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View of Profile of Cytokines (IL-17A, IL-6 and TNF-α) in Sera of Chronic kidney disease of Iraqi patients.

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Profile of Cytokines (IL-17A, IL-6 and TNF-α) in Sera of Chronic kidney disease of Iraqi patients.

Tabarek Salih Mahdi 1 , Jinan M. J. Al-saffar 2, Ali j. Alsaady 3.

1. College of Science/University of Baghdad, Baghdad, Iraq. [email protected].

2. College of Science/University of Baghdad, Baghdad, Iraq. [email protected].

3. Medical City Hospital, Baghdad, Iraq. [email protected].

Corresponding author: [email protected] Abstract

Chronic kidney disease (CKD) is greatly widespread universally and leading to end-stage renal disease (ESRD), cardiovascular disease (CVD), and early death [1]. In this study, 152 samples were collected, including 94 patients with chronic renal impairment who did not reach the dialysis stage and 58 healthy volunteers who did not have any chronic diseases. The purpose of this study was to test the impact of various inflammatory factors, including interleukin 17A (IL-17A), interleukin 6 (IL-6) and tumor necrosis factors (TNF-α), which may influence the aggravation of chronic kidney disease.

The Samples were collected from patients diagnosed by a physician with CKD before dialysis. Patient samples consist of (62 males and 32 females) While the healthy samples were composed of (36 males and 22 females) .Patients' age distributed between 18-83 years old .

The serum level of the immuno-cytokines IL-17A, IL-6 and TNF-α were measured using the ELISA technique. The result showed significant increase in the levels of the three immune cytokines has been observed, due to their pro-inflammatory role in CKD patients compared to healthy subjects with significantly (p<0.0001).

Keywords: Chronic kidney disease, CKD, IL-17A, IL-6, TNF-α.

Introduction

Chronic kidney disease comprises of conditions, which could affect on the kidneys and lead to the decrease of the renal capacity to keep its typical function [2]. Equally important, CKD refers to a gradual decrease in the functions of the kidneys, where it is one-way, not reversed, as well as a change in the pattern of the kidney where it is unable to perform its tasks completely and is accompanied by a decrease in the rate of filtration by the glomeruli.

[3]. CKD also affect on thyroid hormones , showed decreases in the levels of T3 and T4 along with an increase in the level of TSH in the patients [4].

Additionally, CKD may be result as complication of diabetes, high blood pressure and

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cytokines [6]. Chronic inflammation in patients with CKD is also associated with other diseases, as in cases of endocrine glands (insulin resistance) and the neurological system [7].

As well, CKD itself might effect in a complicated inflammatory condition [8]. Infiltration of WBCs (in the site of inflammation) mediates inflammatory response in Chronic kidney disease. [9]

The kidneys are an organ that prone to infection and damage and is also prone to immune diseases. Kidney inflammation results from infection that affects the kidneys in response to it as a result of the immune system stimulating cytokines that go to the site of infection in order to protect the body, which may negatively affect kidney function if not treated properly.

Likewise, IL-17A is secreted in the event of an infection that may affect the kidneys and may be associated with immune diseases that resulted from cytokines attacking the kidneys [10].

IL-17A is an immune cytokine responsible for the inflammatory role produced by Macrophages, neutrophils, NK cell, mast cell and Th17 [11]. The inflammatory role of IL- 17A is multidirectional as it plays a role in many diseases such as hypertension, glomerulonephritis, Chronic kidney disease, nephrotic syndrome and many other diseases [12].

Cytokines with an inflammatory role (IL-6 and TNF-alpha) may stimulate the liver in inflammation to secrete the C reactive protein (CRP) acute phase protein , which is a marker of inflammation [13]. Consequently, if any damage to any organ does not completely solve the problem, or if the anti-inflammatories in the body do not work, the inflammation will continue. The chronic inflammatory condition may be harmful which may cause significant damage to the organ [14]. As in patients with chronic kidney disease, where the chronic inflammation in the kidneys led to a gradual decrease in kidney function, and as observed in chronic kidney disease before dialysis, the rate of inflammation in the body was high, which may be an important indicator of the patient's condition [15].

TNF-α and IL-6 play an essential role in the acute and chronic inflammation and are mainly associated in patients with heart disease and chronic kidney disease pre- and post- dialysis . Therefore, most of the studies depend on their level (TNF-α & IL-6) in association with CKD [16, 17] .

The aim of the current study was to review the impact of various inflammation factors, including interleukin 17A (IL-17A), interleukin 6 (IL-6) and tumor necrosis factors (TNF-α) which may influence the aggravation of chronic kidney insufficiency.

Materials and Methods

The collection of Blood Sample

Five ml of a venous blood sample was collected from each patient and control groups, blood serum isolated by centrifugation at 3000 rpm for 10 min, then tubes were placed in a

cool-box under aseptic condition and stored in the freezer at (-20° C) until further processing.

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Procedure

Serum levels of IL-17A, IL-6 and TNF-α were measured by a commercially available ELISA (peprotech Company, USA).

