Abstract
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 (p < 0.001). When compared to patients with non-nephrotic proteinuria, patients with nephrotic proteinuria had significantly higher plasma hsCRP and HOMA index (p < 0.001). 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.
INTRODUCTION
Adipose tissue is currently considered not only as a store of excess energy but also as a hormonally active system in control of metabolism.[1],[2] Additionally, adiponectin relieves a sexual dimorphism with respect to circulating levels, with women having significantly higher levels than men.[3] Recent experimental data suggest that adiponectin has anti-atherogenic and anti-inflammatory properties.[1],[4] In one experimental study, data have shown that adiponectin deficient mice have severe neointimal thickening and increased proliferation of vascular smooth muscle cells in mechanically injured arteries.[5] In human studies, it has been shown that adiponectin concentration is significantly reduced among obese subjects in comparison with non-obese subjects.[1] This hormone in obese women is negatively correlated with plasma glucose, insulin, and triglyceride levels and body mass index, but positively correlated with plasma levels of HDL-cholesterol.[1],[6],[7] In another study, adiponectin levels were compared in three groups of subjects: non-diabetic individuals, diabetic subjects with coronary artery disease, and diabetic subjects without coronary artery disease.[5] Plasma adiponectin levels were decreased in diabetic as compared to non-diabetic individuals. This decrease was more pronounced in patients who had both diabetes and coronary artery disease. These studies show that adiponectin may protect the endothelium from early atherosclerotic events such as the expression of adhesion molecules or the attachment of monocytic cell, and adiponectin deficiency could be linked to endothelial damage.[6],[8] On the other hand, it has been accepted that proteinuria is an independent major risk factor for cardiovascular diseases because of an established strong relationship between proteinuria, inflammation, and endothelial dysfunction.[9],[10] All of the above findings show that adiponectin is a protective factory for endothelium, while proteinuria is a causative factory for endothelial damage. Adiponectin and proteinuria seem to be interrelated biologically. The aim of this study was to establish the relationship between plasma adiponectin concentration and severity of proteinuria in patients with proteinuria.
PATIENTS AND METHODS
Subjects were prevalent patients referred to the Renal Unit of the Gülhane School of Medicine Medical Center, Ankara, Turkey, between June 2007 and January 2008 for the first time because of proteinuria. This study was performed on the 77 patients with proteinuria and 38 control subjects. These patients were divided by group 1 and group 2 by severity of proteinuria. Group 1 consisted of 44 patients with non-nephrotic proteinuria (<3.5 g/day). Group 2 consisted of 43 patients with nephrotic proteinuria (>3.5 g/day). The primary renal diseases were focal segmental glomerulosclerosis in 35 patients, IgA nephropathy in 9, membranous nephropathy in 16, membranoproliferative glomerulonephritis in 2, and minimal change disease in 15 patients.
Subjects were evaluated by standard physical examination, chest x-ray, baseline electrocardiogram, two-dimensional echocardiography, and routine clinical laboratory tests, including liver and kidney function tests and 24-hour urinary protein measurements. Study exclusion criteria were patients with a prior diagnosis of diabetes, current use of oral anti-diabetic medication or insulin, a fasting glucose level greater than 126 mg/dL, hypertension (systolic blood pressures ≥140 mmHg and/or diastolic blood pressures ≥ 90 mmHg), BMI > 30 kg/m2, coronary heart disease (i.e., patients with ischemic ST-T alterations and voltage criteria for LVH on electrocardiogram and/or a history of revascularization), elevated liver enzymes (AST or ALT levels ≥40 U/L), reduced glomerular filtration rate (serum creatinine levels ≥1.3mg/dL), dyslipidemia (patients with total cholesterol levels higher than 200 mg/dL and/or triglyceride levels higher than 150 mg/dL), smokers, or patients with any other serious chronic and acute co-morbidity requiring continuous medication or treatment. Subjects were also excluded if they were prescribed one or more of the following medications at the time of evaluation: angiotensin-converting enzyme inhibitors (ACE I), angiotensin receptor blockers (ARBs), statins, thiazolidinedione, estrogens or similar, glucocorticoids, α- or β-adrenergic receptor agonists, or supplementary vitamins.
