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Fasting Serum Fatty Acid-binding Protein 4 Level Positively Correlates with Metabolic Syndrome in Hemodialysis Patients
Archives of Medical Research 41 (2010) 536e540
ORIGINAL ARTICLE
Fasting Serum Fatty Acid-binding Protein 4 Level Positively Correlates with Metabolic Syndrome in Hemodialysis Patients Jen-Pi Tsai,a Hung-Hsiang Liou,b Hsiang-Man Liu,c Chung-Jen Lee,g Ru-Ping Lee,f and Bang-Gee Hsud,e a Division of Nephrology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan Division of Nephrology Department of Medicine, Hsin-Jen Hospital, Taipei County, Taiwan c Department of Nursing, dDivision of Nephrology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan e School of Medicine, fDepartment of Nursing, Tzu Chi University, Hualien, Taiwan g Department of Nursing Tzu Chi College of Technology, Hualien, Taiwan b
Received for publication July 5, 2010; accepted September 14, 2010 (ARCMED-D-10-0000343).
Background and Aims. Serum fatty acid-binding protein 4 (FABP4) level increases in patients with metabolic syndrome (MetS). The interrelationships between fasting FABP4 levels and MetS have not been analyzed in hemodialysis (HD) patients. Methods. Fasting blood samples were obtained from 101 chronic HD patients. MetS was defined according to the diagnostic criteria of the International Diabetes Federation. Results. In total, 48 HD patients (47.5%) had MetS. Fasting FABP4 levels positively correlated with MetS ( p 5 0.022). Univariate linear regression analysis showed that the pre-HD body weight ( p !0.001), waist circumference ( p 5 0.003), body mass index ( p 5 0.003), total cholesterol (TCH) ( p !0.001), triglyceride (TG) ( p !0.001), creatinine ( p 5 0.042), insulin level ( p 5 0.014), and homeostasis model assessment of insulin resistance (HOMAIR; p 5 0.015) were positively correlated with serum FABP4 levels, whereas high-density lipoprotein-cholesterol (HDL-C) ( p 5 0.049) and adiponectin level ( p 5 0.004) were negatively correlated with fasting serum FABP4 levels in HD patients. Conclusions. MetS was positively correlated with fasting FABP4 levels in our chronic HD patients. TG, TCH, and waist circumference were independent predictors of serum FABP4 levels in HD patients. Ó 2010 IMSS. Published by Elsevier Inc. Key Words: Fatty acid binding protein 4, Metabolic syndrome, Hemodialysis.
Introduction Fatty acid-binding protein 4 (FABP4) is one member of the fatty acid-binding protein superfamily and is highly expressed in adipose tissue (1). FABP4 is a major cytoplasmic protein that is involved in the regulation of lipid metabolism and is expressed abundantly in mature adipocytes and activated macrophages (2,3). This protein binds fatty acid ligands with high affinity and functions in intracellular trafficking of fatty acids, regulation of lipid metabolism, and modulation of gene expression (4,5). FABP4-deficient mice have been shown to avoid from developing insulin Adress reprint requests to: Dr. Bang-Gee Hsu, Division of Nephrology, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Chung Yang Road, Hualien, Taiwan; Phone: 886-3-8561825; FAX: 886-3-8577161; E-mail: [email protected]
resistance, impaired glucose tolerance, and atherosclerosis (4,6). The following parameters define metabolic syndrome (MetS): increased waist circumference, decreased serum HDL levels, increased serum TG levels, hypertension, and insulin resistance (7). MetS constitutes a major health problem in the West and is estimated to affect at least 20% of the adult population (8). MetS is a significant risk factor for chronic kidney disease in the general population (9), and it also predicts hospitalization in hemodialysis (HD) patients (10). Serum FABP4 level increases in patients with MetS (11,12) and predicts the development of MetS (13). Recently, we have shown that serum FABP4 levels positively correlates with MetS in coronary artery disease patients (14). Thus far, there have been no studies on the correlation between serum FABP4 levels and MetS or the number of MetS criteria in HD patients. Therefore,
0188-4409/$ - see front matter. Copyright Ó 2010 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2010.09.007
Serum Fatty-acid Binding 4 in Hemodialysis Patients
we aim to investigate the relationships between fasting serum FABP4 levels and MS components in HD patients. Materials and Methods Patients Among the patients, 101 HD patients (55 men and 46 women) with the same high-flux polysulfone disposable artificial kidney (FX class dialyzer, Fresenius Medical Care, Bad Homburg, Germany) were studied in June 2009 at the Dalin Tzu Chi General Hospital. Patients from our HD program were invited to participate in this study if they were O20 years of age and were receiving standard dialysis for 4 h three times a weekly with standard bicarbonate dialysate and were on dialysis for at least 12 months. Patients were excluded if they had acute infection, malignancy, life expectancy !3 months, or if they refused or were unable to provide informed consent. This protocol was approved by The Protection of Human Subjects Institutional Review Board at Tzu Chi Hospital. The Kt/V and urea reduction ratio (URR) were measured before dialysis, and blood urea nitrogen (BUN) levels were measured immediately after dialysis by using a formal single-compartment dialysis urea kinetic model. Anthropometric Measurements Body weight was measured to the nearest half kilogram before HD in light clothing and without shoes. Height was measured to the nearest half centimeter. Waist circumference was measured to the nearest half centimeter at the shortest point below the lower rib margin and the iliac crest. Body mass index (BMI) was calculated as weight in kilograms divided by height squared in meters (14,15). Biochemical Investigations Fasting blood samples of |0.5 mL were obtained for the complete blood count (Sysmex K-1000, Bohemia, NY) and other blood samples were immediately centrifuged at 3000 x g for 10 min for biochemical analyses. Serum levels of BUN, creatinine, fasting glucose, total cholesterol (TCH), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), albumin, iron, total iron-binding capacity and high sensitivity-C-reactive protein (hs-CRP) were measured with an autoanalyzer (COBAS Integra 800, Roche Diagnostics, Basel, Switzerland). Serum intact parathyroid hormone (iPTH) levels were measured with enzyme-linked immunosorbent assay (ELISA) (Diagnostic Systems Laboratories, Webster, TX) (15) and serum FABP4 and adiponectin levels by enzyme immunoassay (EIA) (SPI- BIO, Montigny le Bretonneux, France) (14). The limit of detection, calculated as the concentration of human FABP4 corresponding to the blank average minus 3 standard deviations, was 0.1 ng/mL.