Statistical analysis

Analysis of data was carried out using the available statistical package of SPSS-27 (Statistical Packages for Social Sciences- version 27). The significance of differing umeans (quantitative data) has been tested using Students-t-test to differentiate between two independent means ᴏr Paired-t-test for paired observation differences (or two dependent means). The P value was considered statistically significant less than 0.05.

Results and Discussion

The patient samples consist of 62 males and 32 females, while the healthy samples were composed of 36 males and 22 females. Patients' age distributed between 18-83 years old.

The serum level of the immuno-cytokines IL-17A, IL-6 and TNF-α were measured using the ELISA technique. There were significant increase in the levels of the three immuno- cytokines have been observed due to their pro-inflammatory role in chronic renal impairment patients compared to healthy subjects with significantly (p<0.0001).

The results showed that serum level of IL-17A was significantly increased (P ≤ 0.0001) in CKD group (429.48±270.53 pg/ml) as compared with the healthy control group (96.38±39.87 pg/ml). Table 1

Current research results showed a significant increase in the level of IL-17A in CKD patients compared to healthy controls, these results agree with previous study [18]. IL-17A participates in tissue inflammation via inducing the expression of chemokines, pro- inflammatory cytokines and matrix metalloproteases. Besides its role in host defence against infectious diseases, IL-17A is involved in different autoimmune and inflammatory diseases.

IL-17A is involved in the development of atherosclerosis, diabetic nephropathy, hypertension, glomerulonephritis, fibrosis, ischaemia-reperfusion injury, nephrotic syndrome and acute renal allograft rejection. As well as, inhibition of IL-17A may be a promising therapeutic target to inhibit end-stage renal disease. [19], This results agree with Previous study [20],

Table 1-Mean serum levels (pg/ml) of IL-17A in study samples

CKD Patients Healthy controls

IL-17A Concentration Mean±SD 429.48±270.53 96.38±39.87

Range 85.45-968.53 37.67-197.06

Percentile 05th 92.4900 42.4800

25th 171.1600 75.5100

50th (Median) 419.3100 87.2900

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99th 968.5300 197.0600

P value compared to healthy control 0.0001# -

#Significant difference between two independent means using Students-t-test at 0.05 level.

The results showed that serum level of IL-6 was significantly increased (P ≤ 0.0001) in CKD group (907.39±339.31 pg/ml) as compared with the healthy control group (112.09±63.55 pg/ml). Table 2.

The results showed that serum level of TNF-α was significantly increased (P ≤ 0.0001) in CKD group (1567.89±341.70 pg/ml) as compared with the healthy control group (230.67±55.96 pg/ml).Table 3.

In current study, the level of inflammatory cytokines TNF-α and IL-6 was higher in CKD patients compared to healthy subjects, and the level of cytokines IL-6 and TNF-α was independently associated with disease severity, These results are consistent with many results in previous studies [21, 22] .There are many studies linking the level of IL-6 and TNF-α to the development of chronic kidney disease, where the high level of these cytokines has been linked to the progression of the disease [23].

The increase in IL-6 and TNF-α may be due to albuminuria, which stimulates the cytokines, or due to the lack of excretion of cytokines by the body. It may also lead to an increase in its level [24].

There is relationship of disease severity with elevation of inflammatory cytokines TNF-α and IL-6 in patients with chronic kidney disease, regardless of the drugs they use, such as antidiabetics, lipid-lowering drugs and others, patients with acute kidney injury were excluded from this study because our study includes one reading of inflammatory cytokines, which does not represent the rate of cytokines over time [24].

Table 2-Mean serum levels (pg/ml) of IL-6 in study samples.

CKD Patients Healthy controls

IL-6 Concentration Mean±SD 907.39±339.31 112.09±63.55

Range 61.19-1694.67 45.79-279.38

Percentile 05th 393.7600 46.3600

25th 681.7800 66.5600

50th (Median) 940.9700 84.3700

75th 1126.1100 134.7500

95th 1524.1600 266.0300

99th 1694.6700 279.3800

P value compared to healthy control 0.0001# -

#Significant difference between two independent means using Students-t-test at 0.05 level.

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Table 3-Mean serum levels (pg/ml) of TNF-alpha in study samples

CKD Patients Healthy controls TNF-alpha

Concentration

Mean±SD 1567.89±341.70 230.67±55.96

Range 683.09-2074.37 93.09±316.55

Percentile 05th 853.621 154.298

25th 1418.020 188.869

50th (Median) 1626.649 236.847

75th 1781.251 274.840

95th 2034.203 312.860

99th 2074.372 316.556

P value compared to healthy control 0.0001# -

#Significant difference between two independent means using Students-t-test at 0.05 level.

Conclusion

As a conclusion, CKD is global associated with many factors, including inflammation.

Th17 cells stimulate inflammation by secreting inflammatory cytokines IL-17A and TNF-α, which in turn stimulate pro-inflammatory cytokines and chemokines as IL-6. These, in turn, stimulate the white blood cells to recruit the neutrophils, resulting in organ injury.

