and carotid intima-media thickness (CIMT) were measured before transplantation and on the 30th and 90th days posttransplant. RESULTS: Pretransplantation serum fetuin A concentrations and FMD values of patients were significantly lower than those of the controls (P<0.001 for both). These were significantly increased in the 30th and 90th days posttransplantation There was a significant positive correlation between Fetuin A and FMD levels both before and after kidney transplantation (r=0.534, r=0.576; respectively, P<0.001 for both). Carotid intima-media thickness and hsCRP levels decreased after transplantation (P<0.001 for all). According to the regression analysis, fetuin A, intact parathyroid hormone, and hsCRP levels were the independent determinants of FMD. CONCLUSION: The results of the present study suggest that low serum fetuin A levels in CKD may contribute to impaired endothelial functions in CKD. Future studies should clarify the role of fetuin A levels in cardiovascular outcomes of CKD.     

Endothelial functions improve with decrease in asymmetric dimethylarginine (ADMA) levels after renal transplantation

BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular events. The relationships between the markers of inflammation and endothelial dysfunction were investigated both before and after living donor kidney transplantation. METHODS: Twenty-seven renal transplant patients were studied. Eleven patients (six male, five female) were on cyclosporine A, whereas 16 patients (nine male, seven female) were treated with tacrolimus based regimes. Twenty-seven subjects (12 males, 15 females) were studied as controls. Plasma adiponectin, high sensitive C reactive protein (hsCRP), Asymetric dimethyl arginine (ADMA) levels were studied before transplantation and on days 1, 3, 7, 14, and 28. The brachial artery flow mediated dilatation (FMD) was studied before transplantation and on the 28th day. RESULTS: Serum hsCRP and ADMA levels decreased significantly from the first posttransplantation day on each measurement (P<0.001 for all) while the decrement of plasma adiponectin started in the third day (P<0.001 for all). The FMD was lower in the patients than the control group (P<0.001) and improved significantly in the 28th day of transplantation (P<0.001). CONCLUSIONS: The results indicate that ADMA is associated with FMD in CKD both before and after kidney transplantation. Endothelial functions improve at the very beginning of the posttransplantation period with accompanying reduction in ADMA and hsCRP levels.     

内脏脂肪素与糖尿病肾脏病hsCRP及UAER的关系

目的探讨血清内脏脂肪素（visfatin）与糖尿病肾脏病患者高敏C反应蛋白（hsCRP）及尿白蛋白排泄率（UAER）的关系。方法将90例2型糖尿病（T2DM）患者分为单纯T2DM组（A组）46例,糖尿病肾脏病（DKD）组（B组）44例;另设50例健康体检者为正常对照组（C组）。测定身高、体重、腰围（WC）、血压（BP）,计算体重指数（BMI）。检测3组血清visfatin、hsCRP及血糖、血脂、肾功能等各项生化指标。血清visfatin与hsCRP、UAER行相关性分析。结果A、B组血清visfatin水平和hsCRP均明显高于C组（P〈0．01）。B组中血清visfatin水平和hsCRP均明显高于A组（P〈0．05,P〈0．01）。相关性分析中,B组血清visfatin水平与UAER呈正相关（r=0．479,P〈0．01）,与hsCRP亦呈正相关（r=0.376,P〈0．05）。结论血清visfatin与DKD的炎症状态以及尿白蛋白排泄有关,可能在其发病机制中发挥一定作用。     

Study on the relationship of serum fetuin-A concentration with aortic stiffness in patients on dialysis.

