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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 1  |  Page : 257-261

Study of serum level of interleukin-31 in patients with uremic pruritus


1 Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Medical Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission08-Jun-2018
Date of Decision08-Jul-2018
Date of Acceptance22-Jul-2018
Date of Web Publication25-Mar-2020

Correspondence Address:
Amany M Yousef
Quweisna, Menoufia 32631
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_186_18

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  Abstract 

Objective
The aim was to assess the role of interleukin-31 (IL-31) in the pathogenesis of uremic pruritus (UP) in patients with chronic kidney disease (CKD) with and without hemodialysis and its relation to severity of pruritus.
Background
UP is a very distressing symptom in patients with CKD, with unclear etiopathogenesis.
Patients and methods
This study was conducted on 88 patients with CKD. These patients were divided into four groups: group 1 included 22 patients with CKD having pruritus of different degrees, group 2 included 22 patients with CKD not having pruritus (control group), group 3 included 22 patients with end-stage renal disease on maintenance hemodialysis having pruritus of different degrees, and group 4 included 22 patients with end-stage renal disease on maintenance hemodialysis not having pruritus (control group). Itch intensity was scored as mild, moderate, and severe using numerical rating itch scale, and serum levels of IL-31 was evaluated.
Results
The results showed that IL-31 serum level was higher in patients with UP in group 1 compared with the controls in group 2; however, it was not statistically significant. Moreover, IL-31 serum level was higher in patients with UP in group 3 compared with controls in group 4; however, it was not statistically significant. The result also showed no significant difference in IL-31 levels according to severity of UP.
Conclusion
Future studies are need with larger sample sizes to understand the contribution of IL-31 in the pathogenesis of UP.

Keywords: chronic kidney disease, cytokines, hemodialysis, interleukin-31, renal itch, uremic pruritus


How to cite this article:
Haggag MM, Kora MA, Safan MA, Yasien HA, Yousef AM. Study of serum level of interleukin-31 in patients with uremic pruritus. Menoufia Med J 2020;33:257-61

How to cite this URL:
Haggag MM, Kora MA, Safan MA, Yasien HA, Yousef AM. Study of serum level of interleukin-31 in patients with uremic pruritus. Menoufia Med J [serial online] 2020 [cited 2020 Aug 14];33:257-61. Available from: http://www.mmj.eg.net/text.asp?2020/33/1/257/281269




  Introduction Top


Pruritus is a common and annoying symptom in patients with chronic kidney disease (CKD). The most recent epidemiologic data have suggested that approximately 40% of patients with end-stage renal disease (ESRD) complain of moderate to severe pruritus and that uremic pruritus (UP) has a major clinical effect, being associated strongly with impaired sleep, depression, poor quality of life, and increased mortality[1]. Multiple hypotheses have been postulated for the etiopathogenesis of UP. Among them, some evidence supported a major role of an immune hypothesis, based on the findings that serum levels of high-sensitivity C-reactive protein and some inflammatory cytokines, such as interleukin (IL)-2 and IL-6, were elevated in patients with UP[2],[3]. However, a consensus has not yet been reached among these studies, and UP remains poorly characterized.

IL-31 is a novel cytokine derived from T cells. It has been found to induce severe dermatitis and pruritus in transgenic mice, signaling through a heterodimeric receptor formed of IL-31 receptor A and oncostatin M receptor, which is expressed on keratinocytes and epithelial cells[4]. IL-31 has been demonstrated to play direct immunomodulatory propertiesin vitro and might be involved in the recruitment of polymorphonuclear cells, T cells, and monocytes to the skin[4]. In human participants, increased expression of IL-31 is associated with the induction and persistence of pruritus and chronic skin inflammation, such as atopic dermatitis and allergic contact dermatitis[5],[6],[7],[8],[9]. The expression of IL-31 in patients with CKD remains unclear, and the association between IL-31 and UP has not yet been reported.


  Patients and Methods Top


This case–control study was carried out on patients with CKD recruited from the outpatient clinic and dialysis unit of Nephrology Department, Menoufia University Hospitals. The study involved 88 participants classified into four groups:

  1. Group 1: 22 patients with CKD having pruritus of different degrees
  2. Group 2: 22 patients with CKD not having pruritus (control group)
  3. Group 3: 22 patients with ESRD on maintenance hemodialysis having pruritus of different degrees
  4. Group 4: 22 patients (ESRD) on maintenance hemodialysis not having pruritus (control group).


