Аннотация
Медико-социальная значимость врожденных пороков развития мочевыделительной системы (ВПР МВС) у детей очень высока, поскольку они в этиологии хронической болезни почек (ХБП) у детей составляют 48-59% случаев. Широко используемые в клинической практике маркеры ренальной дисфункции – протеинурия, сывороточный креатинин и скорость клубочковой фильтрации (СКФ) позволяют определять поражение почек на поздней стадии болезни, когда процесс поражения почек
уже не обратим. В связи с этим в последнее десятилетие внимание исследователей приковано к поиску малоинвазивных
ранних методов диагностики повреждения почек. Определение содержания биомаркеров в биологических жидкостях организма позволяет зачастую проводить доклиническую или раннюю функционально-морфологическую диагностику ренальной
патологии, определять ее характер и локализацию, устанавливать стадию процесса, оценивать выраженность воспаления
и фибротических изменений почечной паренхимы, что, несомненно, будет способствовать раннему началу лечения и улучшению прогноза заболеваний.
К маркерам, представляющим наибольший интерес при патологии почек, относятся: β2-микроглобулин, микроальбуминурия, липокалин, ассоциированный с желатиназой нейтрофилов (NGAL), цистатин С, молекула почечного повреждения-1
(KIM-1), фактор некроза опухоли-α (ФНО-α), моноцитарный хемоаттрактантный белок-1 (MCP-1), интерлейкин-1β (ИЛ-1β), трансформирующий фактор роста-β (TGF-β), матриксные металлопротеиназы (MMP), эпидермальный фактор роста
(EGF), васкулоэндотелиальный фактор роста (VEGF). В данном обзоре обобщены данные об информативности тубулярных, гломерулярных биомаркеров, продуктов обмена внеклеточного матрикса и цитокинов при повреждении почек у детей
на фоне ВПР МВС, коротко рассмотрены данные крупных исследований последних лет в этой области. Поиск литературы
при написании настоящего обзора осуществляли по базам данных: РИНЦ, CyberLeninka, Scopus, Web of Science, PubMed за
период с 2011 по 2023 год.
Annotation
The medical and social significance of congenital anomalies of the kidney and urinary tract (CAKUT) in children is very high, since
they account for 48-59% of cases in the etiology of chronic kidney disease (CKD) in children. Widely used in clinical practice, markers
of renal dysfunction — proteinuria, serum creatinine and glomerular filtration rate (GFR) — make it possible to determine kidney
damage at a late stage of the disease, when the process of kidney damage is no longer reversible. In this regard, in the last decade,
the attention of researchers has been riveted to the search for minimally invasive early methods for diagnosing kidney damage. In this
regard, the use of determining the content of biomarkers in biological fluids of the body allows for early diagnosis of renal pathology,
determining its nature, as well as clarifying the localization of the pathology, establishing the stage of the process, assessing the
severity of inflammation and fibrotic changes in the renal parenchyma, which will undoubtedly contribute to the early start of treatment
and improvement disease prognosis.
The markers of greatest interest in renal pathology include: β2-microglobulin, microalbumins, neutrophil gelatinase-associated
lipocalin (NGAL), cystatin C, kidney injury molecule-1 (KIM-1), tumor necrosis factor-α (TNF -α), monocyte chemoattractant
protein-1 (MCP-1), interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), type IV collagen, matrix metalloproteinases
(MMPs), epidermal growth factor (EGF), vasculoendothelial growth factor (VEGF). This review summarizes data on the diagnostic
and prognostic significance of biomarkers of kidney damage in congenital malformations of the urinary system (CMVS) in children,
and briefly reviews the data from large recent studies in this area. When writing this review, the literature search was carried out using
the following databases: RSCI, CyberLeninka, Scopus, Web of Science, PubMed, MedLine, The Cochrane Library, EMBASE, Global
Health, for the period from 2011 to 2023.