BACKGROUND: An increase in aortic stiffness, as reflected by an increase in pulse wave velocity (PWV) or aortic augmentation index (AI) is an important predictor of cardiovascular mortality in dialysis patients. Dysregulation of calcification inhibitors, such as fetuin-A, is involved in vascular pathology in dialysis patients and fetuin-A is inversely related to mortality in dialysis patients. In this study, the relation between serum fetuin-A concentration and parameters of aortic stiffness was investigated in patients with end-stage renal disease. METHODS: In a cross-sectional study we included 131 dialysis patients, aged 62+/-14 years (33 on peritoneal dialysis and 98 on haemodialysis), and 41 controls, aged 60+/-8 years. Time-averaged pre-dialysis values of serum albumin, Ca, P and intact parathyroid hormone were included in multiregression analysis, as were high-sensitivity C-reactive protein (hsCRP), fetuin-A, age, mean arterial pressure (MAP) and dialysis modality. PWV and AI were measured with the SphygmoCor device. RESULTS: Mean fetuin-A concentration in dialysis patients (0.63+/-0.16 g/l) did not differ from controls (0.63+/-0.11 g/l). Median hsCRP levels in dialysis patients were higher compared with controls (4.0 vs 1.9 mg/l; P<0.0001). PWV but not AI was higher in dialysis patients than in controls (9.9 vs 7.9 m/s; P<0.0001). In univariate analysis in dialysis patients, fetuin-A levels were inversely related to both PWV (r = - 0.25, P = 0.007) and AI (r = - 0.26, P = 0.006), respectively. However, after correction for age, gender, MAP and diabetes mellitus, this relation lost statistical significance. CONCLUSIONS: In a dialysis population with a relatively low level of inflammatory activity, the soluble calcification inhibitor fetuin-A could not be identified as an independent predictor of aortic stiffness as measured with PWV and AI.     

ADMA levels correlate with proteinuria, secondary amyloidosis, and endothelial dysfunction

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.     

The effect of thiazolidinediones on plasma adiponectin levels in normal,obese, and type 2 diabetic subjects

The insulin-sensitizing effects of thiazolidinediones are thought to be mediated through peroxisome proliferator-activated receptor-gamma, a nuclear receptor that is highly abundant in adipose tissue. It has been reported that adipocytes secrete a variety of proteins, including tumor necrosis factor-alpha, resistin, plasminogen activator inhibitor-1, and adiponectin. Adiponectin is a fat cell-secreted protein that has been reported to increase fat oxidation and improve insulin sensitivity. Our aim was to study the effects of troglitazone on adiponectin levels in lean, obese, and diabetic subjects. Ten diabetic and 17 nondiabetic subjects (8 lean, BMI <27 kg/m(2) and 9 obese, BMI >27 kg/m(2)) participated in the study. All subjects underwent an 80 mU. m(-2). min(-1) hyperinsulinemic-euglycemic glucose clamp before and after 3 months' treatment with the thiazolidinedione (TZD) troglitazone (600 mg/day). Fasting plasma glucose significantly decreased in the diabetic group after 12 weeks of treatment compared with baseline (9.1 +/- 0.9 vs. 11.1 +/- 0.9 mmol/l, P < 0.005) but was unchanged in the lean and obese subjects. Fasting insulin for the entire group was significantly lower than baseline (P = 0.02) after treatment. At baseline, glucose disposal rate (R(d)) was lower in the diabetic subjects (3.4 +/- 0.5 mg. kg(-1). min(-1)) than in the lean (12.3 +/- 0.4) or obese subjects (6.7 +/- 0.7) (P < 0.001 for both) and was significantly improved in the diabetic and obese groups (P < 0.05) after treatment, and it remained unchanged in the lean subjects. Baseline adiponectin levels were significantly lower in the diabetic than the lean subjects (9.0 +/- 1.7 vs. 16.7 +/- 2.7 micro g/ml, P = 0.03) and rose uniformly in all subjects (12.2 +/- 2.3 vs. 25.7 +/- 2.6 micro g/ml, P < 10(-4)) after treatment, with no significant difference detected among the three groups. During the glucose clamps, adiponectin levels were suppressed below basal levels in all groups (10.2 +/- 2.3 vs. 12.2 +/- 2.3 micro g/ml, P < 0.01). Adiponectin levels correlated with R(d) (r = 0.46, P = 0.016) and HDL cholesterol levels (r = 0.59, P < 0.001) and negatively correlated with fasting insulin (r = -0.39, P = 0.042) and plasma triglyceride (r = -0.61, P < 0.001). Our findings show that TZD treatment increased adiponectin levels in all subjects, including normal subjects in which no other effects of TZDs are observed. Insulin also appears to suppress adiponectin levels. We have confirmed these results in normal rats. These findings suggest that adiponectin can be regulated by obesity, diabetes, TZDs, and insulin, and it may play a physiologic role in enhancing insulin sensitivity.     

