Abstract
Peptides involved in the regulation of body composition are of interest in hemodialysis (HD) patients because protein wasting associated with high fat mass (FM) is present in these patients. Zinc-α2-glycoprotein (ZAG), a new adipokine, is involved in the regulation of lipid metabolism, adiposity, and energy balance. The purpose of this study was to evaluate ZAG levels and its relationship with body composition and dietary intake in HD patients. Forty-nine HD patients (28 men, 53.1 ± 12.5 years, and BMI 24.0 ± 4.3 kg/m2) were studied and compared with 20 healthy subjects (9 men, 49.5 ± 15.2 years, and BMI 25.6 ± 4.1 kg/m2). Plasma ZAG levels were measured using the ELISA methods and body composition was evaluated through anthropometric data. Dietary intake was assessed 3 days by 24-hour food recall. Although most of the HD patients (59.2%) were eutrophic according to BMI, 92.3% presented high percentage of body fat (BF), and 43.5%, reduced fat-free mass according to midarm muscle circumference values. ZAG levels were ∼2.5-fold higher in HD patients (135.9 ± 40.9 mg/L) compared with healthy individuals (54.6 ± 23.0 mg/L) (p < 0.0001). Circulating ZAG was not associated with dietary intake; however, this peptide was negatively correlated with %BF and, for each 1% reduction in BF, ZAG levels increased by 2.4 mg/L (p = 0.02). In summary, circulating ZAG is increased and inversely correlated with adiposity in HD patients; however, in spite of its higher plasma levels, the majority of HD patients did not show low BF.
INTRODUCTION
Protein–energy wasting (PEW) is the term proposed to the state of decreased body stores of protein and energy fuels in chronic kidney disease (CKD).Citation1 In hemodialysis (HD) patients, protein wasting is a common feature and it is associated with morbidity and mortality.Citation2,3 On the other hand, high fat mass (FM) and central adiposity are also observed in this population and are related to metabolic disorders.Citation4–7 In this sense, peptides involved in the regulation of body composition can also be related to nutritional status of CKD patients.
The peptide called zinc-α2-glycoprotein (ZAG), a 40-kDa soluble adipokine,Citation8,9 acts as a lipid-mobilizing factor. Some studies have shown that treatment with ZAG can cause reduction of FM without affecting food intake.Citation10,11 The biological activity of ZAG seems to be mediated by β3 adrenoreceptor through the activation of the cyclic AMP pathway.Citation8,10,12 It also inhibits the lipogenic enzymes in adipose tissueCitation13 and activates the uncoupling proteins isoforms in brown adipose tissue and muscle, increasing thermogenesis.Citation10,14,15 Recently, studies in experimental models also revealed that ZAG attenuates muscle atrophy by its ability to bind and stimulate the β3 adrenoreceptor and by reduction in the activity of ubiquitin–proteasome pathway.Citation11,16
In human, the clinical relevance of ZAG still has to be investigated. Recent studies showed the association between ZAG and parameters of obesity, insulin resistance index, and lipid profile in different populations.Citation17–20 However, in chronic diseases, few studies have quantified ZAG levels and only one evaluated the circulating ZAG in HD patients. Phillipp et al.Citation21 showed that serum ZAG levels were twofold higher in HD patients when compared with controls. In that study, markers of insulin resistance and lipid profile were not correlated with circulating ZAG.
In this way, if ZAG has lipid-mobilizing actions and is able to attenuate the protein wasting, it can be associated with the nutritional status of HD patients. This study was aimed to evaluate the ZAG plasma levels and its relationship with body composition and dietary intake in CKD patients undergoing HD.
MATERIALS AND METHODS
Forty-nine HD patients were studied and compared with 20 healthy subjects. Inclusion criteria were anuric patients on HD for at least 6 months and age between 18 and 75 years. Patients with inflammatory liver disease and known malignancies were excluded from this study. The healthy subjects were mainly the staff members of the dialysis unit and were presented similar age and percent body fat (%BF) when compared with the HD patients.
The etiology of CKD was hypertensive nephrosclerosis (26), diabetic nephropathy (6), chronic glomerulonephritis (4), polycystic kidney disease (4), and other diseases or unknown cause (9). To obtain all relevant clinical data, a researcher reviewed each patient’s medical chart. The dialysis sessions were 3.5–4.5 hours 3 times/week, with a blood flow greater than 300 mL/min, a dialysate flow around 600 mL/min, and bicarbonate buffer.
