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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2017  |  Volume : 28  |  Issue : 1  |  Page : 23-29
The evaluation of the relationship between serum levels of Interleukin-6 and Interleukin-10 and metabolic acidosis in hemodialysis patients


Department of Nephrology and Internal Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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Date of Web Publication12-Jan-2017
 

   Abstract 

Chronic kidney disease is defined as progressive kidney dysfunction. The levels of various cytokines increase in hemodialysis (HD) patients. High levels of interleukins (ILs) and presence of metabolic acidosis are described as independent risk factors for morbidity and mortality in these patients. This study was designed to evaluate the relationship between IL-6 and IL-10 and serum bicarbonate and metabolic acidosis in HD patients. In this analytical crosssectional study, patients referred to the HD units of Loghman Hakim and Shahid Ashrafi Esfahani Hospitals were randomly selected. Demographic and laboratory data, such as albumin, creatinine, calcium, phosphorus, parathormone, C-reactive protein, complete blood count, ferritin, ILs-6 and -10, and arterial blood gas analysis, were recorded for each patient. The correlation between IL and serum bicarbonate and other variables were evaluated by SPSS software. The patients were compared for the presence of acidosis and positivity for IL. A total of 84 patients with a mean age of 60.98 years and mean body mass index of 24.86 kg/m[2] were evaluated (53% male and 57% female). The mean dialysis duration was 24.86 ± 3.98 months. Overall, 41.7% of the patients had diabetes mellitus and 36.9% of them had hypotension. The mean serum levels of IL-6 and IL-10 were 6.036 and 17.46 pg/ml, respectively. There was a significant correlation between IL-6 and IL-10 levels and serum bicarbonate and the incidence of metabolic acidosis (P <0.05). Based on the results, metabolic acidosis and bicarbonate could be considered prognostic factors to differentiate the increased levels of IL-6 and IL-10 and associated morbidity and mortality.

How to cite this article:
Zahed NS, Chehrazi S. The evaluation of the relationship between serum levels of Interleukin-6 and Interleukin-10 and metabolic acidosis in hemodialysis patients. Saudi J Kidney Dis Transpl 2017;28:23-9

How to cite this URL:
Zahed NS, Chehrazi S. The evaluation of the relationship between serum levels of Interleukin-6 and Interleukin-10 and metabolic acidosis in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2017 Jul 20];28:23-9. Available from: http://www.sjkdt.org/text.asp?2017/28/1/23/198106

   Introduction Top


Although regular hemodialysis (HD) causes decreased levels of mortality in end-stage renal disease patients, it is considered a condition associated with inflammation.[1] In patients with renal failure, the systemic concentrations of both pro-inflammatory and anti-inflammatory cytokines are several times higher than concentrations in healthy individuals due to both decreased renal clearance and increased production of cytokines.[2] HD results in activation of cytokines, which can induce protein catabolism and promote apoptosis.[3] In HD patients, inflammatory mediators, such as IL-1, IL-6, and tumor necrosis factor alpha, cause synthesis and release of C-reactive protein (CRP), decreased albumin, prealbumin, and increased homocysteine and endothelin I. All these factors cause progression of atherosclerosis.[4] IL-6 increases during HD and is associated with cardiovascular mortality, malnutrition, and resistance to erythropoietin (EPO) in HD patients.[5] It is considered a prognostic marker in these patients.[6]

IL-10 is an anti-inflammatory cytokine, operating as a counter-regulatory mediator.[7] Low IL-10 level has been associated with low requirement of EPO in HD patients.[8]

Acidosis is a common complication of chronic renal failure (CRF), which can cause patients to lose lean body mass by preventing the activation of adaptive responses that maintain protein stores.[9] ,[10] Some effects of acidosis include negative nitrogen balance, muscle wasting, protein catabolism, increased corticosteroid, and parathyroid hormone production.[11] ,[12] ,[13] More recently, it has been shown that acidosis suppresses the growth of otherwise normal infants and children and causes negative nitrogen balance and increased protein and branched amino acids oxidation in adults with CRF including those treated with HD.[14] ,[15] ,[16] ,[17] ,[18] ,[19]

The aim of this study was to measure the inflammatory and anti-inflammatory cytokines in chronic HD patients and investigate their relationship with serum bicarbonate levels.


