Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function.

BACKGROUND: Adiponectin, a newly discovered collagen-like protein of the collectin family exclusively produced by adipocytes, possesses anti-inflammatory properties. Plasma adiponectin is associated with a decreased cardiovascular risk in non-renal patients, and is reduced in obesity and insulin-resistant states. Although reports show an increase in the adiponectin level in maintenance haemodialysis, peritoneal dialysis and end-stage renal disease, there is no documentation of adiponectin levels and regulation in the early stages of chronic kidney disease (CKD). METHODS: We prospectively measured glomerular filtration rate (GFR) in 48 patients with CKD using inulin clearance. Fasting blood was drawn to determine insulin, leptin, adiponectin and C-reactive protein (CRP) levels. Body fat mass was calculated using skinfold thickness measurements. RESULTS: The patients' mean GFR was 53.5+/-24.9 (SD) ml/min/1.73 m2. Adiponectin was in the normal range in men (9.8+/-2.9 mg/l) and women (16.6+/-5.0 mg/l) with CKD, being significantly higher in women than men (P<0.001). Serum leptin was above normal (10.4+/-10.7 microg/l), whereas serum insulin and CRP were within their normal ranges (3.5+/-3.3 microU/ml and 2.6+/-5.0 mg/l, respectively). In linear regression analysis, adiponectin was negatively correlated with GFR (P = 0.02), fat mass (P = 0.03) and body mass index (P = 0.002), and strongly positively correlated with serum leptin (P = 0.003). A positive relationship was also found between plasma adiponectin and the urinary albumin/creatinine ratio (P = 0.007). No relationship was found between adiponectin and insulin or adiponectin and CRP. In multiple regression analysis, adiponectin was significantly positively correlated with leptin (P<0.0001), negatively with body mass index (P<0.0001) and only weakly with GFR (P = 0.04). CONCLUSIONS: Despite an adverse metabolic environment in chronic renal insufficiency, serum adiponectin increases in non-obese patients when renal function deteriorates. Adiponectin is only weakly affected by renal function per se, but appears influenced by proteinuria, and more significantly by body mass index and the change in serum leptin that accompanies decline in renal function.     

Increased serum high-molecular-weight complex of adiponectin in type 2 diabetic patients with impaired renal function

BACKGROUND/AIM: Adiponectin, an adipocyte-derived protein, has been shown to exert antidiabetic, anti-inflammatory, and antiatherosclerotic effects. Although recent reports show an increase in the total adiponectin levels in chronic kidney disease patients and in patients with end-stage renal disease, the nature of biodegradation and renal involvement of adiponectin is largely unknown. We aimed at determining whether the high-molecular-weight (HMW) complex of adiponectin is associated with renal insufficiency in type 2 diabetic patients. METHODS: A total of 179 type 2 diabetic patients were selected from among outpatients and divided into four groups according to their albumin-to-creatinine ratio: patients with normoalbuminuria (n = 86), patients with microalbuminuria (n = 44), patients with macroalbuminuria (n = 23), and patients on hemodialysis (n = 26). The serum HMW adiponectin was specifically assayed with a commercially available enzyme-linked immunosorbent assay kit. RESULTS: The HMW adiponectin levels were higher in patients on hemodialysis (17.1 +/- 8.2 microg/ml) and in those with macroalbuminuria (14.3 +/- 8.7 microg/ml) than in patients with normoalbuminuria (7.2 +/- 5.6 microg/ml) and microalbuminuria (10.8 +/- 7.0 microg/ml). Univariate linear regression analysis showed that the HMW adiponectin concentrations correlated negatively with the estimated glomerular filtration rate in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria (r = -0.42, p < 0.001). Multiple stepwise regression analysis disclosed that estimated glomerular filtration rate, pioglitazone therapy, gender differences, and systolic blood pressure were independently associated with HMW adiponectin levels (r = 0.56). CONCLUSIONS: The serum HMW adiponectin concentrations are higher in type 2 diabetic patients with nephropathy, and these levels are also associated with renal insufficiency.     

Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin.