The study protocol was approved by the Ethics Committee of the School of Medicine of Universidade Federal Fluminense. The HD patients and healthy subjects were aware of this study and signed an informed consent after reading the document.
Nutritional Assessment
Anthropometric measurements were obtained immediately after the HD session by a trained researcher using standard techniques.Citation22 Body mass index (BMI) was calculated as body weight divided by square height, and the cut-off points proposed by the World Health OrganizationCitation23 were considered. Biceps, triceps, subscapular, and suprailiac skinfold thickness was measured to the nearest millimeter using a Lange Skinfold Caliper (Beta Technology Incorporated, Cambridge, MD, USA). Biceps and triceps skinfolds (TSF) and upper midarm circumference (MAC) were measured in the arm with no fistula. Three sets of measurements at each site were averaged and used in the analyzes. Midarm muscle circumference (MMC) area was calculated using the following equation: MMC = [MAC (cm) − π × TSF (cm)].Citation24 More than 10% reduction in relation to 50th percentile of reference population was considered as protein wasting.Citation1 Waist circumference (WC) was measured at a level midway between the lowest lateral border of the ribs and the uppermost lateral iliac crest and classified as proposed by NCEP.Citation25 Body composition variables [fat-free mass (FFM), %BF, and FM] were assessed according to Durnin and Womersley.Citation26 FM/FFM ratio was also calculated. Total percentage of BF lower than 10% was considered as energy wasting.Citation1 The reference values for %BF proposed by Lohman et al.Citation27 were also considered.
Biochemical Variables
Blood samples were obtained from the arterial line of the HD patients immediately before the HD session, after overnight fasting. The serum was immediately frozen at −80°C until analyzed. Plasma ZAG levels were measured by a commercial enzyme-linked immunosorbent assay (Biovendor, Modrice, Czech Republic), according to the manufacturer’s instructions. The sensitivity of the assay was 0.673 ng/mL and the intra- and interassay CVs were less than 5% and 6.5%, respectively. High-sensitivity C-reactive protein (hs-CRP) was determined by turbidimetry. Serum albumin (bromocresol green method), hemoglobin, creatinine, and blood urea nitrogen (BUN) were measured using standard laboratory methods in a certified laboratory. Dialysis dose (single-pool Kt/V − spKt/V) was calculated from the values of BUN (pre- and postdialysis), weight, and dialysis duration using the logarithmic formula and the minimum acceptable target for this parameter is a value of 1.2.Citation28
Dietary Intake
Dietary intake was assessed 3 days by 24-hour food recall (dialysis day, nondialysis day, and a weekend day). Patients were carefully instructed by a dietician to record all kinds and amounts of food (including beverages) ingested, using various models of food and measuring tools to estimate portion sizes and to improve the accuracy of record. Analyzes were conducted with software developed by the Universidade Federal de São Paulo – Nutwin®. The nutrient contents of foods not contained in this software were searched on Brazilian Table of Food Composition.Citation29
Statistical Analyses
Results were expressed as mean ± standard deviation or median (interquartile range). Student’s t-test and the Mann–Whitney test were used as appropriate. Pearson’s or Spearman’s correlation coefficients were calculated to examine univariate analyzes. Linear regression was used to quantify the ZAG influence on adiposity parameters. Statistical significance was accepted as p < 0.05. All analyzes were performed using SPSS software version 11.0 (SPSS, Chicago, IL, USA).
RESULTS
Clinical and anthropometric characteristics of the HD patients and the healthy subjects are summarized in . The time of dialysis and spKt/V were 67.8 ± 41.1 months and 1.45 ± 0.26, respectively. Mean serum albumin was 3.9 ± 0.22 g/dL and nine HD patients (18.4%) had albumin <3.8 g/dL. The hemoglobin, BUN, and creatinine values were 10.6 ± 2.5 g/dL, 64.0 ± 31.4 mg/dL, and 10.4 ± 2.8 mg/dL, respectively. The hs-CRP levels were higher in the HD patients [0.22 (0.44) mg/dL] than those in the healthy subjects [0.02 (0.1) mg/dL] (p < 0.01).
Table 1. Clinical and anthropometric characteristics of HD patients and healthy subjects.