   Materials and Methods Top


This analytic cross-sectional study was performed in the winter of 2014 in the HD wards of Loghman Hakim and Ashrafi Esfahani Hospitals in Tehran, Iran. Men and women undergoing maintenance HD three sessions per week, 4 h each session, were eligible to participate in this study. Inclusion criteria included undergoing dialysis for more than three months, three times per week and being in a stable condition for these three months. Dialysis duration of less than three months, having reasons for being in a catabolic state (infection, inflammation, and surgery), using corticosteroids, intravenous antibiotics, or shall-down catheter, and having body mass index (BMI) >35 were the exclusion criteria for this study. The demographic data, including age, gender, diabetes, type of access for HD, quality of dialysis, and duration on dialysis, were collected from the patients' files.

The BMI was calculated using weight (kg) divided by height square (m2). The concentration of IL-6 and IL-10 was measured using enzyme-linked immunosorbent assay kits specific for human IL-6 (Pharmingen, San Diego, California, USA) and IL-10 (Biolegend, San Diego, California, USA).

The hemoglobin, white blood cells, platelets, calcium, phosphorus, parathyroid hormone, CRP, ferritin, transferrin, serum albumin, blood urea nitrogen, and creatinine (Cr) levels were all tested in a single laboratory before the mid-week HD. Venous blood gas was checked for each patient, and the pH and bicarbonate (HCO3) levels were measured. The patients were divided into two groups; those with acidosis (HCO3 <20) and those without acidosis (HCO3 >20).


   Statistical Analysis Top


Data were analyzed using the Statistical Package for Social Sciences software (SPSS) version 21 for Windows (SPSS Inc, Chicago, IL, USA). The Kolmogorov-Smirnov test was used for checking the normality of the variables. Quantitative variables were compared using independent sample t-test and nonparametric test (Mann-Whitney U-test) between male and female patients. Pearson and its nonparametric equivalent (Spearman) test were also run for evaluation of the correlation between the quantitative variables. Chi-square and Fisher's exact test were used to compare categorical variables between the two groups. P <0.05 was considered statistically significant.

The linear regression model was designed for IL-6 and IL-10 through stepwise method. The colinearity of the variables was checked by variance inflation factor (VIF) and the VIF higher than 10 was obtained from this model. This study was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences. Only stable patients were included in this study, and the study protocol did not interrupt treatment process. All patients' information was kept secure and anonymous. Researchers considered the participants' rights in accordance with the principle of Declaration of Helsinki.


   Results Top


A total of 84 patients, 36 male (43%) and 48 female (57%), with a mean age of 60.98 ± 13.26 years were evaluated in this study. The mean BMI level of the patients was 24.86 ± 3.98 kg/m2. The mean duration on dialysis was 24.86 ± 3.98 months. In this study, 35 patients had diabetes mellitus and 31 patients had hypertension. There were no significant differences in demographic data, dialysis duration, and underlying diseases between male and female patients (P >0.05, [Table 1]).
Table 1. Laboratory parameters in the study patients according to gender.

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The mean serum levels of IL-6 and IL-10 were higher in the acidosis group than in the nonacidosis group ([Figure 1] and [Figure 2]).
Figure 1. Scatter plot of IL-6 among study patients.
IL-6: Interleukin-6.


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The levels of both IL-6 and IL-10 did not show a significant relationship with HCO3 levels in any group. Considering the significant relationship between interleukins (ILs) and HCO3, the conclusion can be drawn that IL-6 and IL-10 levels successfully diagnosed acidosis, but they did not show any correlation with the severity of acidosis.