References

1- Levey, A.S.,and Coresh, J. 2012. Chronic kidney disease. Lancet, 379, pp: 80-165.

2- The National Kidney Foundation. 2016. https://www.kidney.org/atoz/content/ about-chronic- kidney-disease.

3- Longmore, M., Wilkinson, IB., Davidson, E.H., Foulkes, A.,and Mafi AR. 2010. Illustrative Handbook of General Surgery.

4- Sama S. S., Jabbar H. Y. and Ali j. Alsaady.2020. Evaluation of Thyroid Hormones and Some Biochemical Variables in Patients with Chronic Kidney Disease .Iraqi Journal of Science,61(5), pp: 985-992.

5- Zhang, Q-L.,and Rothenbacher, D.2008. Prevalence of chronic kidney disease in population- based studies: systematic review. BMC Public Health, 8(1).

6- Kumar, P.J.,and Clark, M.L. 2009. Kumar and Clark’s Clinical Medicine. Saunders Elsevier,7.

7- Khansari, N., Shakiba, Y.,and Mahmoudi, M.2009 .Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov,3, pp: 73-80.

8- Dungey, M., Hull, K.L., Smith, A.C., Burton ,J.O., and Bishop, N.C.2013. Inflammatory factors and exercise in chronic kidney disease.Int J Endocrinol.

9- Anders, H.J., Sayyed, S.A.,and Vielhauer ,V.2010. Questions about chemokine and chemokine

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11- Owen ,T.A., Punt,J.,Stranford ,S.A., Kuby,W. H., Cortvrindt , C., Speeckaert ,R., Moerman , A., Delanghe ,J.R. and Speeckaert , M.M. 2013. The role of interleukin-17A in the pathogenesis of kidney diseases. Pathology . 49(3). pp: 247-258.

12- Cortvrindt , C., Speeckaert ,R., Moerman , A., Delanghe ,J.R.and Speeckaert , M.M. 2017.

The role of interleukin-17A in the pathogenesis of kidney diseases. Pathology. 49(3), pp:

247-258.

13- Dungey, M., Hull, K.L., Smith, A.C., Burton ,J.O. and Bishop, N.C.2013. Inflammatory factors and exercise in chronic kidney disease.Int J Endocrinol.

14- Kumar, P.J., Clark, M.L.2009. Kumar and Clark’s Clinical Medicine. Edinburgh, UK:

Saunders Elsevier.7.

15- Mezal, E. H., Yousif, A. F., Hanan, Z. K., Hanan, A. K., & Jalil, A. (2020). Isolation, Assessment of Antimicrobial Sensitivity of Bacterial Pathogens from Post-Cesarean section Infection of patients in Thi-Qar Province. European Journal of Molecular & Clinical Medicine, 7(3), 958-964.

16- Saleh, M. M., Jalil, A. T., Abdulkereem, R. A., & Suleiman, A. A. Evaluation of Immunoglobulins, CD4/CD8 T Lymphocyte Ratio and Interleukin-6 in COVID-19 Patients. TURKISH JOURNAL of IMMUNOLOGY, 8(3), 129-134.

17-Pecoits-Filho, R., Bárány, P., Lindholm, B., Heimbürger, O. and Stenvinkel, P.2002.

Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment.

Nephrol Dial Transplant. 17(168) pp:,4–8.

18- Zhu, X., Li, S., Zhang, Q., Zhu , D., Xu, Y., Zhang ,P., Han , J. Duan, Z., Gao, J., Ou,Y.

2018.Correlation of increased Th17/Treg cell ratio with endoplasmic reticulum stress in chronic kidney disease. Medicine (Baltimore).97 (20).

19-Panel,C.C., Reinhart,S., Alena,M., Joris R.D. and Marijn, M.S.2017 .The role of interleukin- 17A in the pathogenesis of kidney diseases. Pathology. 49( 3) pp;247-25.

20- Fatemeh, A., Nader. B., Hedayatollah, Sh. and Mahmoud, R. 2015. The role of Th1 and Th17 cells in glomerulonephritis. J Nephropathol. 4(2): 32-37.

21- Gupta, J., Mitra, N., Kanetsky, P.A., Devaney, J., Wing, M.R., Reilly, M., et al. 2012.

Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin J Am Soc Nephrol.7(19), pp: 38–46.

22- Upadhyay, A., Larson, M.G., Guo, C.Y., Vasan, R.S., Lipinska, I., O’Donnell, C.J., et al.2011. Inflammation, kidney function and albuminuria in the Framingham Offspring cohort.

Nephrol Dial Transplant. 26(9), pp: 20–6.

23- Shankar, A., Sun, L., Klein, B.E., Lee, K.E., Muntner, P., Nieto, F.J., et al. 2011.Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population- based cohort study. Kidney Int.80(123), pp: 1–8.

24- Bemelmans, M.H., Gouma, D.J., Buurman, W.A.1993. Influence of nephrectomy on tumor necrosis factor clearance in a murine model. J Immunol.150(200), pp: 7–17.

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