Mean energy intake was 22.3 ± 9.1 kcal/kg/day (1421.2 ± 521.2 kcal/day), and 75.0% had an energy intake lower than recommendation (35 kcal/kg/day to patients with age <60 years and 30 kcal/kg/day to patients with age >60 years). The daily protein intake was 1.2 g/kg/day in 70.2% of the patients, and the median was 0.99 (1.03) g/kg/day (67.3 ± 27.8 g/day). The percentage of carbohydrate and lipid intake was 53.7 ± 8.2% and 25.1 ± 4.3%, respectively. According to BMI, 59.2% of patients were eutrophic, 36.7% were overweight/obese, and only 4.1% (2 patients) presented BMI <18.5 kg/m2. Most of the patients (51.1%) presented high WC values. Only two patients presented low %BF values and 92.3% presented values above normal. In contrast, reduced MMC values were observed in 43.5% of patients.
ZAG plasma levels were ∼2.5-fold higher in the HD patients (135.9 ± 40.9 mg/L) when compared with the healthy subjects (54.6 ± 23.0 mg/L) (p < 0.0001) (). In the HD patients, ZAG levels were not significantly different according to gender or the presence of diabetes mellitus. However, ZAG levels were lower in the patients with high BF mass (%BF ≥ 25% for men and ≥32% for women) and central obesity (a trend only) (). The hs-CRP was positively correlated with WC (r = 0.37, p = 0.01), %BF (r = 0.33, p = 0.02), FM (r = 0.45, p = 0.002), and sum of skinfolds (r = 0.37, p = 0.01).
Figure 1. Plasma ZAG levels in hemodialysis patients and healthy subjects (p <0.0001).
Table 2. Plasma ZAG levels in hemodialysis patients according to various clinical conditions.
ZAG was not correlated with dietary intake, hs-CRP, dialysis vintage, and spKt/V, but it was inversely correlated with adiposity parameters (sum of skinfolds, %BF, FM, and FM/FFM ratio) () and for each 1% of reduction in BF, ZAG was increased by 2.4 mg/L (p = 0.02). According to linear regression, for each 1 mm of reduction in sum of skinfolds and 1 kg in FM, ZAG increased by 0.72 mg/L (p = 0.005) and 1.64 mg/L (p = 0.04), respectively. Biceps (r = −0.42, p = 0.004), triceps (r = −0.39, p = 0.006), subscapular (r = −0.35, p = 0.01), and suprailiac (r = −0.45, p = 0.02) skinfolds, evaluated isolately were also negatively correlated with circulating ZAG.
Table 3. Univariate correlations with plasma ZAG levels in hemodialysis patients.
DISCUSSION
In this study, we demonstrated that (1) although most of the HD patients presented normal BMI values, they had reduced MMC and high %BF values; (2) plasma ZAG levels were significantly higher in the HD patients compared with the healthy subjects with similar age and %BF; and (3) plasma ZAG levels were negatively correlated with adiposity parameters.
In fact, some studies have shown an increase in FM and a decrease in lean body mass in the first year of dialysis.Citation30–33 The protein wasting is associated with increased mortalityCitation2,3 while obesity is a well-known independent risk factor for metabolic complications, as inflammation and dyslipidemia, that may lead to cardiovascular diseaseCitation34 and are associated with accelerated atherosclerosis and premature death from cardiovascular disease observed in the HD patients.Citation3,35 If ZAG is an adipokine involved in lipid catabolism and attenuation of muscle atrophy, consequently, it may perform a positive role on body composition of HD patients.
To date, only the study by Phillip et al.Citation21 evaluated ZAG in HD patients and reported higher circulating ZAG in these patients when compared with healthy subjects. These authors suggested that renal clearance is an important route of ZAG elimination and, therefore, the accumulation of ZAG in CKD patients was expected. Moreover, the HD procedure is able to remove molecules with molecular weight 500 Da.Citation36 Thus, ZAG can be considered as a nondialyzable molecule, such as β2-microglobulina and leptin. In fact, this study found higher circulating ZAG in HD patients and, additionally, it observed an inverse correlation between ZAG and adiposity parameters.
