Relationship of potential biomarkers of interstitial cystitis/painful bladder syndrome

Abstract

BACKGROUND: Biomarker identification fulfills the need for simple, accurate, and non-invasive diagnostic methods for interstitial cystitis/painful bladder syndrome (IC/PBS). The simultaneous study of cytokines and growth factors is essential for understanding the role of biomarkers.

AIM: This work determines the concentration of interleukins (IL) 6 and 8, nerve growth factor (NGF), heparin-binding epidermal growth factor (HB-EGF), and their relationship in patients with IC/PBS.

MATERIALS AND METHODS: This study examined 126 female patients with IC/PBS, with a mean age of 46.7±14.0 years. The disease duration averaged 6.0±2.8 years. The control group consisted of 20 women without IC/PBS, with a mean age of 35.3±9.7 years. The level of IL-6 and IL-8 in blood serum and urine was determined by ELISA. The NGF and HB-EGF levels were determined by ELISA using the appropriate test kits. Statistical analysis was performed using SPSS software version 15.0. The Student’s t-test and Spearman’s correlation coefficient were calculated.

RESULTS: In patients with IC/PBS, blood levels of IL-6 and IL-8 exceeded the control indicator by 65.99% (t=4.62, p=0.000) and by 67.14% (t=2.81, p=0.006), respectively, the NGF level exceeded it by 8.82% (t=0.10, p=0.920), and the HB-EGF level decreased by 30.84% (t=0.62, p=0.537). In urine, the level of IL-6 in IC/PBS was increased by 52.94% (t=7.62, p=0.000), IL-8 level was increased by 57.53% (t=2.01, p=0.049), NGF was increased by 50.44% (t=2.06, p=0.043), and HB-EGF level was increased by 56.44% (t=2.01, p=0.049). Cytokines correlated with growth factors with weakly bound in blood and urine (p >0.05). A strong, direct relationship was registered between the urine levels of NGF and HB-EGF (r=+0.987, p <0.05).

CONCLUSIONS: Correlations between IL-6 and IL-8 with NGF and HB-EGF in urine indicate an increased risk of damage to the bladder epithelium. The increase in urinary HB-EGF is a response to a significant increase in urinary NGF and may be a bladder epithelial defense mechanism.

Keywords

interstitial cystitis / painful bladder syndrome / women / cytokines / growth factors / correlation / biomarkers

References

[1] Davis NF, Gnanappiragasam S, Thornhill JA. Interstitial cystitis/painful bladder syndrome: the influence of modern diagnostic criteria on epidemiology and on Internet search activity by the public. Transl Androl Urol. 2015;4(5):506–511. doi: 10.3978/j.issn.2223-4683.2015.06.08

[2] Davis N.F., Gnanappiragasam S., Thornhill J.A. Interstitial cystitis/painful bladder syndrome: the influence of modern diagnostic criteria on epidemiology and on Internet search activity by the public // Transl Androl Urol. 2015. Vol. 4, N 5. P. 506–511. doi: 10.3978/j.issn.2223-4683.2015.06.08

[3] Patnaik SS, Lagana AS, Vitale SG, et al. Etiology, pathophysiology and biomarkers of interstitial cystitis/painful bladder syndrome. Arch Gynecol Obstet. 2017;295(6):1341–1359. doi: 10.1007/s00404-017-4364-2

[4] Patnaik S.S., Lagana A.S., Vitale S.G., et al. Etiology, pathophysiology and biomarkers of interstitial cystitis/painful bladder syndrome // Arch Gynecol Obstet. 2017. Vol. 295, N 6. P. 1341–1359. doi: 10.1007/s00404-017-4364-2

[5] Kuz'min IV, Ignashov YA, Slesarevskaja MN, Al'-Shukri SK. Bladder pain syndrome in women: criteria for efficacy and predicting treatment outcomes. Experimental and Clinical Urology. 2020;2: 142–148. (In Russ). doi: 10.29188/2222-8543-2020-12-2-142-148

[6] Кузьмин И.В., Игнашов Ю.А., Слесаревская М.Н., Аль-Шукри С.Х. Синдром болезненного мочевого пузыря у женщин: критерии эффективности и прогнозирование результатов лечения // Экспериментальная и клиническая урология. 2020. № 2. С. 142–148. doi: 10.29188/2222-8543-2020-12-2-142-148

[7] Loran OB, Sinjakova LA, Mitrohin AA, et al. Modern view of the problem of interstitial cystitis. Medical advice. 2011;11-12:15–19. (In Russ).