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Inter- and intra-assay coefficients of variation for FABP4 were 5.1% and 3.9%, respectively. The limit of detection calculated as the concentration of human adiponectin corresponding to the blank average minus three standard deviations was 0.7 mg/mL. Inter- and intra-assay coefficients of variation for adiponectin were 7.3% and 6.4%, respectively. Serum insulin levels were measured by the microparticle enzyme immunosorbent assay (MEIA) method with an autoanalyzer (Abbott Laboratories, Abbott Park, IL). HOMA-IR [glucose (mg/dL) insulin (mU/mL)/405] (16) was applied to evaluate insulin resistance. MetS and Its Components The prevalence of MetS was defined according to the International Diabetes Federation definition (7). People were diagnosed with MetS if they had central (abdominal) obesity with a waist circumference $90 cm (men) or $80 cm (women) (Chinese criteria) and if they had two or more of the following criteria: fasting serum glucose level $110 mg/dL, TG level $150 mg/dL, HDL-C level !40 mg/dL (men) or !50 mg/dL (women), or blood pressure O130/85 mmHg. Patients who use antihypertensive medications were considered as hypertensive. Patients were regarded as diabetic if their fasting plasma glucose level was $126 mg/dL, if their 2 h glucose level during an oral glucose tolerance test was $200 mg/dL, or if the patient was using a diabetes medication (oral or insulin) (17). Statistical Analysis Data are expressed as mean standard deviation. Data were examined for normal distribution by KolmogorovSmirnov statistics. Categorical variables were analyzed by the c2 test. Comparisons between patients were performed using the Student’s independent t test (two-tailed) for normally distributed data (FABP4 levels). Variables that correlated with serum FABP4 levels in HD patients were further evaluated by univariate linear regression analyses and multivariate forward stepwise regression analysis. The significance of the differences in FABP4 levels between the numbers of MetS criteria was analyzed by the Kruskal-Wallis analysis of variance test. SPSS for Windows v.13.0 (SPSS Inc., Chicago, IL) was used for data analysis. A p value !0.05 was considered statistically significant. Results Demographic and biochemical data of our HD patients are presented in Table 1. Of the 101 patients enrolled, 48 patients (47.5%) had IDF-defined MetS. Among the causes of uremia, 28 patients had diabetes mellitus, 19 patients had chronic glomerulonephritis, and 37 patients were hypertensive. Average fasting serum FABP4 levels were 254.93 63.34 ng/mL. Our HD patients with MetS ( p 5 0.022), male ( p 5 0.001), and who used angiotensin-receptor blocker
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Tsai et al./ Archives of Medical Research 41 (2010) 536e540
Table 1. Clinical and analytical characteristics of 101 hemodialysis patients Item Anthropometric data
Biochemical data
Causes of uremia
Parameter
Mean SD
Parameter
Height (cm) Pre-HD body weight (kg) Body mass index (kg/m2) Systolic pressure (mmHg) White blood count (x1000/ml) Albumin (g/dL) Triglyceride (mg/dL) Fasting glucose (mg/dL) Blood urea nitrogen (mg/dL) hs-CRP(mg/dL) Kt/V (Gotch) FABP4 (ng/mL) Iron (mg/dL) Transferrin saturation (%) Adiponectin (mg/mL) Diabetes (%) Glomerulonephritis (%)
154.43 8.16 60.88 13.39 25.73 6.25 145.37 22.36 6.58 3.09 3.97 0.41 136.99 92.00 143.83 65.57 60.95 15.47 0.85 1.97 1.46 0.20 254.93 63.34 73.02 37.29 33.41 16.69 23.55 16.62 28 (27.7) 19 (18.8)
Waist circumference (cm) Age (years) HD duration (months) Diastolic pressure (mmHg) Hemoglobin (g/dL) Total cholesterol (mg/dL) HDL-C (mg/dL) Creatinine (mg/dL) iPTH (pg/mL) URR Insulin (mU/mL) HOMA-IR Total iron-binding capacity EPO dose (units/week) Hypertension (%) Other (%)
Mean SD 88.02 62.00 71.51 78.00 10.56 160.05 43.54 9.11 239.23 0.76 23.54 7.92 224.09 3900.99
10.75 13.62 45.47 14.26 1.38 39.56 16.81 2.09 226.01 0.05 33.60 10.24 51.02 3565.12
37 (36.6) 17 (16.9)
Data are expressed as mean standard deviations or proportion. HD, hemodialysis; HDL-C, high-density lipoprotein-cholesterol; hs-CRP, high-sensitivity C-reactive protein; iPTH, intact parathyroid hormone; URR, urea reduction rate; FABP4, fatty acid-binding protein 4; HOMA-IR, homeostasis model assessment of insulin resistance, EPO, erythropoietin.