BACKGROUND: Type-2 diabetes and diabetic kidney disease have additive effects on cardiovascular risk. Furthermore, the degree of proteinuria is an independent predictor of mortality in this patient group. We hypothesized that altered kidney clearance and/or metabolism of vasoactive peptides occurring during proteinuria could link early diabetic nephropathy to cardio vascular disease (CVD). METHODS: We performed a cross-sectional study of 85 incident patients (51 +/- 5 years, 49 males) with type-2 diabetes and 38 age- and sex-matched controls. We further divided patients by the presence of minor (<500 mg/day; n = 40) or severe (>/=500 mg/day; n = 45) proteinuria. Clinical and anthropometric data, along with ultrasonographic flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thicknesses (CIMT), were recorded in each group. Circulating NAMPT/visfatin, adiponectin (normalized to BMI), AHSG/fetuin-A and hsCRP levels were also measured using commercial ELISA. RESULTS: Plasma NAMPT/visfatin, CIMT, HOMA index and hsCRP levels were all significantly higher in diabetics than in control subjects, and all but CIMT correlated with proteinuria (rho = 0.46; P < 0.001, rho = 0.54; P > 0.05, rho = 0.32; P = 0.003, rho = 0.76; P < 0.001, respectively). FMD, adiponectin and AHSG/fetuin-A levels were significantly lower, and negatively correlated with proteinuria (rho = -0.54; P < 0.001, rho = -0.56; P < 0.001, rho = -0.48; P < 0.001, respectively). In a multivariate regression analysis, the degrees of proteinuria (r(2) = -0.32, P = 0.04) and plasma levels of NAMPT/visfatin (r(2) = -0.33, P = 0.006) were independently related to FMD. CONCLUSIONS: The present study suggests that the presence of proteinuria, regardless of the degree of renal function impairment, is an important predictor of endothelial dysfunction in early diabetic nephropathy and that it is associated with altered circulating levels of NAMPT/visfatin and adiponectin.     

Plasma adiponectin concentration in patients after successful kidney transplantation--a single-center, observational study

BACKGROUND AND AIM: Adiponectin is an anti-inflammatory protein secreted almost exclusively by adipocytes which improves insulin sensitivity and presents antiatherogenic properties. Plasma adiponectin concentration is almost 3 times higher in hemodialysis patients and markedly decreased after successful kidney transplantation. However, until now, there are no studies analyzing plasma adiponectin concentration in kidney transplant patients (KTx) during the long-term period after transplantation. Therefore, the aim of present study was to examine plasma adiponectin concentration in KTx patients during the wide range of time after transplantation. MATERIAL AND METHOD: Single center, cross-sectional study including 228 KTx adult recipients (143 M and 85 F) with estimated glomerular filtration rate (eGFR) > or = 15 ml/min, 80 hemodialysis patients (34 M and 46 F) and 52 healthy subjects (33 M and 19 F). Plasma adiponectin concentration was estimated together with HOMA-IR (homeostasis model assessment insulin resistance index) and plasma lipid profile. RESULTS: In KTx patients plasma adiponectin concentration 14.0 (13.1-15.0) microg/ml was significantly (p < 0.001), lower than in hemodialysis ones 29.0 (24.7-33.3) microg/ml, however, significantly (p < 0.001) higher than in healthy subjects 10.1 (8.8-11.5) microg/ml. Among KTx patients the highest plasma adiponectin concentration was observed in the subgroup of patients surviving with the functioning graft more than 8 years after transplantation. In KTx patients, significant, negative correlations were found between plasma adiponectin concentration and BMI (p = 0.017), HOMA-IR (p = 0.02) and estimated GFR (p < 0.009), respectively. Multiple regression analysis performed in the group of KTx patients, with plasma adiponectin concentration as the dependent variable and BMI, age, gender, estimated GFR as independent variables showed that in this model (R2 = 0.09) plasma adiponectin concentration significantly depends on BMI (p = 0.035), gender (p = 0.004) and eGFR (p = 0.023). CONCLUSIONS: Patients with long-term renal graft survival are characterized by a higher plasma adiponectin concentration. Kidney graft function (assessed as estimated GFR) is an important factor influencing plasma adiponectin concentration.     