Plasma adiponectin is associated with ankle-brachial index in patients on haemodialysis

BACKGROUND: Peripheral arterial disease (PAD) is a leading cause of morbidity in haemodialysis (HD) patients. Recent evidence suggests that adiponectin, an adipose-derived cytokine, may play a role in atherosclerosis. However, the association between plasma levels of the adiponectin and the ankle-brachial index (ABI), an indicator of the presence and severity of PAD, has not been thoroughly studied in HD patients. METHODS: The present cross-sectional study attempted to examine the relationship between plasma adiponectin and PAD in a cohort of 136 chronic HD patients. The ABI was used as an estimate of the presence of PAD. Plasma adiponectin, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor-alpha and lipid profiles were measured. Logistic regression was used to estimate the association between presence of PAD and adiponectin as well as other potential risk factors. RESULTS: Plasma levels of adiponectin were significantly lower among patients with evidence of PAD than among those without (8.51 +/- 5.75 vs 17.15 +/- 11.53; P < 0.001). Univariate analysis showed a positive correlation between ABI values and plasma adiponectin levels (r = 0.369, P < 0.001), high-density lipoprotein cholesterol levels, diastolic blood pressure, Kt/V and serum phosphate. On the other hand, negative correlations between ABI and log-transformed triglyceride, hsCRP, fasting blood sugar, girth circumference and white blood cell counts were noted. Using logistic regression, plasma adiponectin was found to be associated with PAD independently of classical risk factors for atherosclerosis. In addition, models that incorporated plasma adiponectin were significantly better at predicting PAD than models limited to classical confounding factors. CONCLUSION: We conclude that there was a significant inverse correlation between plasma adiponectin levels and the presence of PAD in dialysis patients. This suggests that plasma adiponectin level may have a role in the atherosclerotic process of PAD.     

Serum fetuin-A in nondialyzed patients with diabetic nephropathy: relationship with coronary artery calcification

BACKGROUND: Fetuin-A is the most potent circulating inhibitor of calcium phosphorus precipitation and, possibly, an important mediator of insulin resistance. METHODS: In order to determine the role of fetuin-A in the high coronary artery calcification (CAC) burden seen in nondialyzed individuals with diabetic nephropathy (DN), post-hoc analyses of data collected from a cross-sectional study of 88 patients with type 2 diabetes mellitus was done [age, 40-65 years; normoalbuminuria, N= 30 (Latinos); DN, N= 58 (Latinos and African Americans)]. RESULTS: The serum levels of fetuin-A were significantly higher among Latinos with DN when compared to either African Americans with DN or Latino diabetics with normoalbuminuria. Upon adjusting the data for race/ethnicity, there was a strong, direct relationship between serum fetuin-A levels and the CAC score (r= 0.22, P= 0.038) in the study cohort; however, a strong interaction between the nephropathy status and relationship of serum fetuin-A levels with CAC score was present (DN: r= 0.36, P= 0.006; diabetic controls, r= 0.0, P= 0.98). Among individuals with DN, the significance of the association persisted even after controlling the data for other predictors of CAC (partial r= 0.33, P= 0.018). Furthermore, there was a significant direct relationship between serum fetuin-A and serum triglycerides (partial r= 0.27, P= 0.01) and albumin (partial r= 0.30, P= 0.005), and an inverse relationship with glomerular filtration rate (r=-0.24, P= 0.03). CONCLUSION: This first study in early stages of diabetic chronic kidney disease shows that the role of serum fetuin-A may be far more complex than previously described. During predialysis stage of DN, there is a direct relationship between serum fetuin-A levels and CAC score. The reasons for this association in the presence of nephropathy are unclear, but may be secondary to proatherogenic insulin resistance.     