(ARB) ( p 5 0.012) had higher serum fasting FABP4 levels, whereas patients with diabetes, hypertension, secondary hyperparathyroidism (iPTH O300 pg/mL) or who used angiotensin-converting-enzyme inhibitor (ACEI), calcium channel blocker (CCB), b-blocker, statin, or peroxisome proliferator-activated receptor-g agonist did not have higher serum fasting FABP4 levels (Table 2). The univariate linear analysis of fasting serum FABP4 levels in HD patients is presented in Table 3. Pre-HD body weight (r 5 0.358; p !0.001), waist circumference (r 5 0.296; p 5 0.003), BMI (r 5 0.294; p 5 0.003), TCH (r 5 0.362; p !0.001), TG (r 5 0.439; p !0.001), creatinine level (r 5 0.203; p 5 0.042), insulin level (r 5 0.243; p 5 0.014), and HOMA-IR (r 5 0.242; p 5 0.015) were positively correlated with serum FABP4 levels, whereas HDL-C (r 5 0.196; p 5 0.049) and adiponectin level (r 5 0.280; p 5 0.004) were negatively correlated with serum FABP4 levels in HD patients. Multivariate forward stepwise linear regression analysis of the significant variables (pre-HD body weight, waist circumference, BMI, TCH, TG, creatinine, insulin, HOMA-IR, adiponectin, and HDL-C) showed that TG (r2 change 5 0.193, p 5 0.001), TCH (r2 change 5 0.051, p 5 0.008), and waist circumference (r2 change 5 0.052, p 5 0.008) were the independent predictors of fasting serum FABP4 levels in HD patients (Table 4).
Discussion The results of our study showed that fasting FABP4 levels were positively associated with MetS in HD patients. TG, TCH, and waist circumference were independent predictors of serum FABP4 levels in HD patients.
Recent studies have demonstrated that MetS is one of the risk factors for developing chronic kidney disease in the general population (9), and it also predicts an increasing rate of hospitalization in HD patients (10). The prevalence of MetS was 47.5% in our study, which was comparable to other studies that ranges from 40.1e66.0% (16,18). Serum FABP4 levels were 10-fold higher in HD patients than in patients with normal renal function, which denoted that kidney is a major site for FABP4 clearance (19). In fact, plasma FABP4 concentrations were positively correlated with plasma creatinine levels in type 2 diabetes patients (20) and in our HD patients. Serum FABP4 levels has been reported to be higher in the female population (11e13), which was also found in our female HD patients. Familial combined hyperlipidemia is caused by an increased production rate of TG-rich lipoproteins, mainly liver-derived very low-density lipoproteins (VLDL), with ensuing hyperlipidemia characterized by plasma increases of both TG and TCH (21). Serum FABP4 levels have been found to positively correlate with TG and negatively correlate with HDL-C (3,5). Plasma FABP4 levels are increased in patients with familial combined hyperlipidemia (22). In this study we also observed a similar finding. Circulating FABP4 levels were significantly associated with BMI and waist circumference in obese women and in patients with familial combined hyperlipidemia (22,23). In our study, we noted that a positive association between serum FABP4 concentrations and the indicators of adiposity (BMI, waist circumference, and pre-HD body weight), and may suggests that adipose tissue is the major site for FABP4 secretion in HD patients. Like other studies in Chinese and Caucasian populations (11,12), we also observed that serum insulin levels or HOMA-IR was positively correlated with fasting serum FABP4 levels in HD
Serum Fatty-acid Binding 4 in Hemodialysis Patients Table 2. Clinical characteristics and fasting serum FABP4 levels of 101 hemodialysis patients Characteristic Sex Male Female Diabetes No Yes Hypertension No Yes Hyperparathyroidism No Yes Metabolic syndrome No Yes ACE inhibitor No Yes ARB No Yes b-blocker No Yes CCB No Yes Statin No Yes PPAR-g agonist No Yes
Number (%)
FABP4 level (ng/mL)
539
Table 3. Correlation between fasting serum FABP4 levels and clinical variables in 101 hemodialysis patients by univariate linear regression analyses
p value
55 (54.5) 46 (45.5)
235.83 58.03 277.77 62.40
0.001*
71 (70.3) 30 (29.7)
256.69 66.31 250.76 56.51
0.669
44 (43.6) 57 (56.4)
254.47 55.27 255.28 69.41
0.950
78 (77.2) 23 (22.8)
252.31 61.99 263.82 68.36
0.446
53 (52.5) 48 (47.5)
241.28 54.52 270.00 69.31
0.022*
88 (87.1) 13 (12.9)
258.73 65.36 229.16 40.36
0.117
68 (67.3) 33 (32.7)
265.81 67.34 232.50 47.65
0.012*
71 (70.3) 30 (29.7)
255.80 65.18 252.85 59.77
0.832
56 (55.4) 45 (44.6)
264.38 66.54 243.17 57.68
0.095
96 (95.0) 5 (5.0)
255.08 63.92 251.94 56.88
0.915
90 (89.1) 11 (10.9)
255.10 63.98 254.49 62.76
0.966
Data are expressed as mean standard deviations. FABP4, fatty acid-binding protein 4; ARB, angiotensin-receptor blocker; ACE, angiotensin-converting enzyme; CCB, calcium-channel blocker; PPAR-g, peroxisome proliferator-activated receptor-g; HD, hemodialysis. *p !0.05 was considered statistically significant after Student’s t-test.
