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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2016  |  Volume : 27  |  Issue : 5  |  Page : 977-984
Chemerin: A biomarker for cardiovascular disease in diabetic chronic kidney disease patients


1 Department of Internal Medicine, Zagazig University, Zagazig, Egypt
2 Department of Clinical Pathology, Zagazig University, Zagazig, Egypt
3 Department of Radiology, Zagazig University, Zagazig, Egypt

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Date of Web Publication22-Sep-2016
 

   Abstract 

Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). The carotid intima-media thickness (CIMT) and arterial stiffness are useful markers of subclinical atherosclerosis and significantly correlate with various metabolic risk factors. Chemerin is one of the adipokines that may represent a link between obesity and inflammation and may be a potential candidate playing a role in the pathogenesis of atherosclerosis and cardiovascular complications. Therefore, we studied the relationship of chemerin levels with atherosclerosis as measured by CIMT in diabetic CKD patients, either predialysis or on hemodialysis (HD). In addition, we studied its correlation with other cardiovascular risk factors such as interleukin-6 (IL-6) and insulin resistance (IR). Fifty-eight patients were enrolled in the study; 23 patients with CKD (11 are diabetic) on conservative treatment and 35 (18 are diabetic) on maintenance HD. Serum concentrations of chemerin and IL-6 were determined by ELISA. All participants underwent measurements of CIMT by highresolution ultrasonography. A stepwise increase in serum chemerin levels was found depending on the glomerular filtration rate: 286.6 ± 10.02 ng/mL in the control group, 332.1 ± 21.54 ng/mL in the predialysis group, and 355.7 ± 20 ng/mL in the HD group. A significant rise of serum chemerin level was observed in diabetic CKD patients either on conservative therapy or on HD when compared with nondiabetic CKD patients. Moreover, there was a significant difference in serum levels of chemerin, IL-6, CIMT, serum insulin, and homeostasis model assessment of IR (HOMA-IR) between diabetic and nondiabetic patients in both groups. Chemerin showed a significant positive correlation with HOMA-IR, serum insulin, and C-reactive protein. In conclusion, serum chemerin level was found to be an independent predictive marker of the presence of atherosclerosis in patients with CKD either on conservative treatment or on HD.

How to cite this article:
Salama FE, Anass QA, Abdelrahman AA, Saeed EB. Chemerin: A biomarker for cardiovascular disease in diabetic chronic kidney disease patients. Saudi J Kidney Dis Transpl 2016;27:977-84

How to cite this URL:
Salama FE, Anass QA, Abdelrahman AA, Saeed EB. Chemerin: A biomarker for cardiovascular disease in diabetic chronic kidney disease patients. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Nov 15];27:977-84. Available from: http://www.sjkdt.org/text.asp?2016/27/5/977/190867

   Introduction Top


Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Thus, early prediction and prevention of CVD in CKD patients are crucial. [1] The main pathophysiologic mechanism underlying the high mortality of CKD includes premature atherosclerosis and chronic inflammation. [2]

The carotid intima-media thickness (CIMT) and arterial stiffness are useful surrogate markers of subclinical atherosclerosis and significantly correlate with various metabolic risk factors. [3] In the prospective studies, both arterial stiffness and CIMT have proven to be reproducible and independent predictors of cardiovascular events. [4]

Adipose tissue produces a variety of proteins called adipokines. Thus, adipose tissue is assumed to be an endocrine organ because it affects several organs and systems in the metabolism. Besides inflammatory molecules such as leptin, resistin, and visfatin in the family of adipokines, some useful molecules such as adiponectin are also secreted. In recent years, one of these useful adipokines called chemerin has frequently been studied. [5]

Chemerin, a 16 kDa protein, also known as tazarotene-induced gene-2 protein or retinoic acid receptor responder protein-2 (RARRES2), is a chemo-attractant for chemokine-like receptor-1 expressing cells. Chemerin also serves as a ligand for chemokine C-C motif receptor-like-2 (CCRL-2) and G proteincoupled receptor-1 (GPR-1). Evidence suggests that CCRL-2 is a nonsignaling receptor that binds chemerin and increases the local concentration of the peptide. [6],[7] However, the function of GPR-1 in mammals has not yet been elucidated. Chemerin is found to be highly expressed in adipose tissue and the liver, as well as by cells of the innate immune system, where it modulates the function of innate immune cells. Consequently, chemerin may represent a link between obesity and inflammation [8],[9] and may be a potential candidate playing a role in the pathogenesis of atherosclerosis and cardiovascular complications.