The control subjects declared no family history of hypertension or DM, and all underwent an oral glucose tolerance test (OGTT) showing normal glucose tolerance and had normal blood lipid profiles. All study subjects gave informed consent for participating in the study, which was carried out in accordance with the Helsinki declaration. The local ethical committee of the Gülhane School of Medicine approved the study protocol prior to initiation of the study.
Study Design and Measurements
The study was conceived as a cross-sectional comparison between patients with non-diabetic nephropathy and healthy control subjects. Arterial blood pressure (the average value of three consecutive measurements) and venous blood sampling was performed in the morning hours, always after a 10–15 min resting period. In addition to routine biochemical tests carried out in the hospital laboratory, we stored plasma at −70°C. Estimated glomerular filtration rate (eGFR) was calculated on the basis of serum creatinine by applying the simplified Modification of Diet in Renal Disease (MDRD) formula.[11] Insulin sensitivity was estimated by the homeostasis model assessment (HOMA), calculated as follows:
[12]
To increase the precision of proteinuria estimates, 24–hour urine collection was performed three times, and the average of three 24 h proteinuria measurements was taken as representative of each participant's 24 h protein excretion rate.
Laboratory Procedures
Plasma adiponectin concentrations were measured in duplicate by RIA method (human adiponectin RIA kit, Linco Research, Inc., St. Charles, Missouri, USA; sensitivity: minimum detectable concentration = 1 ng/mL; IntraCV: 3.33%; and InterCV: 8.5%).
For the measurement of hsCRP, serum samples were diluted with a ratio of 1/101 with the diluent solution. The amount of serum samples was calculated as mg/L with a graphic that was made by noting the absorbance levels of the calibrators.
Plasma glucose, blood urea, serum creatinine, total protein, serum albumin, total cholesterol, HDL cholesterol, and triglycerides were determined by enzymatic colorimetric method with Olympus AU 600 auto analyzer using reagents from Olympus Diagnostics, GmbH (Hamburg, Germany). LDL cholesterol was calculated by Friedewald's formula.[13] Proteinuria was determined by a turbidimetric test with trichloroacetic acid (TCA). The serum basal insulin value was determined by the coated tube method (DPC-USA).
Statistical Analysis
Non-normally distributed variables were expressed as median (range), and normally distributed variables were as mean ± SD as appropriate. A p value <0.05 was considered to be statistically significant. Between-group comparisons were performed for nominal variables using the chi-square test. Differences between diabetic and controls groups were tested for significance using by t test and Mann-Whitney U test. Spearman's rank correlation was used to determine correlations with continuous variables. Stepwise multivariate regression analysis was used to assess the predictors for proteinuria levels. All statistical analyses were performed using SPSS 11.0 (SPSS Inc., Chicago, Illinois, USA) statistical package.
RESULTS
In this study, there was no statistical significant difference between patients and control subjects regarding plasma total protein, HDL cholesterol, plasma glucose, BMI, GFR, and systolic and diastolic blood pressure, while there was a statistical significant difference between patients and control groups regarding plasma albumin, total cholesterol, LDL cholesterol, triglyceride, adiponectin, insulin, hsCRP, amount of proteinuria/day, and HOMA-IR (p < 0.001).
Furthermore, there was a statistically significant difference between groups 1 and 2 regarding plasma total protein, albumin, total cholesterol, LDL cholesterol, triglyceride, amount of proteinuria/day, hsCRP, and adiponectin concentrations (p < 0.001; see Table 1), while there was no statistical significant difference between the two groups regarding HDL cholesterol, plasma glucose, GFR, HOMA-IR, BMI, and systolic and diastolic blood pressure.
Table 1 Clinical and laboratory features of the control and patient groups
Univariate Correlations
Proteinuria levels were positively correlated with hsCRP and HOMA levels (rho = 0.35, p = 0.002; rho = 0.26, p = 0.022, respectively) and negatively correlated with adiponectin levels (rho = −0.86, p < 0.001) in all patients (see Table 2 and Figure 1). Plasma adiponectin levels were negatively correlated with hsCRP and HOMA levels (rho = − 0.37, p = 0.001; rho = − 0.29, p = 0.011, respectively).
