Pro-inflammatory cytokines in patients with chronic kidney disease: interleukin-6 in focus

Objective of the study. To assess the clinical and pathogenetic significance of serum interleukin-6 (IL-6) in patients with chronic kidney disease.

Materials and methods. A cross-sectional study enrolled 288 patients with chronic kidney disease (CKD) aged 16 to 86 years, average age (54.5 ± 14.5) years. The study enrolled 146 (50.7%) women and 142 (49.3%) men. Depending on the value of estimated glomerular filtration rate (eGFR), all the examined patients were divided into two groups: 1st (n = 154) - persons with eGFR > 60 ml/min; 2nd (n = 134) - patients with eGFR < 60 ml/min, i.e. renal failure. CKD was identified when there was evidence of damaged and/or reduced renal function. Glomerular filtration rate was calculated using the Hoek equation based on measurement of serum cystatin C, and severity of CKD was based on eGFR values. All patients had concentration of creatinine, cystatin C and IL-6 in their blood serum studied.

Results. In the 2nd group of patients with eGFR below 60 ml/min, average age [(57.9 ± 14.5) years vs. (51.6 ± 13.9) years; p < 0.05], systolic blood pressure [(142 ± 24) mm Hg vs. (133 ± 22) mm Hg; p < 0.05], cystatin C [1.815 (1.430-3.070) mg/l vs. 0.980 (0.900-1.100) mg/l; p < 0.05)] and IL-6 [2.761 (1.400-6.495) pg/ml vs. 1.754 (0.849-3.226) pg/ml; p < 0.05)] levels in blood serum were significantly higher compared with the 1st group. An inverse correlation was found between serum IL-6 and eGFR level (r = -0.144; p = 0.018).

Conclusion. In patients with chronic kidney disease with an eGFR level below 60 ml/min, an increase in systolic blood pressure and serum IL-6 concentration was observed. In chronic kidney disease, an increase in the content of IL-6 was accompanied by a decrease in glomerular filtration rate and an increase in diastolic blood pressure.

1. Mukhin N.A. Nephrology. National leadership. Quick Edition. 2018; 608 p. [In Russian]

2. Moiseev V.S., Mukhin N.A, Smirnov A.V. et al. Cardiovascular risk and chronic kidney disease: cardio-nephroprotection strategies. Rossijskij kardiologicheskij zhurnal. 2014; 8: 7-37. DOI:10.15829/1560-4071-2014-8-7-37. [In Russian]

3. Levey A.S., Stevens L.A. Estimating GFR using the CKD epidemiology collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions. American journal of kidney diseases: the official journal of the National Kidney Foundation. 2010; 55:4:622-27. DOI:10.1053/j.ajkd.2010.02.337

4. Murkamilov I.T., Fomin V.V., Aitbaev K.A. et al. The cytokine model of the development of cardiovascular complications in chronic kidney disease. Klinicheskaya nefrologiya. 2017; 2:71-5. [In Russian]

5. Durlacher-Betzer K., Hassan A., Levi R. et al. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney international. 2018; 94:2:315-25. DOI:https://doi.org/10.1016/j.kint.2018.02.026

6. Rops A.L., Jansen E., van der Schaaf A. et al. Interleukin-6 is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice. Kidney international. 2018;93:6:1356-66. DO I :https://doi.org/10.1016/j.kint.2018.01.005

7. Rakityanskaya I.A., Ryabov S.I. The role of mononuclears in nephron lesion in patients with chronic glomerulonephritis. communication II. The role of interleukins (IL-6 and IL-10) and proliferation of the glomerular and interstitial nephron cells in progression of the mesangioproliferative glomerulonephritis. Nefrologiya. 1998;2(1):30-6. DOI:https://doi.org/10.24884/1561-6274-1998-2-1-30-36 [In Russian]

8. Boswell R.N., Yard B.A., Schrama E. et al. Interleukin 6 production by human proximal tubular epithelial cells in vitro: analysis of the effects of interleukin-1a (IL-1a) and other cytokines. Nephrology Dialysis Transplantation. 1994; 9:6: 599-606. DOI:https://doi.org/10.1093/ndt/9.6.599