Adiponectin and mortality in patients with chronic kidney disease

Adiponectin is presumed to possess antiatherogenic and cardioprotective properties. Limited data exist on the relationship between adiponectin and mortality in the earlier stages of chronic kidney disease. The Modification of Diet in Renal Disease study was a randomized, controlled trial that was conducted between 1989 and 1993. Adiponectin was measured in frozen samples that were obtained at baseline (N = 820). Survival status and cause of death, up to December 31, 2000, were obtained from the National Death Index. Multivariable Cox models were used to examine the relationship of adiponectin with all-cause and cardiovascular mortality. Mean +/- SD age was 52 +/- 12 yr, and mean +/- SD glomerular filtration rate (GFR) rate was 33 +/- 12 ml/min per 1.73 m2. Eighty-five percent of participants were white, and 60% were male. Mean +/- SD adiponectin was 12.8 +/- 8.0 mug/ml. Triglycerides, insulin resistance, glucose, body mass index, GFR, C-reactive protein, and albumin were inversely related and proteinuria and HDL cholesterol were directly related to adiponectin. During the 10-year follow-up period, 201 (25%) participants died of any cause, and 122 (15%) from cardiovascular disease. In multivariable adjusted Cox models, a 1-mug/ml increase in adiponectin was associated with a 3% (hazard ratio 1.03; 95% confidence interval 1.01 to 1.05; P = 0.02) increased risk for all-cause and 6% (hazard ratio 1.06; 95% confidence interval 1.03 to 1.09; P < 0.001) increased risk for cardiovascular mortality. High, rather than low, adiponectin is associated with increased mortality in this cohort of patients with chronic kidney disease stages 3 to 4. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.     

Changes of adiponectin oligomer composition by moderate weight reduction

Adiponectin affects lipid metabolism and insulin sensitivity. However, adiponectin circulates in three different oligomers that may also have distinct biological functions. We aimed to analyze the role of these oligomers in obesity and lipid metabolism after weight reduction. A total of 17 obese volunteers (15 women and 2 men) participated in a weight reduction program. Individuals were characterized before and after 6 months of a balanced diet. Adiponectin was determined by enzyme-linked immunosorbent assay, and oligomers were detected by nondenaturating Western blot. BMI decreased (35.1 +/- 1.2 to 32.8 +/- 1.1 kg/m(2), P < 0.001), which was associated with an improved metabolite profile. Total adiponectin increased from 5.3 +/- 0.5 to 6.1 +/- 0.6 microg/ml (P = 0.076). High (HMW) and medium molecular weight (MMW) adiponectin oligomers significantly increased during weight reduction (HMW: 0.37 +/- 0.07 to 0.4 +/- 0.08 microg/ml, P = 0.042; MMW: 2.3 +/- 0.2 to 2.9 +/- 0.3 microg/ml, P = 0.007), while low molecular weight (LMW) did not significantly change. Body weight inversely correlated with HMW (r = -0.695, P = 0.002) and positively with LMW (r = 0.579, P = 0.015). Interestingly, HDL cholesterol and HMW were strongly correlated (r = 0.665, P = 0.007). Indeed, HMW and free fatty acids before weight reduction predicted approximately 60% of HDL changes during intervention. In conclusion, weight reduction results in a relative increase of HMW/MMW adiponectin and a reduction of LMW adiponectin. Total adiponectin and especially HMW adiponectin are related to circulating HDL cholesterol.     

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 is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors

BACKGROUND: Adiponectin (ADPN), the gene product of apM1, is the most abundant secretory protein of the adipose tissue in human plasma. Altered regulation (reduced synthesis) of this substance may be relevant to endothelial dysfunction and cardiovascular complications in patients with ESRD. METHODS: We investigated the relationship between plasma ADPN, glomerular filtration rate (GFR) (plasma iohexol clearance), and metabolic risk factors in 16 patients with nephrotic syndrome, in 25 patients with chronic nephropathies without nephrotic syndrome, and in 31 healthy subjects. RESULTS: Plasma ADPN was much higher (P < 0.01) in patients with nephrotic syndrome (24.4 +/- 14.9 microg/mL) than in patients with chronic nephropathies without nephrotic syndrome (12.3 +/- 7.2 microg/mL) and healthy subjects (5.9 +/- 2.6 microg/mL). In the aggregate 24-hour, proteinuria (r = 0.53, P < 0.01) and serum cholesterol (r = 0.53, P < 0.01) were strong and direct correlates of plasma ADPN, while serum albumin correlated inversely (r = -0.46, P < 0.01) with this protein. Proteinuria appeared to be an important confounder of the relationship between ADPN and the GFR because in the whole patient population (with and without nephrotic syndrome), this relationship emerged only after data adjustment for 24-hour proteinuria (partial r = -0.31, P = 0.05), while no such relationship was demonstrable on crude data analysis (r = 0.03, P = 0.87). CONCLUSIONS: ADPN is markedly increased in patients with nephrotic syndrome, and proteinuria is strongly related to circulating ADPN in patients with nephrotic and non-nephrotic renal diseases. The relationships between plasma ADPN, serum cholesterol, and serum albumin suggest that this adipocyte protein may serve to mitigate endothelial damage triggered by dyslipidemia and other risk factors in patients with chronic renal diseases.     