Table 2 Analysis of association between proteinuria and various parameters by univariate and multivariate linear regression
Published online:
07 July 2009Figure 1. Scatter plot showing the important relationship between proteinuria and adiponectin levels in all patients.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/irnf20/2009/irnf20.v031.i01/08860220802546461/20150616/images/medium/irnf_a_354814_uf0001_b.gif"})
Figure 1. Scatter plot showing the important relationship between proteinuria and adiponectin levels in all patients.
Multivariate Regression Analysis
In order to investigate the independent predictors of proteinuria, we undertook multiple regression analysis considering demographic factors (age, sex) and covariates that were found to be associated with proteinuria in univariate analysis: adiponectin, hsCRP, and HOMA. In this model, adiponectin levels (beta = −0.608 p < 0.001) were found to be significantly related with proteinuria levels (see Table 2).
DISCUSSION
In recent years, adiponectin has been found to have anti-inflammatory and anti-atherosclerotic properties.[3],[14],[15] Ouchi et al. showed that adiponectin inhibits tumor necrosis factor-alpha (TNF-α) induced the expression of endothelial adhesion molecules in endothelial cells and reduced atherogenic transformation of macrophage to foam cells by suppressing scavenger receptor expression experimentally.[16] Furthermore, an association had been found between adiponectin deficiency and mediators of inflammation in obese women, and that body weight reduction increases the plasma adiponectin concentrations in these patients.[7],[15],[17]Additionally, it has been established that this hormone plays a protective role against atherosclerotic vascular change thorough improving insulin sensitivity. The effect of adiponectin in improving insulin resistance is related to a decrease in plasma fatty acid levels and in triglyceride content in muscle and liver in obese mice.[18] In the study by Tsunekawa, it has been demonstrated that glimepiride improves insulin resistance, probably by its extra pancreatic effects, in elderly patients with type 2 diabetes. This mechanism for the improvement may involve a decrease in plasma TNF-α, presumably induced by increased plasma adiponectin; in addition, HbA1c and blood glucose levels were improved.[19] Adamczak et al. found that essential hypertensive patients are characterized by lower plasma adiponectin concentrations than age-, BMI-, and gender-matched normotensive healthy subjects, as well as by the presence of a significant negative relationship between plasma adiponectin concentrations and blood pressure.[4] All of these studies show that there is an association between hypoadiponectemia and various diseases that may damage the endothelium in cardiovascular system.
In this study, there was a statistically significant difference between proteinuric patients and healthy subjects in according to plasma adiponectin concentrations, HOMA-IR, plasma insulin, total cholesterol, LDL cholesterol, triglyceride, and hsCRP levels. Furthermore, there was also a statistically significant difference between groups 1 and 2 regarding plasma total cholesterol, LDL cholesterol, triglyceride, hsCRP, amount of proteinuria, and plasma adiponectin concentrations. On the other hand, proteinuria levels were positively correlated with hsCRP and HOMA levels and negatively correlated with adiponectin levels in all patients. In addition, plasma adiponectin levels were negatively correlated with hsCRP and HOMA levels. In contrast to our study's results, Zoccali et al. found that plasma adiponectin concentration is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors.[20] They suggested that hyperadiponectinemia in nephrotic syndrome is a counter-regulatory response aimed at attenuating the vasculotoxic effect of the proteinuria and the other biochemical alterations that attend nephrotic syndrome. According to their study, increased metabolic changes, inflammation, and insulin resistance trigger a parallel increase in adiponectin synthesis in fat cell in the patients with nephrotic syndrome. They speculated that the direction of the relationship between adiponectin and metabolic risk factors like cholesterol and albumin in nephrotic patients is just the opposite of that found in other diseases, such as obesity and diabetes. In obesity and type 2 diabetes, which is linked to insulin resistance and positive energy balance, low plasma adiponectin concentrations seem to be an initiating event in the pathogenesis of insulin resistance. In nephrotic syndrome, energy balance is often negative; stimuli amplifying the synthesis of adiponectin prevail on suppressive factors, leading to an increase in plasma concentrations of this protein.