patients. The multivariate forward stepwise linear regression analysis of the significant variables showed that the TG, TCH, and waist circumference were independent predictors of fasting serum FABP4 levels. Adiponectin, a unique insulin sensitizer adipocyte-derived substance, plays an important role in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin-sensitive tissues (24). A decrease in the circulating level of adiponectin has been linked to MetS (25,26). According to our study, serum FABP4 levels negatively correlate with serum adiponectin levels in HD patients and also noted positively associated with MetS in HD patients. In this study, FABP4 levels showed no differences between diabetes group and non-diabetes group. In addition, fasting glucose was not associated with FABP4 levels in HD patients. Many factors may affect serum FABP4 levels such as drugs, clearance of FABP4, and associated
Items
Beta
p value
Age (year) HD duration (months) Height (cm) Pre-HD body weight (kg) WC (cm) BMI (kg/m2) White blood count (x1000/ml) Hemoglobin (g/dL) Albumin (g/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL-C (mg/dL) Fasting glucose (mg/dL) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) hs-CRP (mg/dL) Systolic pressure (mmHg) Diastolic pressure (mmHg) Intact parathyroid hormone (pg/mL) Insulin (mU/dL) HOMA-IR Urea reduction rate (URR) Kt/V (Gotch) Adiponectin (mg/mL)
0.157 0.029 0.020 0.358 0.296 0.294 0.062 0.137 0.174 0.362 0.439 0.196 0.053 0.061 0.203 0.105 0.108 0.027 0.061 0.243 0.242 0.083 0.004 0.280
0.117 0.773 0.843 !0.001* 0.003* 0.003* 0.539 0.170 0.082 !0.001* !0.001* 0.049* 0.598 0.547 0.042* 0.296 0.282 0.787 0.549 0.014* 0.015* 0.407 0.967 0.004
HD, hemodialysis; WC, waist circumference; BMI, body mass index; HDLcholesterol, high-density lipoprotein-cholesterol; hs-CRP, high sensitivityC-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance; FABP4, fatty acid-binding protein 4; HD, hemodialysis. *p !0.05 was considered statistically significant after univariate linear analyses.
diseases. Pharmacological interventions have been shown to influence serum FABP4 levels in humans. Three months treatment with atorvastatin in hyperlipidemic nondiabetic patients, serum FABP4 levels were substantially decreased (27). Another study involving patients with type 2 diabetes mellitus found no difference in FABP4 concentrations in statin-treated patients but reported increased FABP4 levels in thiazolidinedione-treated patients (28). FABP4 levels were lower in patients taking aspirin, and higher values Table 4. Multivariate stepwise linear regression analysis of pre-HD body weight, waist circumference, body mass index, total cholesterol level, triglyceride level, HDL-C level, insulin level, HOMA-IR, adiponectin and creatinine level: correlation with fasting serum FABP4 levels in 101 hemodialysis patients Items
Beta
Triglyceride (mg/dL) 0.317 Total cholesterol (mg/dL) 0.244 Waist circumference (cm) 0.232
R square R square change p value 0.193 0.244 0.296
0.193 0.051 0.052
0.001* 0.008* 0.008*
HDL-C, high-density lipoprotein-cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; FABP4, fatty acid-binding protein 4; HD, hemodialysis. *p !0.05 was considered statistically significant in the multivariate stepwise linear regression analysis.
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Tsai et al./ Archives of Medical Research 41 (2010) 536e540
were observed in coronary artery disease patients taking statins and antihypertensive drugs (29). In this study, HD patients using ARB drugs had lower fasting serum FABP4 levels. Our previous study involving coronary artery disease patients found no difference in FABP4 concentrations in patients taking statins or antihypertensive drugs (14). In this study, our results did not show a relationship between stains or peroxisome proliferator-activated receptor g agonists or other drugs (ACEI, CCB, or b-blocker) and serum FABP4 levels among HD patients. Further studies are required to elucidate the relationship between medication and FABP4 levels in HD patients. Our study has some limitations. First, this study had a cross-sectional design. Therefore, our findings should be investigated in long-term prospective studies before a causal relationship between serum FABP4 levels and MetS in HD patients can be established. Second, serum FABP4 levels were higher in HD patients than in patients with normal renal function, which denoted that kidney is a major site for FABP4 clearance (19). Our study did not measure the clearance of FABP4 before and after HD. Another limitation is that FABP4 usually acts at the interface of inflammatory pathways such as tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), and IL-6 (3). However, our study did not investigate their influence on these inflammatory markers. Further studies are needed to examine the clearance of FABP4 before and after HD and the association between serum FABP4 levels and inflammatory cytokines in HD patients. In summary, we found a positive correlation between circulating fasting FABP4 levels and MetS in HD patients. Serum TG, TCH, and waist circumference were independent predictors of serum FABP4 levels in HD patients. Acknowledgments This work was supported by grants from Dalin Tzu Chi Hospital in Taiwan (DTCRD 98(2)e17).