The study was approved by the ethical committee of medical research of Faculty of Medicine, Menoufia University. Written informed consent was obtained from all participants before the study.

Exclusion criteria

The exclusion criteria included the following:

  1. Pruritus related to any dermatological disease
  2. Pruritus related to any other systemic disease, for example, liver diseases, diabetes, and blood diseases such as lymphoma.


All participants were subjected to the following

Full history taking, complete general examination, dermatological examination, and laboratory investigations including measurement of IL-31 serum levels by enzyme-linked immune sorbent assay (ELISA) technique.

Samples collection

From each participant in the study, 3 ml of venous blood was withdrawn under complete aseptic condition from the cubital vein. Samples were dispensed in plain tubes and allowed to clot at room temperature. Thereafter, the samples were centrifuged at 3000 rpm for 15 min, and the obtained serum was kept frozen at −20°C until analysis.

Measurement of interlukin-31 serum levels

Serum IL-31 level was measured by ELISA technique using the Human IL-31 PicoKine, ELISA Kit (catalog no. Ek0979; Boster Biological Technology Co., Ltd, USA, Pleasanton, California)[10].

Principle of the assay

Boster's human IL-31 ELISA Kit was based on standard sandwich ELISA technology.

A monoclonal antibody from mouse, specific for IL-31, has been precoated onto 96-well plates. Standards (expression system for standard: Escherichia coli, immunogen sequence: S24-T164) and test samples are added to the wells. A detection biotinylated polyclonal antibody from goat, specific for IL-31, is added subsequently and then followed by washing with PBS or tris boric acid sulphate buffer. Avidin–biotin–peroxidase complex was added, and unbound conjugates were washed away with PBS or tris boric acid sulphate buffer horseradish peroxidase (HRP) substrate. Tetramethylbenzidine was used to visualize HRP enzymatic reaction. Tetramethylbenzidine was catalyzed by HRP to produce a blue color product that changed into yellow after adding the acidic stop solution. The density of yellow is proportional to the human IL-31 amount of sample captured in the plate.

Statistical analysis

The collected data were analyzed using International Business Machines Statistical Package for the Social Sciences (IBM SPSS) software package, version 20.0 (IBM Corp., Armonk, New York, USA).

Mann–Whitney test for abnormally distributed quantitative variables was used to compare between two studied groups.

χ2-Test for categorical variables was used to compare between different groups.

Student's t-test for normally distributed quantitative variables was used to compare between two studied groups.

Kruskal–Wallis test was used to assess the statistical significance of the difference between more than two study group ordinal variables.

Spearman's correlation coefficient (r) was used to measure the association between two quantitative variables not normally distributed or one quantitative and other qualitative variables.

P value was used for the level of significance as follows:

  1. P greater than 0.05: nonsignificant
  2. P less than 0.05: significant.



  Results Top


This study included 88 patients, who were divided into four groups: group 1 included 13 (59.1%) males and nine (40.9%) females, and their age ranged from 33 to 71 years, with mean ± SD age of 54.18 ± 9.41 years. Group 2 (control group) included 16 (72.7%) males and six (27.3%) females, and their age ranged from 31–72 years, with a mean ± SD age of 54.50 ± 13.14 years. Group 3 included 15 (68.2%) males and seven (31.8%) females, and their age ranged from 20 to 67 years with mean ± SD age of 46.41 ± 13.31 years. Group 4 (control group) included nine (40.9%) males and 13 (59.1%) females, and their age ranged from 18 to 65 years, with a mean ± SD age of 41.14 ± 13.43 years.

In group 1, regarding the distribution of pruritus, 15 (68.2%) patients had generalized pruritus, whereas seven (31.8%) patients had localized pruritus; regarding the course, nine patients (40.9%) had paroxysmal discomfort whereas 13 (59.1%) patients had long-lasting pruritus; and regarding severity of pruritus, seven (31.8%) patients had mild pruritus, six (27.3%) patients had moderate pruritus, and nine (40.9%) patients had severe pruritus.