[20] We also believe that there is a counter-regulatory response to attenuating the vasculotoxic effect of the proteinuria and the other biochemical alterations in nephrotic syndrome, but this counter-regulatory response results in decreases in plasma adiponectin concentration, and not increases. Decreased plasma adiponectin concentration in patients with proteinuria may be related to its counteraction to inflammatory and the metabolic effects of proteinuria and its expenditure during this process. There appear to be a few possible mechanisms that cause hypoadiponectemia in patients with proteinuria.[21] First, plasma adiponectin concentrations may be linked to insulin sensitivity, and decreasing insulin sensitivity can cause hypoadiponectinemia. It has been shown that insulin suppresses adiponectin gene expression and reduces the levels of adiponectin mRNA dose- and time-dependently. Second, hypoadiponectinemia may be directly linked to early atherosclerotic vascular damage and subsequent endothelial dysfunction. Atherosclerosis is an inflammatory disease, and this inflammation is counteracted in vivo by adiponectin.[22] We may speculate that the counteraction by adiponectin to inflammation may result in an expenditure of this protein. Engeli et al. have found that there were an inverse correlation between plasma adiponectin concentrations and inflammatory markers CRP and IL-6.[7] There was also a significant negative relationship between adiponectin and two biomarkers of inflammation, hsCRP and fibrinogen. Thus, it has been suggested that hypoadiponectinemia may also serve as a marker of increased inflammatory status in end stage renal disease (ESRD) patients in the study by Stenvinkel et al.[23] Moreover, it has been established that adiponectin can accumulate in the vascular wall when the endothelial barrier is damaged. This accumulation may also contribute to hypoadiponectinemia in patients with proteinuria.
In the present study, it had been demonstrated that there is an increase in insulin resistance, as quantified by HOMA-IR test, and inflammation is quantified by plasma hsCRP in patients with proteinuria in comparison with healthy control subjects. Furthermore, there is a significantly inverse correlation between plasma adiponectin concentrations and plasma hsCRP in patients with non-nephrotic proteinuria and plasma insulin concentration and HOMA-IR in patients with nephrotic proteinuria. These results show that inflammation and insulin resistance can play an important role in hypoadiponectinemia in proteinuric patients. In other words, the greater the high insulin resistance and inflammation, the lover plasma adiponectin concentrations were in these patients. We may speculate that plasma adiponectin levels are suppressed by the inflammatory process, and that insulin resistance may result in hypoadiponectinaemia in patients with proteinuria. That patients with obesity, hypertension, coronary artery disease (CAD), diabetes on the cusp of inflammation, and insulin resistance are associated with hypoadiponectinemia supports this speculation.[19],[24],[25]
Although plasma adiponectin concentrations are higher in patients with ESRD than in healthy subjects, the kidney's role in the metabolism of adiponectin is unknown.[8] Guebre et al. has suggested that plasma adiponectin concentrations in chronic kidney disease are related more to metabolic disturbances than to decline in renal function.[26] They found that 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 a decline in renal function. In their study, in non-obese and non-diabetic patients, no relationship was found between adiponectin and serum insulin or CRP, these latter parameters being in their normal ranges. Thus, the plasma adiponectin rise that occurs when renal function deteriorates may represent an adaptive response to the altered metabolic profile associated with a high cardiovascular risk in chronic kidney disease patients.[20] This result shows that insulin resistance and inflammation seems to be important determinant factors for plasma adiponectin concentrations in these patients. In their absence, plasma adiponectin concentrations can be raised by adaptive response to the altered metabolic profile. In the study by Zocalli et al., mean GFR was 70 mL/min, and the presence of hyperadiponectinemia was found in nephrotic patients.[20] According to our speculation, hyperadiponectinemia cannot be explained by adaptive response due to increased insulin resistance and inflammation in these patients. This mild renal insufficiency may partly explain hyperadiponectinemia in nephrotic patients in their study.