Characteristics of population with normal serum creatinine impaired renal function and: the validation of a MDRD formula in a healthy general population

BACKGROUND AND AIMS: Glomerular filtration rate (GFR) provides the most accurate estimation of renal function. This study investigated the clinical characteristics of patients with impaired renal function having a normal serum creatinine level. We also validated whether the new Modification of Diet in Renal Disease (MDRD) formula can be applied in a healthy general population. MATERIAL AND METHODS: A total 393 participants who had serum creatinine concentration below 132.6 micromol/L without underlying diseases were randomly selected on an address basis in Ansan City. According to the level of GFR, they were divided into 3 groups and we analyzed their clinical characteristics. In 75 subjects, who were randomly selected 25 cases in each group based on GFR estimated by Cockcroft-Gault (C-G) formula, true GFR was measured using the 99mTc-DTPA renal clearance method. RESULTS: A total 393 (male: 106, female: 287) participants were as follows: GFR < 60 ml/min/1.73 m2; 4% (n = 25); 60 < or = GFR < 90 ml/min/1.73 m2; 26.2% (n = 103); GFR > or = 90 ml/min/1.73 m2; 67.4% (n = 265). In the group of decreased GFR, the mean age was older (67.4+/-10.7 vs. 48.7+/-12.8 vs. 39.4+/-8.2 years, p < 0.001), the gender was male (90.33+/-28.77 vs. 110.55+/-31.64, p < 0.001), and amount of proteinuria more increased (0.61 (0.56) vs. 0.33 (0.34) vs. 0.38 (0.33) gm/day, p = 0.007). The accuracy and precision of each formula were assessed by the difference in GFR measured by the 99mTc-DTPA renal clearance method--estimated GFR by each formula (deltaGFR), and the coefficient of determination (r2) of different predictive equations. The results were as follows: deltaGFR = -14.78+/-46.03, r2 = 0.79 (24-hour urinary creatinine clearance), deltaGFR=-16.79+/-57.32, r2 = 0.66 (100/serum creatinine), deltaGFR = 9.54+/-39.18, r2 = 0.87 (C-G formula), deltaGFR = -12.30+/-54.31, r2 = 0.66 (AASK formula), deltaGFR = 8.70+/-37.62, r2 = 0.79 (MDRD formula). Multiple linear regression analysis and logistic regression analysis showed that age, serum creatinine, total cholesterol and 24-hour urinary protein excretion were independently related to GFR and associated with a significant increase in the risk of decrement of GFR. CONCLUSIONS: From these results, a more accurate assessment of renal function should be required in a population characterized by older age, male gender and more proteinuria. The MDRD study formula and Cockcroft-Gault formula have greater accuracy and precision with true GFR, and this equation can be applied in subjects with healthy general population.     

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.     

Adiponectin expression from human adipose tissue: relation to obesity,insulin resistance,and tumor necrosis factor-alpha expression

Adiponectin is a 29-kDa adipocyte protein that has been linked to the insulin resistance of obesity and lipodystrophy. To better understand the regulation of adiponectin expression, we measured plasma adiponectin and adipose tissue adiponectin mRNA levels in nondiabetic subjects with varying degrees of obesity and insulin resistance. Plasma adiponectin and adiponectin mRNA levels were highly correlated with each other (r = 0.80, P < 0.001), and obese subjects expressed significantly lower levels of adiponectin. However, a significant sex difference in adiponectin expression was observed, especially in relatively lean subjects. When men and women with a BMI <30 kg/m(2) were compared, women had a twofold higher percent body fat, yet their plasma adiponectin levels were 65% higher (8.6 +/- 1.1 and 14.2 +/- 1.6 micro g/ml in men and women, respectively; P < 0.02). Plasma adiponectin had a strong association with insulin sensitivity index (S(I)) (r = 0.67, P < 0.0001, n = 51) that was not affected by sex, but no relation with insulin secretion. To separate the effects of obesity (BMI) from S(I), subjects who were discordant for S(I) were matched for BMI, age, and sex. Using this approach, insulin-sensitive subjects demonstrated a twofold higher plasma level of adiponectin (5.6 +/- 0.6 and 11.2 +/- 1.1 micro g/ml in insulin-resistant and insulin-sensitive subjects, respectively; P < 0.0005). Adiponectin expression was not related to plasma levels of leptin or interleukin-6. However, there was a significant inverse correlation between plasma adiponectin and tumor necrosis factor (TNF)-alpha mRNA expression (r = -0.47, P < 0.005), and subjects with the highest levels of adiponectin mRNA expression secreted the lowest levels of TNF-alpha from their adipose tissue in vitro. Thus, adiponectin expression from adipose tissue is higher in lean subjects and women, and is associated with higher degrees of insulin sensitivity and lower TNF-alpha expression.     