The IL-6 level had a significant role in the diagnosis of acidosis. The cutoff point of IL-6 for the diagnosis of acidosis (sensitivity 97.6% and specificity 76.2%) was 1.24 pg/mL. The IL-10 level was also significant in the diagnosis of acidosis. The cutoff point for IL-10 for the diagnosis of acidosis was 8.25 pg/mL, (sensitivity 90.5% and specificity 47.6%).

The comparison between IL-positive and IL- negative patients

Based on the cutoff points, the patients were divided into two groups: IL-positive and IL- negative. The mean age in IL-6 positive and negative patients was 61.41 and 60.3 years, respectively. The mean BMI in IL-6 positive and negative patients was 24.3 and 25.75, respectively.

There were no significant differences between the two groups in demographic information and underlying diseases such as diabetes and hypertension. There were, however, significant differences in serum albumin, Cr, pH, and HCO3 levels between the IL 6+ and IL 6− groups. There were no differences between the two groups in the other laboratory test ([Table 2]).
Table 2. Laboratory tests among patients with and without acidosis.

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   Discussion Top


The results of the present study suggested that similar to the studies done by Ryu and Zhang, IL-6 and IL-10 levels increased in HD patients. However, the present study did not benefit from the presence of a healthy control group.[20] ,[21],[22] This study was performed to examine the relationship between serum levels of HCO3 and ILs and the role of ILs in the diagnosis of acidosis in HD patients. Brunet et al reported higher IL-10 levels in chronic HD patients compared with healthy control individuals, and a higher IL-10 expression in longterm HD patients compared with short-term HD patients.[23]

In the present study, a counterregulatory relationship between pro-inflammatory and anti-inflammatory cytokines was reported which is similar to other existing studies.[1] ,[7] Increased IL-10 secretion was associated with higher secretion of IL-6.

In the previous studies, acidosis and cytokines were considered prognostic factors in HD patients, but the relationship between acidosis and cytokines in dialysis patients has not been fully investigated.[6] ,[7] The relationship between acidosis and mortality in dialysis patients has been investigated in other studies.[24] ,[25] ,[26]

Response to EPO may be related to cytokine levels. Costa et al reported increased levels of both IL-6 and IL-10 in HD patients who did not respond to EPO.[27] However, the present study did not evaluate this relationship. The relationship between acidosis and cytokines was not fully evaluated in the present study, but there are some studies reporting the presence of significant relationship between acidosis and cytokines in mice and higher levels of cytokines in diabetic ketoacidosis.[28] ,[29] In the studies performed by Lin et al, Ori et al, and Wann et al, there was no significant relationship between serum HCO3 and level of cytokines.[1] ,[24] ,[30] Ori et al reported significant reduction in the level of IL-10 in acidosis patients which is in contrast to the findings of the present study and other studies. This contrast has several reasons such as age, underlying diseases, duration of chronic kidney disease, duration on dialysis, gender, and severity of acidosis.


   Conclusion Top


Noticing the significant relationship between acidosis and serum cytokines, serum levels of HCO[3] , and acidosis predictably increased the level of cytokines in HD patients and ketoacidosis may act as a prognostic factor in HD patients.

One of the differences between the present study and other studies performed in this regard was the cutoff point of HCO[3] level, which was 20 in our study, but in the study conducted by Ori et al, the cut-off point of HCO3 for determining acidosis was 24. Consideration of the cut-off point in the present study was because, in Iran, most HD patients have acidosis and we had to set the degree of acidosis lower.


   Acknowledgments Top


The authors would like to thank the Clinical Research Development Center (CRDC) of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran for their support, cooperation and assistance throughout the period of study.

Conflict of interest: None declared.