[8] Лоран О.Б., Синякова Л.А., Митрохин А.А., et al. Современный взгляд на проблему интерстициального цистита // Медицинский совет. 2011. № 11–12. С. 15–19.

[9] Onopko VF, Kirilenko EA, Baranova EO, Golubeva VS. Interstitial cystitis or bladder pain syndrome: a modern perspective on the problem. Acta Biomedica Scientifica (East Siberian Biomedical Journal). 2016;1(1):65–69. (In Russ). doi: 10.12737/21489

[10] Онопко В.Ф., Кириленко Е.А., Баранова Е.О., Голубева В.С. Интерстициальный цистит или синдром болезненного мочевого пузыря: современный взгляд на проблему // Acta Biomedica Scientifica (Восточно-Сибирский биомедицинский журнал). 2016. №1 (1). С. 65–69. doi: 10.12737/21489

[11] Slesarevskaja MN, Ignashov YA, Kuz'min IV. Modern approaches to the diagnosis of painful bladder syndrome. Urological statements. 2017;7(2):25–30. (In Russ). doi: 10.17816/uroved7225-30.

[12] Слесаревская М.Н., Игнашов Ю.А., Кузьмин И.В. Современные подходы к диагностике синдрома болезненного мочевого пузыря. Урологические ведомости. 2017. Т. 7, № 2. С. 25–30. doi: 10.17816/uroved7225-30

[13] Zajcev AV, Sharov MN, Ibragimov RA, et al. Bladder pain syndrome/interstitial cystitis: modern view for diagnostic and treatment. Emergency doctor. 2018;8:16–26. (In Russ).

[14] Зайцев А.В., Шаров М.Н., Ибрагимов Р.А., et al. Синдром болезненного мочевого пузыря/интерстициальный цистит: современные подходы к диагностике и лечению // Врач скорой помощи. 2018. № 8. С. 16–26.

[15] Yoshimura N, Oguchi T, Yokoyama H, et al. Bladder afferent hyperexcitability in bladder pain syndrome/interstitial cystitis. Int J Urol. 2014;21(Suppl 1):18–25. doi: 10.1111/iju.12308

[16] Yoshimura N., Oguchi T., Yokoyama H., et al. Bladder afferent hyperexcitability in bladder pain syndrome/interstitial cystitis // Int J Urol. 2014. Vol. 21, N Suppl 1. P. 18–25. doi: 10.1111/iju.12308

[17] Magalhaes TF, Baracat EC, Doumouchtsis SK, Haddad JM. Biomarkers in the diagnosis and symptom assessment of patients with bladder pain syndrome: a systematic review. Int Urogynecol J. 2019;30(11):1785–1794. doi: 10.1007/s00192-019-04075-9

[18] Magalhaes T.F., Baracat E.C., Doumouchtsis S.K., Haddad J.M. Biomarkers in the diagnosis and symptom assessment of patients with bladder pain syndrome: a systematic review // Int Urogynecol J. 2019. Vol. 30, N 11. P. 1785–1794. doi: 10.1007/s00192-019-04075-9

[19] Liu HT, Kuo HC. Biomarkers for patients with interstitial cystitis/bladder pain syndrome. Urological Science. 2015;26(4):225–229. doi: 10.1016/j.urols.2015.02.002

[20] Liu H.T., Kuo H.C. Biomarkers for patients with interstitial cystitis/bladder pain syndrome // Urological Science. 2015. Vol. 26, N 4. P. 225–229. doi: 10.1016/j.urols.2015.02.002

[21] Kim SR, Moon YJ, Kim SK, Bai SW. NGF and HB-EGF: potential biomarkers that reflect the effects of fesoterodine in patients with overactive bladder syndrome. Yonsei Med J. 2015;56(1):204–211. doi: 10.3349/ymj.2015.56.1.204

