Significance of cytokine profile in renal complications in children during the COVID-19 pandemic: An observational cohort retrospective clinical study

Background. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents a new global health challenge, potentially affecting all organs, including the kidneys. Renal pathology has been observed more frequently in younger children and individuals with comorbidities. Acute kidney injury has been reported in some patients with urinary tract pathology triggered by COVID-19 at the time of hospital discharge.

Objectives. To investigate critical aspects of the cytokine profile in serum and urine of children aged 9 to 14 years with acute pyelonephritis, both in the context of COVID-19 and without it.

Methods. The observational cohort retrospective clinical study involved 28 children diagnosed with acute pyelonephritis from the Nephrology Department, Samarkand Regional Children’s Multidisciplinary Medical Center, Uzbekistan. The control group consisted of 14 healthy children undergoing routine medical examinations according to their age and/or seeking medical advice in the outpatient clinic. Laboratory analyses of biological samples were conducted at the clinical diagnostic laboratory of the institution where the children were treated and monitored, as well as at international multidisciplinary medical center Innova Expert (Samarkand) and the Central Scientific Research Laboratory of the Institute of Immunology and Human Genomics, along with the laboratory of the Gunchamed clinic (Tashkent). Participants were selected for the study from January 2021 to December 2022. Children with acute pyelonephritis were included in the study upon hospitalization and were divided into two groups based on their COVID-19 history: Group 1 (n = 14) consisted of children with acute pyelonephritis without a history of COVID-19, while Group 2 (n = 14) included patients recovering from COVID-19 with a convalescent period ranging from 3 weeks to 3 months. The primary outcome consisted in the assessment of the cytokine profile (interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma) in serum and urine. A secondary outcome comprised the evaluation of renal function based on the condition of proximal and distal tubules. Statistical analysis of laboratory results was performed using Excel (Microsoft Office, 2016, USA) and StatPlus version 7 (AnalystSoft Inc., USA). The differences were considered statistically significant at p < 0.05.

Results. A statistically significant increase in the concentrations of interleukin-6, interleukin-4, tumor necrosis factor-alpha, and interferon-gamma was observed in urine samples. In Group 1, tumor necrosis factor-alpha levels were found to be 4.9 times higher and interferon-gamma levels were 11.0 times higher compared to the control group. In Group 2, these values exceeded those of healthy children by 8.8 and 14.8 times, respectively. Additionally, interleukin-4 levels in urine exceeded those of the control group by 4.7 times for Group 1 and by 5.6 times for Group 2. The analysis results indicate a significant role of interleukin-6 as an aggressive factor in the development of tubulointerstitial renal diseases, with its level in urine being increased by 37.9 times in children from Group 1 and by 47.1 times in patients from Group 2 compared to healthy children. A substantial growth in interleukin-6 levels even with less pronounced tubulointerstitial injury and a rise in its values as the tubulointerstitial injury grows suggest an increased cytokine excretion in urine due to tubular function impairment caused by SARS-CoV-2, leading to proximal tubular damage.

Conclusion. Controlling the course of latent lesions of tubular functions (screening study) in patients who have undergone COVID-19 implies studying the level of cytokines (interleukin-6, interferon-γ, tumor necrosis factor-α, interleukin-4) in urine, in order to determine the degree of proliferative changes in the tubulointerstitial tissue of the kidneys and forming risk groups of patients for chronicity of the process.

1. Aroca-Martínez G, Avendaño-Echavez L, Garcia C, Ripoll D, Dianda D, Cadena-Bonfanti A, Musso CG. Renal tubular dysfunction in COVID-19 patients. Ir J Med Sci. 2023;192(2):923–927. https://doi.org/10.1007/s11845-022-02993-0

2. Akhmedzhanova NI, Akhmedzhanov IA, Ismailova ZA, Gapparova GN. Clinical and laboratory evaluation of renal complications in children during the COVID-19 pandemic. Doktor axborotnomasi. 2023;2(110):13–16 (In Russ.). https://doi.org/10.38095/2181-466X-20231102-13-16

3. Kiseleva AV, Leskova AV, Skvortsov VV. Kidney pathology in COVID-19 patients. Lechaschi Vrach. 2022;9(25):19–23 (In Russ.). https://doi.org/10.51793/OS.2022.25.9.003

4. Morozov D, Morozova O, Budnik I, Pervouchine D, Pimenova E, Zakharova N. Urinary cytokines as markers of latent inflammation in children with chronic pyelonephritis and anorectal malformations. J Pediatr Urol. 2016;12(3):153.e1–6. https://doi.org/10.1016/j.jpurol.2016.01.013

5. Laudanski K, Okeke T, Hajj J, Siddiq K, Rader DJ, Wu J, Susztak K. Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure. Sci Rep. 2021;11(1):19675. https://doi.org/10.1038/s41598-021-99102-5

6. Robbins-Juarez SY, Qian L, King KL, Stevens JS, Husain SA, Radhakrishnan J, Mohan S. Outcomes for Patients With COVID-19 and Acute Kidney Injury: A Systematic Review and Meta-Analysis. Kidney Int Rep. 2020;5(8):1149–1160. https://doi.org/10.1016/j.ekir.2020.06.013. PMID: 32775814; PMCID: PMC7314696

7. Ronco C, Reis T. Kidney involvement in COVID-19 and rationale for extracorporeal therapies. Nat Rev Nephrol. 2020;16(6):308–310. https:// doi.org/10.1038/s41581-020-0284-7

8. Shaikh N, Hoberman A, Keren R, Gotman N, Docimo SG, Mathews R, Bhatnagar S, Ivanova A, Mattoo TK, Moxey-Mims M, Carpenter MA, Pohl HG, Greenfield S. Recurrent Urinary Tract Infections in Children With Bladder and Bowel Dysfunction. Pediatrics. 2016;137(1):e20152982. https://doi.org/10.1542/peds.2015-2982