Association of the circulating adiponectin concentration with coronary in-stent restenosis in haemodialysis patients.

BACKGROUND: Success of coronary stenting is limited by in-stent restenosis. We aimed to determine whether circulating levels of the cytokines, which have anti-inflammatory properties such as adiponectin or interleukin-10, could be associated with the occurrence of coronary in-stent restenosis in patients with end-stage renal disease (ESRD). METHODS: We enrolled 71 consecutive ESRD patients undergoing haemodialysis (mean age: 64.9+/-8.9 years; 19 women, 52 men; mean haemodialysis duration: 78.2+/-87.5 months), who received stenting for a single coronary lesion. Plasma concentrations of adiponectin and IL-10 were measured within one week before coronary stenting. RESULTS: Of the 71 patients who had received stenting, in-stent restenosis occurred in 37 patients (52.1%) within 6 months after stenting. In univariate logistic analysis, the homeostasis model assessment index of insulin resistance, blood haemoglobin, serum concentrations of high density lipoprotein-cholesterol or triglycerides and plasma concentrations of insulin or adiponectin were significantly associated with coronary in-stent restenosis. In a multiple logistic regression analysis among these variables, however, only the plasma adiponectin concentration was associated with the coronary in-stent restenosis: the odds ratio of the increase in 1 microg/ml of plasma adiponectin concentration for having restenosis was 0.651 (P = 0.001, 95% confidence interval: 0.506-0.839). Patients with restenosis had lower plasma adiponectin concentrations than those without [6.2+/-2.2 microg/ml (2.1-10.4 microg/ml; n = 37) vs 27.2+/-10.8 microg/ml (17.9-79.8 microg/ml; n = 34); P = 0.0001]. CONCLUSIONS: Circulating adiponectin concentrations may be associated with the occurrence of coronary in-stent restenosis in ESRD patients undergoing maintenance haemodialysis.     

Low plasma dehydroepiandrosterone sulfate level and its relationship to adiponectin in hemodialysis patients

The aim of the present study was to assess the relationship between plasma DHEA-S and adiponectin concentrations in hemodialyses patients (HD). Plasma adiponectin, DHEA-S, cholesterol, and albumin levels were estimated in 94 HD and 46 healthy subjects (HS). In HD, a significantly lower plasma DHEA-S concentration (2.5+/-0.2 vs. 4.7+/-0.4 micromol/L respectively; p = 0.002) but significantly higher plasma adiponectin level (15.0+/-0.7 vs. 8.7+/-0.8 microg/mL respectively; p = 0.004) than in HS were found. Only in uremic patients was a significant negative correlation found between plasma adiponectin and DHEA-S concentrations (tau = -0.210; p = 0.001). Decreased plasma DHEA-S level is associated with increased adiponectinemia in uremic patients.     

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.     

The association between serum adiponectin levels and nutritional status of hemodialysis patients