[22] Kim S.R., Moon Y.J., Kim S.K., Bai S.W. NGF and HB-EGF: potential biomarkers that reflect the effects of fesoterodine in patients with overactive bladder syndrome // Yonsei Med J. 2015. Vol. 56, N 1. P. 204–211. doi: 10.3349/ymj.2015.56.1.204

[23] Kim SW, Im YJ, Choi HC, et al. Urinary nerve growth factor correlates with the severity of urgency and pain. Int Urogynecol J. 2014;25(11):1561–1567. doi: 10.1007/s00192-014-2424-8

[24] Kim S.W., Im Y.J., Choi H.C., et al. Urinary nerve growth factor correlates with the severity of urgency and pain // Int Urogynecol J. 2014. Vol. 25, N 11. P. 1561–1567. doi: 10.1007/s00192-014-2424-8

[25] Kim J, Kim WT, Kim WJ. Advances in urinary biomarker discovery in urological research. Investig Clin Urol. 2020;61(Suppl 1):S8–S22. doi: 10.4111/icu.2020.61.S1.S8

[26] Kim J., Kim W.T., Kim W.J. Advances in urinary biomarker discovery in urological research // Investig Clin Urol. 2020. Vol. 61, N Suppl 1. P. S8–S22. doi: 10.4111/icu.2020.61.S1.S8

[27] Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol. 1988;140(1):203–206. doi: 10.1016/s0022-5347(17)41529-1

[28] Gillenwater J.Y., Wein A.J. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28–29, 1987 // J Urol. 1988. Vol. 140, N 1. P. 203–206. doi: 10.1016/s0022-5347(17)41529-1

[29] World Medical A. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–2194. doi: 10.1001/jama.2013.281053

[30] World Medical A. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects // JAMA. 2013. Vol. 310, N 20. P. 2191–2194. doi: 10.1001/jama.2013.281053

[31] Corcoran AT, Yoshimura N, Tyagi V, et al. Mapping the cytokine profile of painful bladder syndrome/interstitial cystitis in human bladder and urine specimens. World J Urol. 2013;31(1):241–246. doi: 10.1007/s00345-012-0852-y

[32] Corcoran A.T., Yoshimura N., Tyagi V., et al. Mapping the cytokine profile of painful bladder syndrome/interstitial cystitis in human bladder and urine specimens // World J Urol. 2013. Vol. 31, N 1. P. 241–246. doi: 10.1007/s00345-012-0852-y

[33] Tonyali S, Ates D, Akbiyik F, et al. Urine nerve growth factor (NGF) level, bladder nerve staining and symptom/problem scores in patients with interstitial cystitis. Adv Clin Exp Med. 2018;27(2):159–163. doi: 10.17219/acem/69231

[34] Tonyali S., Ates D., Akbiyik F., et al. Urine nerve growth factor (NGF) level, bladder nerve staining and symptom/problem scores in patients with interstitial cystitis // Adv Clin Exp Med. 2018. Vol. 27, N 2. P. 159–163. doi: 10.17219/acem/69231

[35] Don ES, Tarasov AV, Jepshtejn OI, Tarasov SA. Biomarkers in medicine: search, selection, study and validation. Clinical laboratory diagnostics. 2017;62(1):52–59. (In Russ). doi: 10.18821/0869-2084-2017-62-1-52-59

[36] Дон Е.С., Тарасов А.В., Эпштейн О.И., Тарасов С.А. Биомаркеры в медицине: поиск, выбор, изучение и валидация // Клиническая лабораторная диагностика. 2017. Т. 62. № 1. С. 52–59. doi: 10.18821/0869-2084-2017-62-1-52-59

[37] Liu HT, Kuo HC. Increased urine and serum nerve growth factor levels in interstitial cystitis suggest chronic inflammation is involved in the pathogenesis of disease. PLoS One. 2012;7(9):e44687. doi: 10.1371/journal.pone.0044687

[38] Liu H.T., Kuo H.C. Increased urine and serum nerve growth factor levels in interstitial cystitis suggest chronic inflammation is involved in the pathogenesis of disease // PLoS One. 2012. Vol. 7, N 9. P. e44687. doi: 10.1371/journal.pone.0044687

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