In conclusion, these results show that plasma adiponectin concentrations are reduced by insulin resistance, inflammation, and severity of proteinuria in proteinuric patients.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
| Controls (n = 38) | Patients (n = 77) | Group I proteinuria (<3.5 g/day, n = 34) | Group II proteinuria (>3.5 g/day, n = 43) | p | p† | |
|---|---|---|---|---|---|---|
| Age (yr) | 46 ± 5 | 46 ± 6 | 46 ± 5 | 47 ± 4 | 0.395† | 0.523 |
| Sex (M/F) | 22/16 | 44/33 | 26/18 | 21/22 | 0.136‡ | 0.642 |
| GFR (ml/min/ 1.73 m2) | 93 ± 7 | 91 ± 7 | 90 ± 6 | 92 ± 7 | 0.061† | 0.171 |
| Total protein (g/dl) | 6.6 ± 0.3 | 6.1 ± 0.9 | 6.9 ± 0.4 | 5.6 ± 0.8 | 0.002† | <0.001 |
| Serum albumin (g/dl) | 4.1 ± 0.2 | 3.5 ± 0.6 | 4.0 ± 0.4 | 3.1 ± 0.5 | <0.001† | <0.001 |
| Systolic BP (mmHg) | 127 ± 7 | 128 ± 7 | 128 ± 9 | 129 ± 6 | 0.316§ | 0.675 |
| Diastolic BP (mmHg) | 83 ± 5 | 83 ± 3 | 83 ± 3 | 84 ± 3 | 0.856§ | 0.130 |
| Total cholesterol (mg/dl) | 189 ± 22 | 243 ± 52 | 205 ± 26 | 274 ± 48 | <0.001† | <0.001 |
| Triglycerides (mg/dl) | 117 ± 15 | 168 ± 51 | 128 ± 22 | 199 ± 46 | <0.001† | <0.001 |
| LDL cholesterol (mg/dl) | 110 ± 16 | 137 ± 29 | 112 ± 16 | 157 ± 21 | <0.001† | <0.001 |
| HDL cholesterol (mg/dl) | 45 ± 6 | 43 ± 5 | 43 ± 5 | 43 ± 6 | 0.165† | 0.951 |
| BMI (kg/m2) | 26 ± 2 | 26 ± 3 | 26 ± 2 | 27 ± 2 | 0.933† | 0.330 |
| Amount of proteinuria (g/day) | 0.08 ± 0.02 | 3.9 ± 1.6 | 2.5 ± 0.8 | 4.8 ± 1.4 | <0.001† | <0.001 |
| hsCRP (mg/l) | 2.3 ± 0.9 | 13.2 ± 3.3 | 11.8 ± 2.7 | 14.3 ± 3.3 | <0.001† | <0.001 |
| FPG (mg/dl) | 83 ± 11 | 81 ± 15 | 80 ± 16 | 81 ± 14 | 0.490† | 0.870 |
| Insulin (μIU/ml) | 6 ± 1 | 12 ± 5 | 10 ± 3 | 13 ± 7 | <0.001† | 0.039 |
| HOMA | 1.2 ± 0.4 | 2.4 ± 1.2 | 2.1 ± 0.6 | 2.6 ± 1.4 | <0.001† | 0.078 |
| Adiponectin (μg/ml) | 24.65 ± 3.67 | 7.09 ± 3.94 | 10.30 ± 3.84 | 4.56 ± 1.27 | <0.001† | <0.001 |
*Patients versus control. These variables are matched for in analyses. †t test, §Mann-Whitney U test, and ‡chi-square test, †t test, according to the severity of proteinuria (between groups 1 and 2).
Abbreviations: BP = blood pressure, BMI = body mass index, FPG = fasting plasma glucose, GFR = glomerular filtration rate, hsCRP = high sensitive C reactive protein, HOMA = homeostasis model assessment.
| Parameters | Univariate beta (p) | Multivariate beta (p) |
|---|---|---|
| Adiponectin (μg/ml) | − 0.86 (<0.001) | − 0.608 (<0.001) |
| hsCRP(mg/l) | 0.35 (0.002) | |
| HOMA | 0.26 (0.022) | |
| GFR (ml/min/ 1.73 m2) | 0.19 (0.09) | |
| Age (yr) | 0.09 (0.460) | |
| Sex | 0.06 (0.615) |
Abbreviations: GFR = glomerular filtration rate, hsCRP = high sensitive C reactive protein, HOMA = homeostasis model assessment.