Serum visfatin increases with progressive beta-cell deterioration

Visfatin has shown to be increased in type 2 diabetes but to be unrelated to insulin sensitivity. We hypothesized that visfatin is associated with insulin secretion in humans. To this aim, a cross-sectional study was conducted in 118 nondiabetic men and 64 (35 men and 29 women) type 2 diabetic patients. Type 1 diabetic patients with long-standing disease (n = 58; 31 men and 27 women) were also studied. In nondiabetic subjects, circulating visfatin (enzyme immunoassay) was independently associated with insulin secretion (acute insulin response to glucose [AIRg] from intravenous glucose tolerance tests) but not with insulin sensitivity (Si) or other metabolic or anthropometric parameters, and AIRg alone explained 8% of visfatin variance (beta = -0.29, P = 0.001). Circulating visfatin was increased in type 2 diabetes (mean 18 [95% CI 16-21] vs. 15 ng/ml [13-17] for type 2 diabetic and nondiabetic subjects, respectively; P = 0.017, adjusted for sex, age, and BMI), although this association was largely attenuated after accounting for HbA1c (A1C). Finally, circulating visfatin was found to be increased in patients with long-standing type 1 diabetes, even after adjusting for A1C values (37 ng/ml [34-40]; P < 0.0001, adjusted for sex, age, BMI, and A1C compared with either type 2 diabetic or nondiabetic subjects). In summary, circulating visfatin is increased with progressive beta-cell deterioration. The study of the regulation and role of visfatin in diabetes merits further consideration.     

Carotid artery intima-media thickness correlates with oxidative stress in chronic haemodialysis patients with accelerated atherosclerosis.

BACKGROUND: Accelerated atherosclerosis is the major cause of mortality in patients on chronic haemodialysis (HD). Increased oxidative stress might be the major factor leading to high cardiovascular mortality rate in HD patients. The aim of our study was to clarify effects of uraemia and dialysis on oxidative stress parameters and explore the relation between oxidative stress markers and carotid artery intima-media thickness (CIMT) as an indicator of atherosclerosis. METHODS: Twenty chronic HD patients, 20 predialytic uraemic patients and 20 healthy subjects were included in the study. Serum thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCO) and nitrite/nitrate levels were determined as oxidative stress markers. Serum vitamin E, plasma sulfhydryl (P-SH), erythrocyte glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities were measured as antioxidants. CIMT was assessed by carotid artery ultrasonography. RESULTS: Both chronic HD and predialytic uraemic patients had enhanced oxidative stress indicated by higher levels of nitrite/nitrate, TBARS and PCO, and lower levels of P-SH, SOD, CAT and GPx compared to controls. HD patients had significantly higher CIMT and nitrite/nitrate while significantly lower P-SH,vitamin E, SOD, CAT and GPx compared to predialytic uraemic patients. There was a significant positive correlation between CIMT and TBARS (r = 0.38, P = 0.003) and nitrite/nitrate levels (r = 0.41, P = 0.001), while there was a significant negative correlation between CIMT and SOD (r = -0.35, P = 0.01), CAT (r = -0.65, P < 0.001) and P-SH levels (r = -0.50, P < 0.001). A linear regression analysis showed that TBARS were still significantly and positively correlated with CIMT (P = 0.001), while CAT and P-SH were significantly and negatively correlated with CIMT (P = 0.002 and P = 0.048, respectively). CONCLUSIONS: HD exacerbates oxidative stress and disturbances in antioxidant enzymes in uraemic patients. We propose that serum TBARS and nitrite/nitrate can be used as positive determinants, while erythrocyte SOD, CAT and P-SH may be used as negative determinants of atherosclerosis assessed by CIMT in uraemic and HD patients.     

Effect of antihypertensive agents on plasma adiponectin levels in hypertensive patients with metabolic syndrome

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 < 0.001), systolic (r = -502, P < 0.001) and diastolic blood pressures (r = -235, P = 0.021). The independent predictors of plasma adiponectin levels were HOMA (beta = -0.199, P = 0.02), body mass index (beta = -0.313, P < 0.001) and systolic blood pressures (beta = -0.483, P < 0.001). Ramipril and valsartan increased the plasma adiponectin levels significantly higher than the other regimens (P < 0.05 for both) while metoprolol did not make a significant effect. CONCLUSION: According to the results, plasma adiponectin levels are associated with the arterial blood pressures, body fat content and the lipid parameters in hypertensive patients with metabolic syndrome. The effects of antihypertensive drugs on plasma adiponectin levels are parallel to their effects on blood pressures and insulin sensitivities. The different effects of several regimens on plasma adiponectin levels and insulin sensitivities may account for the diversity of the cardiovascular outcomes in patients with hypertension.     