This study was designed to determine the relationship of circulating chemerin levels with atherosclerosis as measured by CIMT in CKD patients either in predialysis stage or maintained on hemodialysis (HD) and compared with healthy control participants. In addition, we aimed to study the correlation between chemerin and other cardiovascular risk factors, such as interleukin-6 (IL-6), insulin resistance (IR), and other metabolic and anthropometric variables in diabetic and nondiabetic CKD patients.


   Patients and Methods Top


Patients

Fifty-eight patients were enrolled in this cross-sectional study. They included 23 patients with CKD on conservative treatment (11 of them were diabetic) (Group I) and 35 patients on maintenance HD (18 of them were diabetic) (Group II). All HD patients were receiving bicarbonate HD using a low-flux synthetic dialyzer with an average blood flow of 300- 350 mL/min and a monthly spKt/V value of >1.2. The exclusion criteria included the presence of active infections, autoimmune diseases, thrombotic complications, hepatic diseases, chronic infl ammatory diseases, cancer, thyroid dysfunction, and alcohol or drug abuse at the time of the study. Female patients taking hormonal replacement therapy were also excluded from the study.

Twenty sexand age-matched healthy volunteers were enrolled as control participants (Group III). None of them had any historical evidence of endocrine or metabolic disturbances, cerebrovascular or CVD and renal disease.

The study design was approved by an Institutional Review Board (IRB) of Zagazig University Hospital, Egypt. Volunteers enrolled in the study gave informed written consent in accordance with the Declaration of Helsinki.

Clinical and laboratory measurements

The body mass index (BMI) and waist circumference were recorded for all patients. Investigations were performed in the morning after an overnight fast. Blood samples were collected directly from the arteriovenous fistula, immediately before the beginning of a routine 4 h HD session. In the controls and CKD patients on conservative therapy, blood was withdrawn from the antecubital vein.

Estimated glomerular filtration rate (eGFR) was calculated using a modification of diet in renal disease equation. [10] Serum triglyceride and high-density lipoprotein-cholesterol (HDL-C) levels were determined enzymatically using a chemical analyzer (Hitachi 747; Hitachi Inc., Tokyo, Japan). Low-density lipoprotein (LDL)cholesterol concentration was estimated using the Friedewald formula. [11] The glucose oxidase method was applied to measure plasma glucose and an electrochemiluminescence immunoassay (Roche Diagnostics, Indianapolis, IN, USA) was utilized to measure insulin levels. IR was calculated by the homeostasis model assessment of IR (HOMA-IR), which was calculated by the following equation: HOMAIR = fasting insulin (μU/mL) × FBG (mg/ dL)/405. [12] Highly sensitive C-reactive protein (hsCRP) levels were measured by latexenhanced turbidimetric immunoassay (HiSens hsCRP LTIA, HBI Co., Ltd., Korea).

The estimated 10-year risk for CVD (CVD risk) was calculated according to the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk and the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to reduce atherosclerotic cardiovascular risk in adults. [13]

Determination of circulating chemerin and interleukin-6 levels

Serum concentrations of chemerin were determined by enzyme-linked immunosorbent assay (ELISA) kit (Biovendor R&D, Czech Republic), serum IL-6 was determined by ELISA kit (AviBion, Orgenium, Vantaa, Finland).