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7. Alberti KG, Zimmet PZ, Shaw J. Metabolic syndrome—a new worldwide definition. A consensus statement from the International Diabetes Federation. Diabet Med 2006;23:469e480. 8. Scott CL. Diagnosis, prevention, and intervention for the metabolic syndrome. Am J Cardiol 2003;92:35ie42i. 9. Peralta CA, Kurella M, Lo JC, et al. The metabolic syndrome and chronic kidney disease. Curr Opin Nephrol Hypertens 2006;15:361e365. 10. Yang SY, Chiang CK, Hsu SP, et al. Metabolic syndrome predicts hospitalization in hemodialysis patients: a prospective Asian cohort study. Blood Purif 2007;25:252e259. 11. Stejskal D, Karpisek M. Adipocyte fatty acid binding protein in a Caucasian population: a new marker of metabolic syndrome? Eur J Clin Invest 2006;36:621e625. 12. Xu A, Wang Y, Xu JY, et al. Adipocyte fatty acid binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem 2006;52:405e413. 13. Xu A, Tso AW, Cheung BM, et al. Circulating adipocyte fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study. Circulation 2007;115:1537e1543. 14. Hsu BG, Chen YC, Lee RP, et al. Fasting serum level of fatty-acidbinding protein 4 positively correlates with metabolic syndrome in patients with coronary artery disease. Circ J 2010;74:327e331. 15. Lee CC, Lee RP, Subeq YM, et al. Fasting serum total ghrelin level inversely correlates with metabolic syndrome in hemodialysis patients. Arch Med Res 2008;39:785e790. 16. Okano K, Ohba T, Matsugami K, et al. Analysis of plasma adipocytokines related to clinical and laboratory data in the maintenance hemodialysis patients. Intern Med 2008;47:1379e1386. 17. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. I. Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539e553. 18. Tsangalis G, Papaconstantinou S, Kosmadakis G, et al. Prevalence of the metabolic syndrome in hemodialysis. Int J Artif Organs 2007;30: 118e123. 19. Sommer G, Ziegelmeier M, Bachmann A, et al. Serum levels of adipocyte fatty acid-binding protein (AFABP) are increased in chronic haemodialysis. Clin Endocrinol 2008;69:901e905. 20. Cabre A, Lazaro I, Girona J, et al. Plasma fatty acid-binding protein 4 increases with renal dysfunction in type 2 diabetic patients without microalbuminuria. Clin Chem 2008;54:181e187. 21. Wierzbicki AS, Graham CA, Young IS, et al. Familial combined hyperlipidaemia: under-defined and under-diagnosed? Curr Vasc Pharmacol 2008;6:13e22. 22. Cabre A, Lazaro I, Cofan M, et al. FABP4 plasma levels are increased in familial combined hyperlipidemia. J Lipid Res 2010;51:1173e1178. 23. Choi KM, Kim TN, Yoo HJ, et al. Effect of exercise training on A-FABP, lipocalin-2 and RBP4 levels in obese women. Clin Endocrinol 2009;70: 569e574. 24. Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes Obes Metab 2007;9:282e289. 25. Wang J, Li H, Franco OH, et al. Adiponectin and metabolic syndrome in middle-aged and elderly Chinese. Obesity 2008;16:172e178. 26. Yun JE, Sull JW, Lee HY, et al. Serum adiponectin as a useful marker for metabolic syndrome in type 2 diabetic patients. Diabetes Metab Res Rev 2009;25:259e265. 27. Karpisek M, Stejskal D, Kotolova H, et al. Treatment with atorvastatin reduces serum adipocyte-fatty acid binding protein value in patients with hyperlipidaemia. Eur J Clin Invest 2007;37:637e642. 28. Cabre A, Lazaro I, Girona J, et al. Fatty acid binding protein 4 is increased in metabolic syndrome and with thiazolidinedione treatment in diabetic patients. Atherosclerosis 2007;195:e150ee1508. 29. Rhee EJ, Lee WY, Park CY, et al. The association of serum adipocyte fatty acid-binding protein with coronary artery disease in Korean adults. Eur J Endocrinol 2009;160:165e172.
ORIGINAL ARTICLE
Fasting Serum Fatty Acid-binding Protein 4 Level Positively Correlates with Metabolic Syndrome in Hemodialysis Patients Jen-Pi Tsai,a Hung-Hsiang Liou,b Hsiang-Man Liu,c Chung-Jen Lee,g Ru-Ping Lee,f and Bang-Gee Hsud,e a Division of Nephrology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan Division of Nephrology Department of Medicine, Hsin-Jen Hospital, Taipei County, Taiwan c Department of Nursing, dDivision of Nephrology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan e School of Medicine, fDepartment of Nursing, Tzu Chi University, Hualien, Taiwan g Department of Nursing Tzu Chi College of Technology, Hualien, Taiwan b
Received for publication July 5, 2010; accepted September 14, 2010 (ARCMED-D-10-0000343).
Background and Aims. Serum fatty acid-binding protein 4 (FABP4) level increases in patients with metabolic syndrome (MetS). The interrelationships between fasting FABP4 levels and MetS have not been analyzed in hemodialysis (HD) patients. Methods. Fasting blood samples were obtained from 101 chronic HD patients. MetS was defined according to the diagnostic criteria of the International Diabetes Federation. Results. In total, 48 HD patients (47.5%) had MetS. Fasting FABP4 levels positively correlated with MetS ( p 5 0.022). Univariate linear regression analysis showed that the pre-HD body weight ( p !0.001), waist circumference ( p 5 0.003), body mass index ( p 5 0.003), total cholesterol (TCH) ( p !0.001), triglyceride (TG) ( p !0.001), creatinine ( p 5 0.042), insulin level ( p 5 0.014), and homeostasis model assessment of insulin resistance (HOMAIR; p 5 0.015) were positively correlated with serum FABP4 levels, whereas high-density lipoprotein-cholesterol (HDL-C) ( p 5 0.049) and adiponectin level ( p 5 0.004) were negatively correlated with fasting serum FABP4 levels in HD patients. Conclusions. MetS was positively correlated with fasting FABP4 levels in our chronic HD patients. TG, TCH, and waist circumference were independent predictors of serum FABP4 levels in HD patients. Ó 2010 IMSS. Published by Elsevier Inc. Key Words: Fatty acid binding protein 4, Metabolic syndrome, Hemodialysis.