In group 3, regarding the distribution of pruritus, 19 (86.4%) patients had generalized pruritus, whereas three (31.6%) patients had localized pruritus; regarding the course, six (27.3.%) patients had paroxysmal discomfort, 13 (59.1%) patients had long-lasting pruritus, two (9.1%) patients had pruritus during dialysis, and one (4.5%) patient had pruritus before the session of hemodialysis; regarding the severity of pruritus, six (27.3%) patients had mild pruritus, five (22.7%) patients had moderate pruritus, and 11 (50%) patients had severe pruritus.

According to the comparison between IL-31 serum levels in patients with CKD with and without pruritus, our results showed that IL-31 serum level was higher in patients with UP in group 1, with mean (SD) of 8.59 (11.71), compared with the group 2 controls, with 3.54 (4.99); however, it was not statistically significance. Moreover, the IL-31 serum level was higher in patients with UP in group 3, with mean (SD) of 6.44 (7.88) compared with group 4 controls, with mean (SD) of 3.58 (3.84); however, it was not statistically significant, with P value of 0.199 by using Kruskal–Wallis test [Table 1]. The result also showed no significant difference of IL-31 levels according to the severity of UP, with P value of 0.061 in group 1, and 0.199 in group 3 by using Kruskal–Wallis test [Table 2].
Table 1: Statistical comparison between the different studied groups according to serum level of interleukin-31

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Table 2: Serum interleukin-31 level in patients with mild, moderate or severe pruritus in group 1 and group 3

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  Discussion Top


UP is a very distressing symptom in patients with CKD, with unclear etiopathogenesis.

In this study, no significant elevation was detected in the serum level of IL-31 in patients with UP as compared with patients without pruritus.

These results are not in accordance with Ko et al.[11] who demonstrated a significant increase in the serum IL-31 in hemodialysis patients with UP compared with those without UP.

The discrepancy between the aforementioned studies may be explained by the fact that the study of Ko et al.[11] was performed in a group consisting of 178 patients, of which, 62 patient had UP, whereas in our study, 88 patients were included, of which, only 44 patients had UP. Although our results showed an insignificant difference between the studied and the control group regarding the IL-31 levels, there is an apparent increased serum level of IL-31 in the studied group, represented by an increased mean and standard deviation value. This may be owing to the small number of the sample. This means that the evaluation of the role of IL-31 in the pathogenesis of renal pruritus requires follow-up studies on a larger group of patients.

It is known that activated mastocytes contribute to higher expression of mRNA for IL-31 receptors[9],[12]. It is possible that overactivation of mastocytes, which causes degranulation, may be also responsible for overexpression of mRNA for IL-31 receptors, which may be the reason for low concentration of IL-31 in serum. Literature data also show that IL-31A receptors present on typical, human keratinocytes have different variants which depend on progress of cell division and also on effect of proinflammatory cytokines such as interferons[12].

May be in the course of UP, there is deposition of IL-31 in the skin. The obtained result suggests the need to continue research especially taking into consideration assessment of IL-31 mRNA expression in skin biopsies from patients with UP.

It is known that IL-31 acts also through Janus Kinase (JAK)/Signal Transducer and Activator of Transcription proteins (STAT) signaling pathway and activates not only JAK-1 and JAK-2 but also STAT-1, STAT-3, and STAT-5[9]. Thus, low concentration of IL-31 in patients' serum may be because of the involvement of IL-31 into the mentioned signaling pathway. The involvement of IL-31 in the pathogenesis of UP needs future researches. Moreover, literature data showed that IL-31 is rather responsible for itch induction compared with development of inflammatory skin lesions[13].

It is known that IL-31 is induced by IL-4, promotes T-helper (Th2)-driven inflammation, and is expressed by activated CD4+ T cells (mainly Th2) and to lesser extent by CD8+ T cells[14]. Our result is supported by Fallahzadeh et al.[2] who showed that the serum levels of IL-4 as a marker of TH2 activity were not different between the case with UP and the control groups.

Moreover, Kimmel et al.[3] point to a central role of inflammation in the pathogenesis of UP in HD patients by finding that it is related to an augmented Th1 differentiation and not related to Th2 differentiation by finding that the number of Th1 cells indicated by CXC chemokine receptor 3 (CXCR3)-expressing and IFN-c-secreting CD4 cells was demonstrated to be significantly higher in HD patients with UP compared with those without UP but no increase in the number of TH2 cells as indicated by CCR4 chemokine receptor-expressing and IL4-secreting CD4 cells. This is in agreement with our study, which demonstrates no significant increase in the level of IL-31 (Th2 cytokine) in patient with UP.