Ultrasonography of carotid artery

All volunteers underwent measurements of CIMT by high-resolution real-time B-mode ultrasonography with a 7.5-MHz linear transducer (SSH 140A Toshiba, Japan). Each volunteer was examined in a supine position. The examination included sections of approximately 2-3 cm of common carotid artery just below the carotid bulb. CIMT was defined as the distance between the leading edge of the first echogenic line (lumen-intima interface) and the second echogenic line (media-adventitia interface) of the far wall. All measurements were established at a plaque-free site. CIMT >0.8 mm was taken as intimal thickening. Carotid plaque was defined as a focal structure with irregular surface, encroaching into the arterial lumen and with a thickness ≥1.3 mm. [14]


   Statistical Analysis Top


The normally distributed data were expressed as a mean ± standard deviation. Multiple group comparisons were performed by one-way analysis of variance. Univariate correlations between study variables were calculated by Spearman's rank correlation coefficients (R). Multiple regression analysis was performed using a stepwise model to determine which variables predict chemerin changes. A twotailed P <0.05 was considered statistically significant. All statistical analyses and linear regression analyses were performed using the SPSS 18.0 software package (SPSS, Chicago, IL, USA).


   Results Top


Patients' characteristics

The clinical and demographic data of the patients are presented in [Table 1]. There was no significant difference between the control and the predialysis groups in age (years), BMI (kg/m 2 ), total cholesterol (mg/dL), HDL (mg/ dL), and LDL (mg/dL) with a significant difference in the other parameters. Moreover, there was no significant difference between the control and HD groups in waist circumference (cm) and triglycerides (mg/dL) with a significant difference in other parameters. Likewise, there was no significant difference between the predialysis and HD groups in age (years), systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), BMI (kg/m 2), waist circumference (cm), total cholesterol (mg/dL), and Hb level (g/dL), with significant difference in other parameters.
Table 1: Clinical and laboratory characteristics of the studied groups.

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A stepwise increase in serum chemerin levels was found depending on the eGFR: 286.6 ± 10.02 ng/mL in the control group, 332.1 ± 21.54 ng/mL in the predialysis group, and 355.7 ± 20 ng/mL in the HD group [Table 1]. Compared with the control participants, predialysis patients and patients on HD had significantly higher chemerin levels (P = 0.001 and P <0.001). In addition, the chemerin level in patients on HD was higher than that in predialysis patients (P <0.001).

Relationship between chemerin, interleukin-6, and clinical parameters

Simple linear regression analysis revealed a significant positive correlation between chemerin levels and BMI, FBG, HOMA-IR, TG, TC, hsCRP, IL-6, and CIMT [Figure 1] and a significant negative correlation with HDL and eGFR [Figure 2].
Figure 1. Correlation between chemerin levels (ng/mL) and carotid intima-media thickness (mm).

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Figure 2. Correlation between chemerin levels (ng/mL) and glomerular filtration rate (mL/min).

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On multiple linear stepwise regression analysis using chemerin as the dependent variable, and BMI, TC, TG, HDL, LDL, FBG, insulin, HOMA-IR, IL-6, CIMT as independent variables, only IL-6 (β = 0.24, P <0.018), TG (β = 0.246, P <0.0001), CIMT(β = 0.214, P <0.004), and insulin (β = 0.14, P <0.024) remained significantly associated with chemerin.

With regard to IL-6 levels, simple linear regression analysis revealed a significant positive correlation with FBG, insulin, HOMA-IR, TG, TC, LDL, CIMT, hsCRP, and chemerin, with significant negative correlation with HDL.

Multiple linear stepwise regression analysis with IL-6 as a dependent variable and BMI, TC, TG, HDL, LDL, FBG, insulin, HOMA-IR, chemerin, CIMT as independent variables, only chemerin (β = 0.375, P <0.0001) was significantly associated with IL-6.

Effect of diabetes on chemerin and interleukin6 in chronic kidney disease patients

As shown in [Table 2], there was a significant difference between diabetic and nondiabetic patients within the predialysis and HD groups in serum levels of chemerin and CIMT. Furthermore, there was a significant difference between diabetic and nondiabetic patients in both groups, in serum levels of chemerin, IL6, CIMT, serum insulin, and HOMA-IR.
Table 2: Clinical, laboratory results in nondiabetic and diabetic patients in both groups.