Introduction Fatty acid-binding protein 4 (FABP4) is one member of the fatty acid-binding protein superfamily and is highly expressed in adipose tissue (1). FABP4 is a major cytoplasmic protein that is involved in the regulation of lipid metabolism and is expressed abundantly in mature adipocytes and activated macrophages (2,3). This protein binds fatty acid ligands with high affinity and functions in intracellular trafficking of fatty acids, regulation of lipid metabolism, and modulation of gene expression (4,5). FABP4-deficient mice have been shown to avoid from developing insulin Adress reprint requests to: Dr. Bang-Gee Hsu, Division of Nephrology, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Chung Yang Road, Hualien, Taiwan; Phone: 886-3-8561825; FAX: 886-3-8577161; E-mail: [email protected]
resistance, impaired glucose tolerance, and atherosclerosis (4,6). The following parameters define metabolic syndrome (MetS): increased waist circumference, decreased serum HDL levels, increased serum TG levels, hypertension, and insulin resistance (7). MetS constitutes a major health problem in the West and is estimated to affect at least 20% of the adult population (8). MetS is a significant risk factor for chronic kidney disease in the general population (9), and it also predicts hospitalization in hemodialysis (HD) patients (10). Serum FABP4 level increases in patients with MetS (11,12) and predicts the development of MetS (13). Recently, we have shown that serum FABP4 levels positively correlates with MetS in coronary artery disease patients (14). Thus far, there have been no studies on the correlation between serum FABP4 levels and MetS or the number of MetS criteria in HD patients. Therefore,
0188-4409/$ - see front matter. Copyright Ó 2010 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2010.09.007
Serum Fatty-acid Binding 4 in Hemodialysis Patients
we aim to investigate the relationships between fasting serum FABP4 levels and MS components in HD patients. Materials and Methods Patients Among the patients, 101 HD patients (55 men and 46 women) with the same high-flux polysulfone disposable artificial kidney (FX class dialyzer, Fresenius Medical Care, Bad Homburg, Germany) were studied in June 2009 at the Dalin Tzu Chi General Hospital. Patients from our HD program were invited to participate in this study if they were O20 years of age and were receiving standard dialysis for 4 h three times a weekly with standard bicarbonate dialysate and were on dialysis for at least 12 months. Patients were excluded if they had acute infection, malignancy, life expectancy !3 months, or if they refused or were unable to provide informed consent. This protocol was approved by The Protection of Human Subjects Institutional Review Board at Tzu Chi Hospital. The Kt/V and urea reduction ratio (URR) were measured before dialysis, and blood urea nitrogen (BUN) levels were measured immediately after dialysis by using a formal single-compartment dialysis urea kinetic model. Anthropometric Measurements Body weight was measured to the nearest half kilogram before HD in light clothing and without shoes. Height was measured to the nearest half centimeter. Waist circumference was measured to the nearest half centimeter at the shortest point below the lower rib margin and the iliac crest. Body mass index (BMI) was calculated as weight in kilograms divided by height squared in meters (14,15). Biochemical Investigations Fasting blood samples of |0.5 mL were obtained for the complete blood count (Sysmex K-1000, Bohemia, NY) and other blood samples were immediately centrifuged at 3000 x g for 10 min for biochemical analyses. Serum levels of BUN, creatinine, fasting glucose, total cholesterol (TCH), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), albumin, iron, total iron-binding capacity and high sensitivity-C-reactive protein (hs-CRP) were measured with an autoanalyzer (COBAS Integra 800, Roche Diagnostics, Basel, Switzerland). Serum intact parathyroid hormone (iPTH) levels were measured with enzyme-linked immunosorbent assay (ELISA) (Diagnostic Systems Laboratories, Webster, TX) (15) and serum FABP4 and adiponectin levels by enzyme immunoassay (EIA) (SPI- BIO, Montigny le Bretonneux, France) (14). The limit of detection, calculated as the concentration of human FABP4 corresponding to the blank average minus 3 standard deviations, was 0.1 ng/mL.
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Inter- and intra-assay coefficients of variation for FABP4 were 5.1% and 3.9%, respectively. The limit of detection calculated as the concentration of human adiponectin corresponding to the blank average minus three standard deviations was 0.7 mg/mL. Inter- and intra-assay coefficients of variation for adiponectin were 7.3% and 6.4%, respectively. Serum insulin levels were measured by the microparticle enzyme immunosorbent assay (MEIA) method with an autoanalyzer (Abbott Laboratories, Abbott Park, IL). HOMA-IR [glucose (mg/dL) insulin (mU/mL)/405] (16) was applied to evaluate insulin resistance. MetS and Its Components The prevalence of MetS was defined according to the International Diabetes Federation definition (7). People were diagnosed with MetS if they had central (abdominal) obesity with a waist circumference $90 cm (men) or $80 cm (women) (Chinese criteria) and if they had two or more of the following criteria: fasting serum glucose level $110 mg/dL, TG level $150 mg/dL, HDL-C level !40 mg/dL (men) or !50 mg/dL (women), or blood pressure O130/85 mmHg. Patients who use antihypertensive medications were considered as hypertensive. Patients were regarded as diabetic if their fasting plasma glucose level was $126 mg/dL, if their 2 h glucose level during an oral glucose tolerance test was $200 mg/dL, or if the patient was using a diabetes medication (oral or insulin) (17). Statistical Analysis Data are expressed as mean standard deviation. Data were examined for normal distribution by KolmogorovSmirnov statistics. Categorical variables were analyzed by the c2 test. Comparisons between patients were performed using the Student’s independent t test (two-tailed) for normally distributed data (FABP4 levels). Variables that correlated with serum FABP4 levels in HD patients were further evaluated by univariate linear regression analyses and multivariate forward stepwise regression analysis. The significance of the differences in FABP4 levels between the numbers of MetS criteria was analyzed by the Kruskal-Wallis analysis of variance test. SPSS for Windows v.13.0 (SPSS Inc., Chicago, IL) was used for data analysis. A p value !0.05 was considered statistically significant. Results Demographic and biochemical data of our HD patients are presented in Table 1. Of the 101 patients enrolled, 48 patients (47.5%) had IDF-defined MetS. Among the causes of uremia, 28 patients had diabetes mellitus, 19 patients had chronic glomerulonephritis, and 37 patients were hypertensive. Average fasting serum FABP4 levels were 254.93 63.34 ng/mL. Our HD patients with MetS ( p 5 0.022), male ( p 5 0.001), and who used angiotensin-receptor blocker
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Table 1. Clinical and analytical characteristics of 101 hemodialysis patients Item Anthropometric data
Biochemical data
Causes of uremia
Parameter
Mean SD
Parameter
Height (cm) Pre-HD body weight (kg) Body mass index (kg/m2) Systolic pressure (mmHg) White blood count (x1000/ml) Albumin (g/dL) Triglyceride (mg/dL) Fasting glucose (mg/dL) Blood urea nitrogen (mg/dL) hs-CRP(mg/dL) Kt/V (Gotch) FABP4 (ng/mL) Iron (mg/dL) Transferrin saturation (%) Adiponectin (mg/mL) Diabetes (%) Glomerulonephritis (%)
154.43 8.16 60.88 13.39 25.73 6.25 145.37 22.36 6.58 3.09 3.97 0.41 136.99 92.00 143.83 65.57 60.95 15.47 0.85 1.97 1.46 0.20 254.93 63.34 73.02 37.29 33.41 16.69 23.55 16.62 28 (27.7) 19 (18.8)
Waist circumference (cm) Age (years) HD duration (months) Diastolic pressure (mmHg) Hemoglobin (g/dL) Total cholesterol (mg/dL) HDL-C (mg/dL) Creatinine (mg/dL) iPTH (pg/mL) URR Insulin (mU/mL) HOMA-IR Total iron-binding capacity EPO dose (units/week) Hypertension (%) Other (%)
Mean SD 88.02 62.00 71.51 78.00 10.56 160.05 43.54 9.11 239.23 0.76 23.54 7.92 224.09 3900.99
10.75 13.62 45.47 14.26 1.38 39.56 16.81 2.09 226.01 0.05 33.60 10.24 51.02 3565.12
37 (36.6) 17 (16.9)
Data are expressed as mean standard deviations or proportion. HD, hemodialysis; HDL-C, high-density lipoprotein-cholesterol; hs-CRP, high-sensitivity C-reactive protein; iPTH, intact parathyroid hormone; URR, urea reduction rate; FABP4, fatty acid-binding protein 4; HOMA-IR, homeostasis model assessment of insulin resistance, EPO, erythropoietin.
