Assessment of the Diagnostic and Prognostic Value of the Serum Netrin-1 Level in Patients Presenting the Emergency Department with Sepsis

Öz

Aim: Sepsis affects approximately 50 million people across the world each year and causes 11 million deaths. Many biomarkers have been investigated for the early diagnosis of sepsis and patient responses to infection and treatment, as well as to help clinicians predict risk and plan treatment. Netrin-1 plays an important role by directing the migration of neutrophils, particularly monocytes, in inflamed tissue. This study aimed to determine whether Netrin-1 was an effective marker in the diagnosis, treatment follow-up, and prognosis evaluation of patients with sepsis and septic shock. Material and Method: This observational and prospective study was conducted at the emergency department with 121 individuals over 18, including 71 patients diagnosed with sepsis and 50 healthy volunteers. The patients were further evaluated in two subgroups: sepsis and septic shock. Blood samples were taken from the patient and control groups at the time of presentation and on the third day. Netrin-1 levels were examined in both groups. Results: The netrin-1 levels of the patients with sepsis and septic shock upon presentation to the hospital were significantly higher than the control group (p<0.0001). However, there was no significant difference between the netrin-1 levels measured at the time of presentation and on the third day in the sepsis and septic shock groups (p: 0.0522 and 0.0786, respectively). Neither the presentation nor the third-day netrin-1 level had a statistically significant correlation with mortality (p=0.075 and 0.254, respectively). Conclusion: Our results showed that netrin-1 was an effective biomarker for diagnosing sepsis and septic shock. However, it was not a risk factor for mortality or clinical risk scores in patients with these conditions.

Anahtar Kelimeler

• netrin-1
• sepsis
• emergency department

Kaynakça

1. 1. Singer M., Deutschman C., Seymour C. W., Shankar-Hari M., Annane D., Bauer, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama,. 2016;315(8), 801–810.
2. 2. Yao R. Q., Zhao P. Y., Li Z. X., Liu Y. Y., Zheng L. Y., DuanY, et al. Single-cell transcriptome profiling of sepsis identifies HLADR low S100A high monocytes with immunosuppressive function. Military Medical Research,. 2023;10(1), 27.
3. 3. Rudd, K. E., Johnson, S. C., Agesa, K. M., Shackelford, K. A., Tsoi, D., Kievlan, D. et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet,. 2020;395(10219), 200–211.
4. 4. Reinhart, K., Daniels, R., Kissoon, N., Machado, F. R., Schachter, R. D., & Finfer, S. Recognizing sepsis as a global health priority—a WHO resolution. New England Journal of Medicine,. 2017;377(5), 414–417.
5. 5. Torres LK, Pickkers P, van der Poll T. Sepsis-induced immunosuppression. Annu Rev Physiol. 2022;84:157–81.
6. 6. Venet, F., Demaret, J., Gossez, M., Monneret, G. Myeloid cells in sepsis‐acquired immunodeficiency. Annals of the New York Academy of Sciences,. 2021;1499(1), 3–17.
7. 7. Martin-Loeches, I., Perner, A. Focus on infection and sepsis in intensive care patients. Intensive Care Medicine,. 2016;42(4), 491–493.
8. 8. Marshall, J. C., Dellinger, R. P., Levy, M. The Surviving Sepsis Campaign: a history and a perspective. Surgical infections,. 2010;11(3), 275–281.