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   Discussion Top


Adipose tissue dysfunction, which is characterized by altered adipokine secretion and chronic low-grade inflammation, is the key feature in obesity and plays an important role in the occurrence of obesity-related disorders including IR, type 2 diabetes, dyslipidemia, hypertension, and atherosclerosis. [15]

Chemerin has been identified as a novel adipokine-regulating adipogenetic factor and enhances insulin signaling in fat. [16],[17],[18] Another study reported that chemerin may also induce IR in human skeletal muscle cells, [19] which plays a considerable role in the development of type-2 diabetes and its complications. [20]

Our study shows the elevated levels of serum chemerin levels in patients maintained on regular HD compared to predialysis patients. To the best of our knowledge, so far only four studies have examined serum chemerin concentration in CKD patients. [21],[22],[23],[24]

Pfau et al [21] reported that serum chemerin concentration is elevated in HD patients and that residual renal function independently predicts serum chemerin concentration. Yamamoto et al [22] reported elevated serum chemerin concentration in HD patients, which was positively correlated with parameters of the metabolic syndrome. Hu and Feng [23] reported that the elevated serum chemerin concentration is associated with renal dysfunction in diabetic patients. Finally, Rutkowski et al [24] reported that there was a negative association between chemerin and eGFR, including a consistent increase in chemerin levels in patients with anuria and normalization of chemerin level after renal transplantation. These results suggest that the decrease of renal function may have a significant impact on serum chemerin concentration.

Arterial stiffness is recognized as a result of structural and functional changes in the vascular tree. [25] Vascular endothelium plays an important role in the functional regulation of arterial stiffness by secreting nitric oxide, endothelin-1, and natriuretic peptides. [26] Endothelial dysfunction is an early and potentially reversible event in atherogenesis. [27] CIMT quantitatively measures the arterial morphology consisting of intimal lesions and medial hypertrophy. [14]

The present study demonstrated a positive correlation between serum chemerin and CIMT in predialysis and HD patients. This concurs with previous studies which also found that chemerin is associated with the extent of coronary artery disease. [28] These findings indicate that serum chemerin might play an important pathogenic role not only in the occurrence but also in the severity and extent of atherosclerosis.

Chemerin showed a positive correlation with CRP and IL-6, which are considered inflammatory markers. This may be explained because chemerin has a dual nature as an adipokine and a chemokine. [16],[29] These results indicate that chemerin may play a role in the development of an inflammatory process which is a cornerstone in the pathogenesis of atherosclerosis and cardiovascular complications in CKD patients.

Our study revealed a significant rise of the serum chemerin level in diabetic CKD patients, either on conservative therapy or on HD, when compared with nondiabetic CKD patients. In addition, a significant elevation in chemerin levels was seen in diabetic CKD patients when compared with nondiabetic CKD patients. These results are in agreement with previous studies confirming the elevation of serum chemerin level in the metabolic syndrome and diabetic patients, either with ischemic heart disease or diabetic kidney disease. [23],[30]

In addition, we observed a significant positive correlation between serum chemerin levels and HOMA-IR and serum insulin. These findings can be explained since chemerin inhibits glycogen synthase kinase phosphorylation, an enzyme necessary for glycogen synthesis and storage, and thus inhibits glucose uptake. In addition, chemerin activates extracellular signal-regulated kinase (ERK). Inhibition of the ERK prevents chemerin-induced IR, pointing to involvement of this pathway in chemerin action. [19]

There were some limitations to our study. First, this study enrolled a small number of a limited population; therefore, the relationship between circulating chemerin and CIMT should be studied further in other ethnic groups, including a larger number of participants. Second, due to the drawback of the cross-sectional design, the causal relationship and underlying mechanism could not be defined in the present study.

Finally, one has to keep in mind that assessment of biologically active chemerin would be crucial for a better understanding of the role of chemerin in ESRD patients. Unfortunately, the chemerin ELISA employed in this study allows for the measurement of the total level of serum chemerin concentration. Moreover, today, no simple assay to measure biologically active chemerin is available. It is possible, therefore, that the relationship between renal function and biologically active form of chemerin may be different when compared to total chemerin concentration.

Thus, the pathological significance of the results presented here is limited and requires further study.

In conclusion, serum chemerin level was found to be an independent predictive marker of the presence of atherosclerosis in patients with CKD, either on conservative treatment or on HD.

Conflict of interest: None declared.

 
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Correspondence Address:
Farag E Salama
Department of Internal Medicine, Zagazig University, Zagazig
Egypt
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DOI: 10.4103/1319-2442.190867

PMID: 27752007

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