(ARB) ( p 5 0.012) had higher serum fasting FABP4 levels, whereas patients with diabetes, hypertension, secondary hyperparathyroidism (iPTH O300 pg/mL) or who used angiotensin-converting-enzyme inhibitor (ACEI), calcium channel blocker (CCB), b-blocker, statin, or peroxisome proliferator-activated receptor-g agonist did not have higher serum fasting FABP4 levels (Table 2). The univariate linear analysis of fasting serum FABP4 levels in HD patients is presented in Table 3. Pre-HD body weight (r 5 0.358; p !0.001), waist circumference (r 5 0.296; p 5 0.003), BMI (r 5 0.294; p 5 0.003), TCH (r 5 0.362; p !0.001), TG (r 5 0.439; p !0.001), creatinine level (r 5 0.203; p 5 0.042), insulin level (r 5 0.243; p 5 0.014), and HOMA-IR (r 5 0.242; p 5 0.015) were positively correlated with serum FABP4 levels, whereas HDL-C (r 5 0.196; p 5 0.049) and adiponectin level (r 5 0.280; p 5 0.004) were negatively correlated with serum FABP4 levels in HD patients. Multivariate forward stepwise linear regression analysis of the significant variables (pre-HD body weight, waist circumference, BMI, TCH, TG, creatinine, insulin, HOMA-IR, adiponectin, and HDL-C) showed that TG (r2 change 5 0.193, p 5 0.001), TCH (r2 change 5 0.051, p 5 0.008), and waist circumference (r2 change 5 0.052, p 5 0.008) were the independent predictors of fasting serum FABP4 levels in HD patients (Table 4).
Discussion The results of our study showed that fasting FABP4 levels were positively associated with MetS in HD patients. TG, TCH, and waist circumference were independent predictors of serum FABP4 levels in HD patients.
Recent studies have demonstrated that MetS is one of the risk factors for developing chronic kidney disease in the general population (9), and it also predicts an increasing rate of hospitalization in HD patients (10). The prevalence of MetS was 47.5% in our study, which was comparable to other studies that ranges from 40.1e66.0% (16,18). Serum FABP4 levels were 10-fold higher in HD patients than in patients with normal renal function, which denoted that kidney is a major site for FABP4 clearance (19). In fact, plasma FABP4 concentrations were positively correlated with plasma creatinine levels in type 2 diabetes patients (20) and in our HD patients. Serum FABP4 levels has been reported to be higher in the female population (11e13), which was also found in our female HD patients. Familial combined hyperlipidemia is caused by an increased production rate of TG-rich lipoproteins, mainly liver-derived very low-density lipoproteins (VLDL), with ensuing hyperlipidemia characterized by plasma increases of both TG and TCH (21). Serum FABP4 levels have been found to positively correlate with TG and negatively correlate with HDL-C (3,5). Plasma FABP4 levels are increased in patients with familial combined hyperlipidemia (22). In this study we also observed a similar finding. Circulating FABP4 levels were significantly associated with BMI and waist circumference in obese women and in patients with familial combined hyperlipidemia (22,23). In our study, we noted that a positive association between serum FABP4 concentrations and the indicators of adiposity (BMI, waist circumference, and pre-HD body weight), and may suggests that adipose tissue is the major site for FABP4 secretion in HD patients. Like other studies in Chinese and Caucasian populations (11,12), we also observed that serum insulin levels or HOMA-IR was positively correlated with fasting serum FABP4 levels in HD
Serum Fatty-acid Binding 4 in Hemodialysis Patients Table 2. Clinical characteristics and fasting serum FABP4 levels of 101 hemodialysis patients Characteristic Sex Male Female Diabetes No Yes Hypertension No Yes Hyperparathyroidism No Yes Metabolic syndrome No Yes ACE inhibitor No Yes ARB No Yes b-blocker No Yes CCB No Yes Statin No Yes PPAR-g agonist No Yes
Number (%)
FABP4 level (ng/mL)
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Table 3. Correlation between fasting serum FABP4 levels and clinical variables in 101 hemodialysis patients by univariate linear regression analyses
p value
55 (54.5) 46 (45.5)
235.83 58.03 277.77 62.40
0.001*
71 (70.3) 30 (29.7)
256.69 66.31 250.76 56.51
0.669
44 (43.6) 57 (56.4)
254.47 55.27 255.28 69.41
0.950
78 (77.2) 23 (22.8)
252.31 61.99 263.82 68.36
0.446
53 (52.5) 48 (47.5)
241.28 54.52 270.00 69.31
0.022*
88 (87.1) 13 (12.9)
258.73 65.36 229.16 40.36
0.117
68 (67.3) 33 (32.7)
265.81 67.34 232.50 47.65
0.012*
71 (70.3) 30 (29.7)
255.80 65.18 252.85 59.77
0.832
56 (55.4) 45 (44.6)
264.38 66.54 243.17 57.68
0.095
96 (95.0) 5 (5.0)
255.08 63.92 251.94 56.88
0.915
90 (89.1) 11 (10.9)
255.10 63.98 254.49 62.76
0.966
Data are expressed as mean standard deviations. FABP4, fatty acid-binding protein 4; ARB, angiotensin-receptor blocker; ACE, angiotensin-converting enzyme; CCB, calcium-channel blocker; PPAR-g, peroxisome proliferator-activated receptor-g; HD, hemodialysis. *p !0.05 was considered statistically significant after Student’s t-test.