REFERENCES
- Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 2003; 148: 293–300 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Wiecek A, Kokot F, Chudek J, Adamczak M. The adipose tissue—a novel endocrine organ of interest to the nephrologist. Nephrol Dial Transplant. 2002; 17: 191–195 [Google Scholar]
- Berg AH, Combs TP, Scherer PE. ACRP/adiponectin: An adipokine regulating glucose and lipid metabolism. Trends in Endocrinology and Metabolism 2002; 13(2)84–89 [Google Scholar]
- Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y. Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens. 2003; 16(1)72–75 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Haluzik M, Parizkova J, Haluzik MM. Adiponectin and its role in the obesity-induced insulin resistance and related complications. Physiol Res. 2004; 53: 123–129 [PubMed], [Web of Science ®], [Google Scholar]
- Yang W, Lee W, Funahashi T, al et. Weight reduction increases plasma levels of an adipose-derived anti-inflamatory protein, adiponectin. J Clin Endocrinol Metab. 2001; 86: 3815–3816 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Engeli S, Feldpausch M, Gorzelniak K, al et. Association between adiponectin and mediators of inflamation in obese women. Diabetes. 2003; 52: 942–947 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Zocalli C, Mallamaci F, Tripepi G, al et. Adiponectin, metabolic risk factors, and cadiovascular events among patients with end-stage renal disease. J Am Soc Nephrol. 2002; 13: 134–141 [Google Scholar]
- Chobanian AV, Bakris GL, Black HR, al et. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003; 289(19)2560–2572 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Perticone F, Maio R, Tripepi G, Sciacqua A, Mallamaci F, Zoccali C. Microalbuminuria, endothelial dysfunction and inflammation in primary hypertension. J Nephrol. 2007; 20(Suppl. 12)S56–S62 [Google Scholar]
- Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130(6)461–470 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28(7)412–419 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18(6)499–502 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Zoccali C, Mallamaci F, Tripepi G. Adipose tissue as a source of inflammatory cytokines in health and disease: Focus on end-stage renal disease. Kidney Int Suppl. 2003; 84: S65–S68 [Google Scholar]
- Murakami H, Ura N, Furuhashi M, Higashiura K, Miura T, Shimamoto K. Role of adiponectin in insulin-resistant hypertension and atherosclerosis. Hypertens Res. 2003; 26(9)705–710 [Google Scholar]
- Ouchi N, Kihara S, Arita Y, al et. Novel modulator for endothelial adhesion molecules: Adipocyte-derived plasma protein adiponectin. Circulation. 1999; 100(25)2473–2476 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Hotta K, Funahashi T, Arita Y, al et. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000; 20(6)1595–1599 [Google Scholar]
- Havel PJ. Control of homeostasis and insulin action by adipocyte hormones: Leptin, acylation stimulating protein, and adiponectin. Curr Opin Lipidol. 2002; 13(1)51–59 [Google Scholar]
- Tsunekawa T, Hayashi T, Suzuki Y, al et. Plasma adiponectin plays an important role in improving insulin resistance with glimeripiride in elderly type 2 diabetic subjects. Diabetes Care. 2003; 26(2)285–289 [Google Scholar]
- Zoccali C, Mallamaci F, Panuccio V, al et. Adiponectin is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors. Kidney Int Suppl. 2003; 84: S98–S102 [Google Scholar]
- Shimabukuro M, Higa N, Asahi T, al et. Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab. 2003; 88(7)3236–3240 [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dislipidemia. J Clin Endocrinol Metab. 2002; 87(6)2764–2769 [Google Scholar]
- Stenvinkel P, Marchlewska A, Pecoits-Filho R, al et. Adiponectin in renal disease: Relationship to phenotype and genetic variation in the gene encoding adiponectin. Kidney Int. 2004; 65(1)274–281 [Google Scholar]
- Shand BI, Scott RS, Elder PA, George PM. Plasma adiponectin in overweight, nondiabetic individuals or without insulin resistance. Diabetes Obes Metab. 2003; 5(5)349–353 [Google Scholar]
- Yenicesu M, Yilmaz MI, Caglar K, al et. Adiponectin levels is reduced and inversely correlated with the degree of proteinuria in type 2 diabetic patients. Clin Nephrol. 2005; 64(1)12–19 [Google Scholar]
- Guebre-Egziabher F, Bernhard J, Funahashi T, Hadj-Aissa A, Fouque D. Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function. Nephrol Dial Transplant. 2005; 20(1)129–134 [Google Scholar]