Adiponectin plays an important role in the regulation of body weight, insulin sensitivity, lipid metabolism, and the inflammatory response. Adiponectin is elevated in hemodialysis patients. We investigated the association between altered serum adiponectin levels and the nutritional-inflammation status of hemodialysis patients. Forty-four hemodialysis patients (21 men and 23 women; mean age 53.9 ± 9.2 years) were enrolled and 32 healthy volunteers were included as the control group. Serum adiponectin was measured using a commercial radioimmunoassay kit. Serum albumin, cholesterol, triglyceride, high-sensitivity C-reactive protein, urea, creatinine, transferrin, lean body mass, fat mass, body mass index (BMI), the subjective global assessment (SGA) score, and the malnutrition-inflammation score (MIS) were measured in all patients. Adiponectin levels were significantly elevated in the hemodialysis patients compared with the healthy subjects (24.8 ± 10.4 μg/mL and 6.8 ± 4.2 μg/mL, respectively, p < 0.0001). Serum adiponectin correlated positively with SGA (r = 0.47) and MIS (r = 0.38), and negatively with BMI (r = -0.34), triglyceride (r = -0.53), and glucose levels (r = -0.42). Serum adiponectin levels were significantly higher in malnourished patients than in well-nourished patients when assessed with SGA (20.5 ± 10.4 μg/mL and 29.0 ± 8.7 μg/mL, respectively, p = 0.005). In conclusion, serum adiponectin levels reflect the nutritional-inflammation status of hemodialysis patients. Adiponectin may also be associated with insulin resistance, dyslipidemia, and the inflammatory response in these patients.     

Markers of endothelial cell activation/injury: CD146 and thrombomodulin are related to adiponectin in kidney allograft recipients

BACKGROUND: Adiponectin may be used for assessing the risk of coronary artery disease (CAD) and may be related to the development of acute coronary syndrome. Decreased adiponectin has been associated with some risk factors for cardiovascular diseases such as male sex, obesity and diabetes mellitus. Adiponectin has antiatherogenic properties and attenuates endothelial inflammatory responses. CD146, a novel cell adhesion molecule, is localized at the endothelial junction. In kidney allograft recipients, endothelial dysfunction and atherosclerosis are almost universal. The aim of this cross-sectional study was to evaluate possible relations between adiponectin, CD146, and other markers of endothelial cell injury in 82 stable kidney transplant recipients (mean age 45 years, mean time after transplantation 47 months) with and without CAD. METHODS: Adiponectin and markers of endothelial injury: CD146, von Willebrand factor, thrombomodulin, ICAM, CD40L, P-selectin and other hemostatic markers were assessed using commercially available kits. RESULTS: Patients with CAD had evidence of more pronounced endothelial dysfunction, procoagulant state and lower adiponectin than patients without CAD. Adiponectin correlated significantly, in univariate analysis, with CD146 (r = 0.29, p = 0.009), thrombomodulin (r = 0.37, p = 0.001), protein Z (r = -0.25, p = 0.03), BMI (r = -0.26, p = 0.047), serum creatinine (r = 0.26, p = 0.02) and urea (r = 0.38, p = 0.001). CD146 correlated significantly with von Willebrand factor (r = 0.33, p = 0.002), thrombomodulin (r = 0.25, p = 0.025), age (r = 0.34, p = 0.001), platelets (r = -0.33, p = 0.002), serum urea (r = 0.24, p = 0.039), cholesterol (r = 0.24, p = 0.046), ICAM (r = 0.23, p = 0.036), protein C activity (r = -0.26, p = 0.019) and tended to correlate with serum creatinine and time after transplantation. In multivariate linear regression, independent predictors of adiponectin were CD146, thrombomodulin and urea, and of CD146 was mainly age of patients. CONCLUSIONS: Endothelial dysfunction and procoagulant state are more pronounced in kidney transplant recipients with CAD, particularly in those with lower GFR. In kidney transplant recipients, markers of endothelial cell injury are significantly increased relative to healthy volunteers. Elevation of adiponectin may be a defense mechanism against endothelial damage, reflected by elevated CD146 and thrombomodulin.     

Lower plasma adiponectin levels are associated with larger tumor size and metastasis in clear-cell carcinoma of the kidney