patients. The multivariate forward stepwise linear regression analysis of the significant variables showed that the TG, TCH, and waist circumference were independent predictors of fasting serum FABP4 levels. Adiponectin, a unique insulin sensitizer adipocyte-derived substance, plays an important role in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin-sensitive tissues (24). A decrease in the circulating level of adiponectin has been linked to MetS (25,26). According to our study, serum FABP4 levels negatively correlate with serum adiponectin levels in HD patients and also noted positively associated with MetS in HD patients. In this study, FABP4 levels showed no differences between diabetes group and non-diabetes group. In addition, fasting glucose was not associated with FABP4 levels in HD patients. Many factors may affect serum FABP4 levels such as drugs, clearance of FABP4, and associated
Items
Beta
p value
Age (year) HD duration (months) Height (cm) Pre-HD body weight (kg) WC (cm) BMI (kg/m2) White blood count (x1000/ml) Hemoglobin (g/dL) Albumin (g/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL-C (mg/dL) Fasting glucose (mg/dL) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) hs-CRP (mg/dL) Systolic pressure (mmHg) Diastolic pressure (mmHg) Intact parathyroid hormone (pg/mL) Insulin (mU/dL) HOMA-IR Urea reduction rate (URR) Kt/V (Gotch) Adiponectin (mg/mL)
0.157 0.029 0.020 0.358 0.296 0.294 0.062 0.137 0.174 0.362 0.439 0.196 0.053 0.061 0.203 0.105 0.108 0.027 0.061 0.243 0.242 0.083 0.004 0.280
0.117 0.773 0.843 !0.001* 0.003* 0.003* 0.539 0.170 0.082 !0.001* !0.001* 0.049* 0.598 0.547 0.042* 0.296 0.282 0.787 0.549 0.014* 0.015* 0.407 0.967 0.004
HD, hemodialysis; WC, waist circumference; BMI, body mass index; HDLcholesterol, high-density lipoprotein-cholesterol; hs-CRP, high sensitivityC-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance; FABP4, fatty acid-binding protein 4; HD, hemodialysis. *p !0.05 was considered statistically significant after univariate linear analyses.
diseases. Pharmacological interventions have been shown to influence serum FABP4 levels in humans. Three months treatment with atorvastatin in hyperlipidemic nondiabetic patients, serum FABP4 levels were substantially decreased (27). Another study involving patients with type 2 diabetes mellitus found no difference in FABP4 concentrations in statin-treated patients but reported increased FABP4 levels in thiazolidinedione-treated patients (28). FABP4 levels were lower in patients taking aspirin, and higher values Table 4. Multivariate stepwise linear regression analysis of pre-HD body weight, waist circumference, body mass index, total cholesterol level, triglyceride level, HDL-C level, insulin level, HOMA-IR, adiponectin and creatinine level: correlation with fasting serum FABP4 levels in 101 hemodialysis patients Items
Beta
Triglyceride (mg/dL) 0.317 Total cholesterol (mg/dL) 0.244 Waist circumference (cm) 0.232
R square R square change p value 0.193 0.244 0.296
0.193 0.051 0.052
0.001* 0.008* 0.008*
HDL-C, high-density lipoprotein-cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; FABP4, fatty acid-binding protein 4; HD, hemodialysis. *p !0.05 was considered statistically significant in the multivariate stepwise linear regression analysis.
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were observed in coronary artery disease patients taking statins and antihypertensive drugs (29). In this study, HD patients using ARB drugs had lower fasting serum FABP4 levels. Our previous study involving coronary artery disease patients found no difference in FABP4 concentrations in patients taking statins or antihypertensive drugs (14). In this study, our results did not show a relationship between stains or peroxisome proliferator-activated receptor g agonists or other drugs (ACEI, CCB, or b-blocker) and serum FABP4 levels among HD patients. Further studies are required to elucidate the relationship between medication and FABP4 levels in HD patients. Our study has some limitations. First, this study had a cross-sectional design. Therefore, our findings should be investigated in long-term prospective studies before a causal relationship between serum FABP4 levels and MetS in HD patients can be established. Second, serum FABP4 levels were higher in HD patients than in patients with normal renal function, which denoted that kidney is a major site for FABP4 clearance (19). Our study did not measure the clearance of FABP4 before and after HD. Another limitation is that FABP4 usually acts at the interface of inflammatory pathways such as tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), and IL-6 (3). However, our study did not investigate their influence on these inflammatory markers. Further studies are needed to examine the clearance of FABP4 before and after HD and the association between serum FABP4 levels and inflammatory cytokines in HD patients. In summary, we found a positive correlation between circulating fasting FABP4 levels and MetS in HD patients. Serum TG, TCH, and waist circumference were independent predictors of serum FABP4 levels in HD patients. Acknowledgments This work was supported by grants from Dalin Tzu Chi Hospital in Taiwan (DTCRD 98(2)e17).
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