 
   References Top

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Ori Y, Bergman M, Bessler H, et al. Cytokine secretion and markers of inflammation in relation to acidosis among chronic hemodialysis patients. Blood Purif 2013;35:181-6.  Back to cited text no. 1
    
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Panichi V, Maggiore U, Taccola D, et al. Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients. Nephrol Dial Transplant 2004;19:1154-60.  Back to cited text no. 4
    
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Raj DS, Boivin MA, Dominic EA, Boyd A, Roy PK, Rihani T, et al. Haemodialysis induces mitochondrial dysfunction and apoptosis. Eur J Clin Invest 2007;37:971-7.  Back to cited text no. 5
    
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Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: Central factors in the altered cytokine network of uremia - The good, the bad, and the ugly. Kidney Int 2005;67:1216-33.  Back to cited text no. 7
    
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Attia FM, Tawfik GA, Kalil KA, Mossalam MF. Production of interleukin-10 in serum and erythropoietin sensitivity in ESRD patients on hemodialysis. Int J Lab Hematol 2010;32:524- 9.  Back to cited text no. 8
    
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Mitch WE, Price SR, May RC, Jurkovitz C, England BK. Metabolic consequences of uremia: Extending the concept of adaptive responses to protein metabolism. Am J Kidney Dis 1994;23:224-8.  Back to cited text no. 13
    
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Kalhoff H, Diekmann L, Kunz C, Stock GJ, Manz F. Alkali therapy versus sodium chloride supplement in low birthweight infants with incipient late metabolic acidosis. Acta Paediatr 1997;86:96-101.  Back to cited text no. 14
    
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Papadoyannakis NJ, Stefanidis CJ, McGeown M. The effect of the correction of metabolic acidosis on nitrogen and potassium balance of patients with chronic renal failure. Am J Clin Nutr 1984;40:623-7.  Back to cited text no. 16
    
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Reaich D, Channon SM, Scrimgeour CM, Daley SE, Wilkinson R, Goodship TH. Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am J Physiol 1993;265(2 Pt 1):E230-5.  Back to cited text no. 17
    
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Kim KW, Chung BH, Jeon EJ, Kim BM, Choi BS, Park CW, et al. B cell-associated immune profiles in patients with end-stage renal disease (ESRD). Exp Mol Med 2012;44:465-72.  Back to cited text no. 20
    
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Ryu JH, Kim SJ. Interleukin-6 -634 C/G and-174 G/C polymorphisms in Korean patients undergoing hemodialysis. Korean J Intern Med 2012;27:327-37.  Back to cited text no. 21
    
22.
Zhang W, Wang W, Yu H, et al. Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage. Hypertension 2012; 59:136-44.  Back to cited text no. 22
    
23.
Brunet P, Capo C, Dellacasagrande J, Thirion X, Mege JL, Berland Y. IL-10 synthesis and secretion by peripheral blood mononuclear cells in haemodialysis patients. Nephrol Dial Transplant 1998;13:1745-51.  Back to cited text no. 23
    
24.
Lin SH, Lin YF, Chin HM, Wu CC. Must metabolic acidosis be associated with malnutrition in haemodialysed patients? Nephrol Dial Transplant 2002;17:2006-10.  Back to cited text no. 24
    
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Chang TI, Oh HJ, Kang EW, et al. A low serum bicarbonate concentration as a risk factor for mortality in peritoneal dialysis patients 2013;8:e82912.  Back to cited text no. 26
    
27.
Costa E, Lima M, Alves JM, et al. Inflammation, T-cell phenotype, and inflammatory cytokines in chronic kidney disease patients under hemodialysis and its relationship to resistance to recombinant human erythropoietin therapy. J Clin Immunol 2008;28:268-75.  Back to cited text no. 27
    
28.
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29.
Karavanaki K, Karanika E, Georga S, et al. Cytokine response to diabetic ketoacidosis (DKA) in children with type 1 diabetes (T1DM). Endocr J 2011;58:1045-53.  Back to cited text no. 29
    
30.
Wann JG, Hsu YH, Yang CC, et al. Neutrophils in acidotic haemodialysed patients have lower intracellular pH and inflamed state. Nephrol Dial Transplant 2007;22:2613-22.  Back to cited text no. 30
    

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Correspondence Address:
Narges Sadat Zahed
Department of Nephrology and Internal Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran
Iran
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DOI: 10.4103/1319-2442.198106

PMID: 28098099

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