OBJECTIVES: To examine a possible relationship between plasma adiponectin levels and renal cell carcinoma (RCC). Adiponectin, a cytokine secreted by adipocytes, is a potent antiangiogenic factor. Plasma levels of adiponectin in patients with RCC and tumor adiponectin receptors R1 and R2 (AdipoR1&2) expression levels were measured and correlated with disease characteristics. METHODS: Preoperative plasma samples from 42 patients were analyzed in triplicate for adiponectin levels with a specific ELISA assay. All patients had clear-cell RCC, including 15 with metastatic disease. Diabetic patients were excluded; all had normal renal function. The RCC and surrounding normal renal tissue were comparatively analyzed for AdipoR1&2 expressions (immunoblotting) in 15 patients. RESULTS: Mean, median, and range of plasma adiponectin levels were 6.33, 5.84, and 1-25.2 microg/ml, respectively. A strong inverse correlation was found between plasma adiponectin levels and tumor size with significantly lower levels of adiponectin in tumors > or =4 cm (p<0.01). The median adiponectin levels in metastatic and nonmetastatic patients were 4.08 and 7.4 microg/ml, respectively (p=0.029). A trend toward significant lower adiponectin levels in high versus low Fuhrman grade (3 and 4 vs. 1 and 2) was noted (p=0.057). Expression of AdipoR1&R2 was found to be lower in tumor tissue compared with the patient's normal surrounding kidney tissues in 40% of the cases. Metastatic tumors expressed lower levels of AdipoR2. Body mass index was not inversely correlated with adiponectin levels. CONCLUSIONS: Lower blood levels of adiponectin are positively associated with clear-cell RCC aggressiveness and could potentially be used as a biomarker.     

ADMA, proteinuria, and insulin resistance in non-diabetic stage I chronic kidney disease

The rationale of this study is based on the fact that, both proteinuria and elevated asymmetric dimethyl arginine (ADMA) levels have been linked to the progression of vascular disease. Currently, there is not enough knowledge about any association between the levels of proteinuria and ADMA levels. Seventy-eight non-diabetic patients (42 men, 36 women, mean age of 26.1+/-5.2 years) with proteinuria having normal glomerular filtration rate were enrolled along with 38 healthy subjects (20 men, 18 women, mean age of 26.9+/-5.9 years). Proteinuria was below 3.5 g/day in 40 patients and above 3.5 g/day in 38 patients. Both groups had similar age, gender, and body mass index distributions. Serum ADMA, symmetric dimethyl arginine (SDMA), immunoreactive insulin, and high sensitivity C reactive protein (hsCRP) levels were measured. Insulin resistance was determined by homeostasis model assessment (HOMA). Serum ADMA, SDMA, insulin, hsCRP levels, and HOMA indexes were significantly higher in patients than in healthy control subjects. The above parameters were higher in the nephrotic range proteinuria group when compared to patients having protein levels below 3.5 g/day. There were significant correlations between the levels of proteinuria and the above parameters. According to the regression analysis, levels of proteinuria and hsCRP were significant determinants of serum ADMA levels. Our results indicate that, independent of other risk factors, ADMA is directly associated with proteinuria. Further studies are recommended to find out whether elevated ADMA levels are implicated in the high cardiovascular risk of proteinuric nephropathies.     

Neutrophil gelatinase-associated lipocalin in patients with autosomal-dominant polycystic kidney disease

It is known that many tubular proteins are involved in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which causes 8-10% of the cases of end-stage renal disease (ESRD) worldwide. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein expressed on tubular cells of which the production is markedly increased in response to harmful stimuli such as ischemia or toxicity. In the present study, serum and urinary NGAL levels were evaluated in 26 ADPKD subjects. Both levels were significantly higher in patients than in controls (sNGAL 174 +/- 52 vs. 50 +/- 27 ng/ml, p < 0.05; uNGAL 119 +/- 42 vs. 7 +/- 6 ng/ml, p < 0.005) and a close correlation was also found between these parameters and the residual renal function (sNGAL/GFR: r = -0.8, p = 0.006; sNGAL/Creatinine: r = 0.9, p = 0.007; uNGAL/GFR: r = -0.49, p < 0.05; uNGAL/Creatinine: r = 0.84, p < 0.001). Patients were further divided into two groups according to the cystic development assessed with echotomography; subjects with higher cystic growth (HCG) presented higher sNGAL and uNGAL levels with respect to others (sNGAL: 242 +/- 89 vs. 88 +/- 34 ng/ml, p < 0.05; uNGAL: 158 +/- 45 vs. 73 +/- 27 ng/ml, p < 0.05). The strict correlation between NGAL levels and residual renal function is perfectly in accord with recent studies on patients with other ESRD-associated diseases. We can hypothesize that tubular cells produce big quantities of NGAL as a consequence of increased apoptosis following chronic damage or as a compensatory response, similar to that observed in acute stress conditions (ischemia, toxicity ...). Finally, our last finding that patients with HCG showed higher levels of NGAL suggests that this protein could be also involved in the cyst growth process, as previously reported about epithelial and tumoral expansion.