However, the role of ZAG in body composition is still controversial. Some authors did not find a relationship between ZAG and BMI.Citation21,37 Yeung et al.Citation19 observed higher ZAG levels in obese/overweight subjects when compared with lean subjects. On the other hand, Gong et al.Citation13 found an inverse correlation between circulating ZAG and body weight, BMI, waist and hip circumference, %BF, and FM, which was assessed by bioelectrical impedance after adjusting for age and gender. Selva et al.Citation18 also observed lower serum concentration of ZAG in obese subjects when compared with lean subjects and it was inversely correlated with BMI. In addition, Ceperuello-Mallafré et al.Citation17 measured ZAG mRNA in adipose tissue and observed that tissue mRNA levels were lower in obese subjects when compared with lean individuals.
Studies at tissue level revealed that the expression of ZAG in subcutaneous abdominal adipose tissue was downregulated to a magnitude of 70%Citation38 and 69%Citation39 in obese subjects compared with lean subjects. Ceperuello-Mallafré et al.Citation17 also observed reduced ZAG expression in subcutaneous, but not in visceral adipose tissue in overweight/obese subjects when compared with lean subjects. This differential regulation according to the origin of adipose tissue depots and its relevance on autocrine/paracrine actionsCitation40 can explain the stronger correlation between ZAG and skinfolds thickness and their sum compared with total %BF (this estimates the total BF).
A question still remains is “Would circulating ZAG be associated with better metabolic profile or with energy wasting in HD patients?” Our data showed that patients with high %BF and central adiposity presented lower ZAG levels. Then, HD patients with high ZAG levels presented low body FM, including central adiposity. In CKD patients, abdominal fat has been associated with inflammation, insulin resistance, oxidative stress, and increased mortality.Citation4–7 In fact, our results showed that adiposity parameters were inversely related to hs-CRP, an important inflammation marker. Thus, ZAG may have a protective role, through its lipid-mobilizing effect, in the prevention of obesity and its associated disorders.
Interestingly, despite its higher ZAG levels, HD patients did not have energy wasting. In our study, even an increase of 2.5 times in ZAG levels in HD patients may not be sufficient to induce an important reduction in FM. In CKD patients, there is a “resistance” for action of many hormones and adipokines, as parathormone,Citation41 insulin-like growth factorCitation42 and visfatin.Citation43 In fact, in an experimental study, a clear dose–response was observed up to 15 μg ZAG, but further increases in ZAG concentration did not produce a further decrease in BF, suggesting that receptor occupancy was saturated.Citation12
Recent studies showed that ZAG has the potential to attenuate muscle atrophy associated with insulin resistance and other catabolic conditions.Citation11,16 The treatment of hyperglycemic (ob/ob) mice with ZAG increased the skeletal muscle through an increase in protein synthesis and decrease in protein degradation.Citation11 Additionally, the activity of ubiquitin–proteasome pathway seems to be decreased by the administration of ZAG.Citation16,44 In another study, this proteolytic pathway was related to loss of skeletal muscle observed in CKD patients,Citation45 although in this study ZAG levels were not associated with muscle mass.
Circulating ZAG was not associated with dietary intake, as observed in experimental studies.Citation10,11 In mice, the administration of ZAG induced a reduction in FM10 with parallel increase in skeletal muscle massCitation11 without affecting food and water intake. Obviously, the food behavior is more complex in humans and, to our knowledge, this is the first study to evaluate the relationship between ZAG and dietary intake in humans.
Our study has some limitations. First, the cross-sectional nature of our study does not permit to infer causative process between ZAG and adiposity and establish a relationship between this peptide and mortality. Second, the evaluation of expression levels of ZAG could explain the higher circulating levels in HD patients. Third, dual-energy X-ray absorptiometry (DXA) is considered as the reference method to body composition assessment in HD patientsCitation46 and, in this study the anthropometry was performed. Nevertheless, the most simple, inexpensive, long-established method of skinfold thickness showed to be more reliable to assess BF in HD patients.Citation47 Fourth, the small number of diabetics HD patients did not allow to address differences in ZAG levels and its association with adiposity in this patient subgroup.
In summary, high ZAG levels were found in HD patients. Circulating ZAG was not correlated with dietary intake; however, a negative correlation between ZAG and adiposity was observed. In spite of higher ZAG levels, HD patients did not show signs of energy wasting and, therefore, ZAG can be associated with better metabolic profile in these patients.
ACKNOWLEDGMENTS
This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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