All the aforementioned findings may indicate why IL-31 was not significantly elevated in patients with UP in our study.

In our study, there is no statistically significant difference between the levels of IL-31 and severity of pruritus, and this was against Ko et al.[11] who showed that there was a positive relationship between serum IL-31 and pruritus intensity.

This difference can be explained by that our results show that intensity of itch, which is present in the course of UP, was scored by numerical rating scale as mild, moderate and severe, for the preceding 2 weeks, whereas Ko et al.[11] scored pruritus by using the visual analog score of pruritus, and a detailed interview questionnaire based on the short form of the McGill Pain Questionnaire to assess different characteristics of pruritus for all patients, for more than 3 months, which is different than the scale used in our study. That is why it is difficult to easily compare obtained results.


  Conclusion Top


It could be concluded that IL-31 was higher in the serum of patients with UP than in controls; however, this difference was not statistically significant. This might be owing to the small sample size of the study. Future studies with larger sample sizes should be performed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Combs SA, Teixeira JP, Germain MJ. Pruritus in kidney disease. Semin Nephrol 2015; 35:383–391.  Back to cited text no. 1
    
2.
Fallahzadeh MK, Roozbeh J, Geramizadeh B, Namazi MR. Interleukin-2 serum levels are elevated in patients with uremic pruritus: a novel finding with practical implications. Nephrol Dial Transplant 2011; 26:3338–3344.  Back to cited text no. 2
    
3.
Kimmel M, Alscher DM, Dunst R, Braun N, Machleidt C, Kiefer T, et al. The role of micro-inflammation in the pathogenesis of uremic pruritus in hemodialysis patients. Nephrol Dial Transplant 2006; 21:749–755.  Back to cited text no. 3
    
4.
Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 2004; 5:752–760.  Back to cited text no. 4
    
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Raap U, Wichmann K, Bruder M, Stander S, Wedi B, Kapp A, et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 2008; 122:421–423.  Back to cited text no. 5
    
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Ezzat MH, Hasan ZE, Shaheen KY. Serum measurement of interleukin-31 (IL-31) in pediatric atopic dermatitis: elevated levels correlate with severity scoring. J Eur Acad Dermatol Venereol 2011; 25:334–339.  Back to cited text no. 6
    
7.
Neis MM, Peters B, Dreuw A, Wenzel J, Bieber T, Mauch C, et al. Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J Allergy Clin Immunol 2006; 118:930–937.  Back to cited text no. 7
    
8.
Dambacher J, Beigel F, Seiderer J, Haller D, Goke B, Auernhammer CJ, et al. Interleukin 31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is up regulated in inflammatory bowel disease. Gut 2007; 56:1257–1265.  Back to cited text no. 8
    
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Cornelissen C, Luscher-Firzlaff J, Baron JM, Luscher B. Signaling by IL-31 and functional consequences. Eur J Cell Biol 2012; 91:552–566.  Back to cited text no. 9
    
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Ip Wk, Wong Ck, Li ML, Li PW, Cheung PF, Lam CW. Interleukin – 31 induces cytokine and chemokine production from human bronchial epithelial cells through activation of mitogen-activated protein kinase signaling pathways: implications for the allergic response. Immunology 2007; 122:532–541.  Back to cited text no. 10
    
11.
Ko MJ, Peng YS, Chen HY, Hsu SP, Pai MF, Yang JY, et al. Interleukin-31 is associated with uremic pruritus in patients receiving hemodialysis J Am Acad Dermatol 2014; 71:1151–1159.  Back to cited text no. 11
    
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Zhang Q, Putheti P, Zhou Q, Liu Q, Gao W. Structures and biological functions of IL-31 and IL-31 receptors. Cytokine Growth Factor Rev 2008; 19:347–356.  Back to cited text no. 12
    
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Rabenhorst A, Hartmann K. Interleukin-31: a novel diagnostic marker of allergic diseases. Curr Allergy Asthma Rep 2014; 14:423.  Back to cited text no. 13
    
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Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, et al. Interleukins from 1 to 37 and interferon-γ: receptors, functions and roles in diseases. J Allergy Clin Immunol 2011; 127:701–721.  Back to cited text no. 14
    



 
 
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