9. Naka T., Nishimoto N., Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res. 2002;4(Suppl 3): S233-42. DOI:https://doi.org/10.1186/ar565

10. Akira S., Taga T., Kishimoto T. Interleukin-6 in biologie and medicine. Adv. Immmunol. 1993; 54:1-78. DOI:https://doi.org/10.1016/S0065-2776(08)60532-5

11. Akchurin O., Akchurin O., Patino E. et al. Interleukin-6 Contributes to the Development of Anemia in Juvenile CKD. Kidney International Reports. 2019; 4(3):470-83. DO I :https://doi.org/10.1016/j.ekir.2018.12.006

12. Henaut L., Massy Z.A. New insights into the key role of interleukin 6 in vascular calcification of chronic kidney disease. Nephrology Dialysis Transplantation. 2018; 33:4:543-48. DOI:https://doi.org/10.1093/ndt/gfx379

13. Scarpioni R., Obici L. Renal involvement in autoinflammatory diseases and inflammasome-mediated chronic kidney damage. Clin. Exp. Rheumatol. 2018; 36:54-60.

14. Levey A.S., Coresh J., Bolton K. et al. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. American Journal of Kidney Diseases. 2002; 39(2 Suppl 1): S1-266.

15. Hoek F.J., Kemperman F.A., Krediet R.T. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular fi ltration rate. Nephrol Dial Transplant. 2003;18(10): 2024-31. DOI:10.1093/ndt/gfg349

16. Shalhoub R.J. Pathogenesis of lipoid nephrosis: a disorder of T-cell function.The Lancet. 1974; 304: 7880:556-60. DOI:https://doi.org/10.1016/S0140-6736(74)91880-7

17. Lutticken C., Wegenka U.M., Yuan J. et al. Association of transcription factor APRF and protein kinase Jak 1 with the interleukin-6 signal transducer gp130.Science. 1994; 263: 5143:89-92.

18. Band L., Fougueray В., Philippe C. Involvement of tumor necrosis factor L in glomerulas injury.Springer Seminars in Immunopathology.1994;16:53-61.

19. Murkamilov I.T., Aitbaev K.A., Fomin V.V. et al. Cytokines and arterial stiffness at the early stage of chronic kidney disease: the relationship and prognostic role. Klinicheskaya nefrologiya. 2018; 4:25-32. [In Russian].

20. Rose-John S., Heinrich P.C. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J. 1994;300(Pt2):281-90. DOI:10.1042/bj3000281

21. Su H., Lei C.T., Zhang C. Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update. Front. Immunol. 2017; 8:405. DOI:10.3389/fimmu.2017,00405

22. Muller-Newen G., Kuster A., Hemmann U. et al. Soluble IL-6 receptor potentiates the antagonistic activity of soluble gp130 on IL-6 responses. J Immunol. 1998; 161:11:6347-6355.

23. Abbasi F., Chu J.W., Lamendola C. et al. Discrimination between obesita and insulin resistance in the relationship with adiponectin.Diabetes. 2004;53:3:585-90. DOI: https://doi.org/10.2337/diabetes.53.3.585

24. Abdelnabi A.M., Sadek A.M. Role of interleukin 6 and highly sensitive C-reactive protein in diabetic nephropathy. Egypt J Intern Med. 2018;30(3): 103-9. DOI:10.4103/ejim.ejim_27_18

25. Klein B., Zhang X.G., Lu Z.Y. et al. Interleukin-6 in human multiple myeloma. Blood. 1995;85(4):863-872.

26. Aitbaev K.A., Murkamilov I.T., Fomin V.V. et al. Inflammation in chronic kidney disease: sources, consequences and antiinflammatory therapy. Klinicheskaya meditsina. 2018;4(96):314-20 DOI:10.18821/0023-2149-2018-96-4-314-320 [In Russian]