Steroid pulse therapy impaired endothelial function while increasing plasma high molecule adiponectin concentration in patients with IgA nephropathy.

BACKGROUND: Decreased plasma adiponectin is associated with impaired endothelial function and, thereby, increased risk for cardiovascular events. Glucocorticoid (GC) affects vascular endothelial cells either favourably or harmfully depending upon the dosages and duration. We examined the effect of GC pulse therapy on vascular endothelial function. METHODS: Fourteen young patients with IgA nephropathy were evaluated for flow-mediated vasodilation (FMD), plasma levels of adiponectin both in high molecular weight (HMW adiponectin) form and in single molecular form (total adiponectin), hepatocyte growth factor (HGF), asymmetric dimethylarginine (ADMA), and high-sensitive C-reactive protein, before and after a course of GC pulse therapy. RESULTS: GC pulse therapy significantly decreased FMD (from 7.2 +/- 2.6 to 5.7 +/- 2.5%, P < 0.01). Meanwhile, plasma adiponectin levels were significantly augmented (total adiponectin: from 10.2 +/- 4.0 to 12.1 +/- 6.3 microg/ml, P < 0.05; HMW: from 6.5 +/- 3.2 to 7.7 +/- 3.3 microg/ml, P < 0.05). In parallel, elevated concentrations of serum HGF (from 0.28 +/- 0.12 to 0.63 +/- 0.38 ng/ml, P < 0.01) and plasma ADMA (from 0.45 +/- 0.07 to 0.53 +/- 0.04 nmol/ml, P < 0.05) were observed. CONCLUSIONS: GC pulse therapy impaired endothelial function while increasing plasma adiponectin levels, which may in turn restore the endothelial function in patients with IgA nephropathy.     

Endothelial dysfunction relates to folate status in children and adolescents with type 1 diabetes

Endothelial dysfunction occurs early in the development of vascular disease in diabetes. Total plasma homocyst(e)ine (tHcy) is associated with endothelial dysfunction. We therefore aimed to assess endothelial function in children with type 1 diabetes in relation to tHcy and its determinants. Endothelial function was assessed in 36 children with type 1 diabetes aged 13.7 +/- 2.2 years and 20 age- and sex-matched control subjects using ultrasound assessment of flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-dependent brachial artery responses. von Willebrand factor (vWF) and thrombomodulin, markers of endothelial activation, were measured in 64 children with type 1 diabetes and 52 control subjects. Fasting glucose, tHcy, serum and red cell folate, vitamin B12, HbA(1c), creatinine, and lipids were also measured. FMD (5.2 +/- 4.7 vs. 9.1 +/- 4.0%, P = 0.002) and the ratio of FMD:GTN-induced dilatation (0.22 +/- 0.39 vs. 0.41 +/- 0.29%, P = 0.008) were significantly lower in diabetic subjects, indicating endothelial dysfunction. In diabetic subjects, red cell folate correlated independently with FMD (beta = 0.42, P = 0.028) and the ratio of FMD:GTN-induced dilatation (beta = 0.59, P < 0.001). Resting vessel diameter correlated independently with tHcy (beta = -0.51, P < 0.001) and height (beta = 0.65, P < 0.001). vWF correlated independently with HbA(1c) (beta = 0.38, P = 0.003), and thrombomodulin correlated independently with red cell folate (beta = -0.38, P = 0.005), tHcy (beta = -0.37, P = 0.004), diastolic blood pressure (beta = -0.28, P = 0.025), and creatinine clearance (beta = 0.26, P = 0.033). Children with type 1 diabetes have early endothelial dysfunction. Better folate status is associated with better endothelial function, as measured by higher FMD, higher FMD:GTN ratio, and lower thrombomodulin. Folate may therefore protect against endothelial dysfunction in children with diabetes.