9. Stewart DJ, Hartley JC, Johnson M, Marks SD, du Pré P, Stojanovic J. Renal dysfunction in hospitalised children with COVID-19. Lancet Child Adolesc Health. 2020;4(8):e28–e29. https://doi.org/10.1016/S2352-4642(20)30178-4

10. Kang SH, Kim SW, Kim AY, Cho KH, Park JW, Do JY. Association between Chronic Kidney Disease or Acute Kidney Injury and Clinical Outcomes in COVID-19 Patients. J Korean Med Sci. 2020;35(50):e434. https://doi.org/10.3346/jkms.2020.35.e434

11. Renata Y, Jassar H, Katz R, Hochberg A, Nir RR, Klein-Kremer A. Urinary concentration of cytokines in children with acute pyelonephritis. Eur J Pediatr. 2013;172(6):769–774. https://doi.org/10.1007/s00431-012-1914-2

12. Shen Q, Wang M, Che R, Li Q, Zhou J, Wang F, Shen Y, Ding J, Huang S, Yap HK, Warady BA, Xu H, Zhang A; Chinese Society of Pediatric Nephrology and Chinese Medical Doctor Association of Pediatric Nephrology. Consensus recommendations for the care of children receiving chronic dialysis in association with the COVID-19 epidemic. Pediatr Nephrol. 2020;35(7):1351–1357. https://doi.org/10.1007/s00467-020-04555-x

13. Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, Yi F, Yang HC, Fogo AB, Nie X, Zhang C. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020;98(1):219–227. https://doi.org/10.1016/j.kint.2020.04.003

14. Raina R, Chakraborty R, Mawby I, Agarwal N, Sethi S, Forbes M. Critical analysis of acute kidney injury in pediatric COVID-19 patients in the intensive care unit. Pediatr Nephrol. 2021;36(9):2627–2638. https://doi.org/10.1007/s00467-021-05084-x

15. Tantisattamo E, Dafoe DC, Reddy UG, Ichii H, Rhee CM, Streja E, Landman J, Kalantar-Zadeh K. Current Management of Patients With Acquired Solitary Kidney. Kidney Int Rep. 2019;4(9):1205–1218. https://doi.org/10.1016/j.ekir.2019.07.001

16. Tramma D, Hatzistylianou M, Gerasimou G, Lafazanis V. Interleukin-6 and interleukin-8 levels in the urine of children with renal scarring. Pediatr Nephrol. 2012;27(9):1525–1530. https://doi.org/10.1007/s00467012-2156-2

17. Fragkou PC, De Angelis G, Menchinelli G, Can F, Garcia F, Morfin-Sherpa F, Dimopoulou D, Mack E, de Salazar A, Grossi A, Lytras T, Skevaki C. ESCMID COVID-19 guidelines: diagnostic testing for SARS-CoV-2. Clin Microbiol Infect. 2022;28(6):812–822. https://doi.org/10.1016/j.cmi.2022.02.011

18. Andrusev AM, Tomilina NA, Peregudova NG, Shinkarev MB. Renal replacement therapy for End Stage Renal Disease in Russian Federation, 2014–2018. Russian National Renal Replacement Therapy Registry Report of Russian Public Organization of Nephrologists “Russian Dialysis Society”. Nephrology and Dialysis. 2020;22(1):1–71 (In Russ.). https://doi.org/10.28996/2618-9801-2020-1suppl-1-71

19. Tsai JD, Lin CC, Yang SS. Diagnosis of pediatric urinary tract infections. Urological Science. 2016;27(3):131–134. http://dx.doi.org/10.1016/j.urols.2016.10.001

20. van Veldhuisen DJ, Ruilope LM, Maisel AS, Damman K. Biomarkers of renal injury and function: diagnostic, prognostic and therapeutic implications in heart failure. Eur Heart J. 2016;37(33):2577–2585. https://doi.org/10.1093/eurheartj/ehv588

21. Joyce E, Glasner P, Ranganathan S, Swiatecka-Urban A. Tubulointerstitial nephritis: diagnosis, treatment, and monitoring. Pediatr Nephrol. 2017;32(4):577–587. https://doi.org/10.1007/s00467-016-3394-5

22. Kravchenko AYa, Kontsevaya AV, Budnevsky AV, Chernik TA. Novel coronavirus infection (COVID-19) and kidney disease. Russian Journal of Preventive Medicine. 2022;25(3):92–97 (In Russ.). https://doi.org/10.17116/profmed20222503192

23. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–1069. https://doi.org/10.1001/jama.2020.1585

24. Widiasta A, Sribudiani Y, Nugrahapraja H, Hilmanto D, Sekarwana N, Rachmadi D. Potential role of ACE2-related microRNAs in COVID-19-associated nephropathy. Noncoding RNA Res. 2020;5(4):153–166. https://doi.org/10.1016/j.ncrna.2020.09.001

25. Xiao G, Hu H, Wu F, Sha T, Zeng Z, Huang Q, Li H, Han J, Song W, Chen Z, Cai S. [Acute kidney injury in patients hospitalized with COVID-19 in Wuhan, China: a single-center retrospective observational study]. Nan Fang Yi Ke Da Xue Xue Bao. 2021;41(2):157–163. https:// doi.org/10.12122/j.issn.1673-4254.2021.02.01

26. Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, Guo Q, Sun X, Zhao D, Shen J, Zhang H, Liu H, Xia H, Tang J, Zhang K, Gong S. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020;26(4):502–505. https://doi.org/10.1038/s41591-020-0817-4