9. 9. Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Critical care medicine,. 2021;49(11), e1063–e1143.
10. 10. Póvoa, P., Coelho, L., Dal-Pizzol, F., Ferrer, R., Huttner, A., Conway Morris, et al. How to use biomarkers of infection or sepsis at the bedside: guide to clinicians. Intensive care medicine,. 2023;49(2), 142–153.
11. 11. Póvoa, P., Martin-Loeches, I., Ramirez, P., Bos, L. D., Esperatti, M., Silvestre, J, et al. Biomarker kinetics in the prediction of VAP diagnosis: results from the BioVAP study. Annals of intensive care,. 2016;6, 1–11.
12. 12. de Jong, E., van Oers, J. A., Beishuizen, A., Vos, P., Vermeijden, W. J., Haas, L. et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. The Lancet Infectious Diseases,. 2016;16(7), 819–827.
13. 13. Pierrakos, C., Velissaris, D., Bisdorff, M., Marshall, J. C., Vincent, J. L. Biomarkers of sepsis: time for a reappraisal. Critical Care,. 2020;24, 1–15.
14. 14. Xu, K., Wu, Z., Renier, N., Antipenko, A., Tzvetkova-Robev, D., Xu, Y., et al. Structures of netrin-1 bound to two receptors provide insight into its axon guidance mechanism. Science,. 2014;344(6189), 1275–1279.
15. 15. Cirulli, V.;Yebra, M. Netrins: Beyond the brain. Nat. Rev. Mol. Cell Biol. 2007, 8, 296–306.
16. 16. Bruikman, C. S.;Zhang, H.;Kemper, A. M.;van Gils, J. M. Netrin Family: Role for Protein Isoforms in Cancer. J. Nucleic Acids 2019, 2019, 3947123.
17. 17. Miloudi, K.;Binet, F.;Wilson, A.;Cerani, A.;Oubaha, M.;Menard, et al. Truncated netrin-1 contributes to pathological vascular permeability in diabetic retinopathy. J. Clin. Investig. 2016, 126, 3006–3022.
18. 18. Kruger, R. P.;Lee, J.;Li, W.;Guan, K. L. Mapping netrin receptor binding reveals domains of Unc5 regulating its tyrosine phosphorylation. J. Neurosci. 2004, 24, 10826–10834.
19. 19. Claro, V.;Ferro, A. Netrin-1: Focus on its role in cardiovascular physiology and atherosclerosis. JRSM Cardiovasc. Dis. 2020, 9, 2048004020959574.
20. 20. Castets, M.;Mehlen, P. Netrin-1 role in angiogenesis: To be or not to be a pro-angiogenic factor? Cell Cycle 2010, 9, 1466–1471.
21. 21. Ziegon, L., & Schlegel, M. Netrin-1: A modulator of macrophage driven acute and chronic inflammation. International Journal of Molecular Sciences,. 2021;23(1), 275.
22. 22. Kaya, S., Turhan, U., Dağ, I., Polat, İ. Association of maternal serum Netrin-1 and Netrin-4 levels with placenta accreta spectrum. European Review for Medical & Pharmacological Sciences,. 2023;27(10).
23. 23. Xia, X., Hu, Z., Wang, S., & Yin, K. Netrin-1: An emerging player in inflammatory diseases. Cytokine & Growth Factor Reviews,. 2022;64, 46–56.
24. 24. Schlegel, M.;Kohler, D.;Korner, A.;Granja, T.;Straub, A.;Giera, M.;et al. The neuroimmune guidance cue netrin-1 controls resolution programs and promotes liver regeneration. Hepatology 2016, 63, 1689–1705.
25. 25. Mirakaj, V.;Dalli, J.;Granja, T.;Rosenberger, P.;Serhan, C. N. Vagus nerve controls resolution and pro-resolving mediators of inflammation. J. Exp. Med. 2014, 211, 1037–1048.
26. 26. Azoulay E, Vincent JL, Angus DC, Arabi YM, Brochard L, Brett SJ, et al. Recovery after critical illness: putting the puzzle together-a consensus of 29. Crit Care. 2017;21:296.
27. 27. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock:2016. Crit Care Med. 2017;45:486–552.
28. 28. Hwang, S. Y., Kim, I. K., Jeong, D., Park, J. E., Lee, G. T., Yoo, J., et al. Prognostic Performance of Sequential Organ Failure Assessment, Acute Physiology and Chronic Health Evaluation III, and Simplified Acute Physiology Score II Scores in Patients with Suspected Infection According to Intensive Care Unit Type. Journal of Clinical Medicine,. 2023;12(19), 6402.
29. 29. Kramer, A. A., Zimmerman, J. E., Knaus, W. A. Severity of illness and predictive models in society of critical care medicine’s first 50 years: a tale of concord and conflict. Critical Care Medicine,. 2021;49(5), 728–740.
30. 30. van der Poll T, Shankar-Hari M, Wiersinga WJ. The immunology of sepsis. Immunity. 2021;54(11):2450–64.
31. 31. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862–74.
32. 32. Samudra, D., Santoso, S., Asmoro, A. A., Khotimah, H., Ansori, A. N., Sabdoningrum, E. K. The Effect of Escherichia coli on Pro-Inflammatory Mediators Level and Kidney and Liver Function of Sepsis in Rattus novergicus. Indian Journal of Forensic Medicine & Toxicology,. 2020;14(4).
33. 33. Liu, J., Du, J., Cheng, X., Zhang, X., Li, Y., Fu, X, et al. ). Effect of netrin-1 anti-inflammatory factor on acute lung injury in sepsis rats. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research,. 2019;25, 7928.
34. 34. Tu, Y., Wang, H., Sun, R., Ni, Y., Ma, L., Xv, F, et al. Urinary netrin-1 and KIM-1 as early biomarkers for septic acute kidney injury. Renal failure,. 2014;36(10), 1559–1563.