Key words: congenital malformations of the urinary system; children; early diagnosis; biomarkers; review
Список литературы
1. Chevalier R.L. CAKUT: A pediatric and evolutionary perspective on the leading cause of CKD in childhood. Pediatr. Rep. 2023; 15(1):143- 53. DOI: 10.3390/pediatric15010012
2. Kutyrlo I., Savenkova N. CAKUT–syndrome in children. Nefrologiya. 2017; 21(3):18-24. DOI: 10.24884/1561-6274-2017-3-18-24. (in Russian)
3. Yatsyk S.P.,MavlyanovF.Sh.,MavlyanovSh.Kh. Immunohistopathological characteristics of obstructive uropathy in children: review.Uzbek journal of case reports. 2022; 2(2):29–32. DOI: 10.55620/ujcr.2.2.2022.6.
4. Patel V.B., Preedy V.R. Biomarkers in kidney disease. Dordrecht: Springer Netherlands; 2016. DOI: 10.1007/978-94-007-7699-9.
5. Morozov D.A., Morrison V.V., Morozova O.L., Lakomova D.Y. Pathogenic basis and modern prospects in early diagnostics of
nephrosclerosis in children with vesicoureteral reflux. Saratovskiy nauchno-meditsinskiy zhurnal. 2011;7(1):151-7. (in Russian)
6. Madsen M.G. Urinary biomarkers in hydronephrosis. Dan. Med. J.2013; 60:B4582.
7. Bastos F.M., Leal C.R.V., Vaz de Castro P.A.S., Silva Filha R.D., Simхes E Silva A.C. Tubular and glomerular biomarkers of renal tissue
function in the urine of fetuses with posterior urethral valves. J. Pediatr Urol. 2022; 18(3):368.e1-368.e9. DOI: 10.1016/j.jpurol.2022.03.019.8.
8. Sergeeva S.V. Diagnosis and treatment of infants with severe hydronephrosis (literature review). Rossiyskiy vestnik detskoy khirurgii,
anesteziologii i reanimatologii. 2020; 10(3):339-52. DOI: 10.17816/ psaic681. (in Russian)
9. Stankovic A. Promising biomarkers in pediatric chronic kidney disease through the kaleidoscope of CAKUT background complexity. Pediatr. Nephrol. 2021; 36:1321–5. DOI: 10.1007/s00467-020-04877-w.
10. Bobkova I.N., Chebotareva N.V., Kozlovskaya L.V., Neprintseva N.V. Кidney self-defense system: modern view on the mechanisms defining
a current and an outcome of glomerulonephritis review. Nefrologiya i dializ. 2013. 15(3):174-83. (in Russian)
11. Kashtalyan O.A., Ushakova L.Yu. Cytokines as universal regulation system. Meditsinskie novosti. 2017; 9:3-7. (in Russian)
12. Morozova O.L., Morozov D.A., Budnik I.A., Maltseva L.D., Melnikova Yu.A. Macrophages — a new target for anti-fibrotic therapy in children
with obstructive uropathy. Pediatriya. Zhurnal im. G.N. Speranskogo. 2015; 94(3):182–7. (in Russian)
13. Goremykin I.V., Krasnova E.I., Deryugina L.A., Zakharova N.B. Assessment of the activity of chronic obstructive pyelonephritis
in children with congenital megaureter with using biomarkers of inflammation, angiogenesis and fibrogenesis. Byulleten` meditsivskikh
internet-konferentsiy. 2014; 4(1):54-7. (in Russian)
14. Bartoli F., Pastore V., Calи I. Prospective Study on Several Urinary Biomarkers as Indicators of Renal Damage in Children with CAKUT.
Eur. J. Pediatr. Surg. 2019; 29(02):215-22. DOI: 10.1055/s-0038- 1646960.
15. Maslyakova G.N., Rossolovskiy A.N., Napsheva A.M. Epithelialmesenchymal transformation as a factor in the progression of chronic kidney disease. Byulleten` meditsivskikh internet-konferentsiy. 2014;4(1): 81-3. (in Russian)
16. Lopez-Giacoman S., Madero M. Biomarkers in chronic kidney disease, from kidney function to kidney damage. World J. Nephrol. 2015; 4:57-73.
17. Simхes e Silva A.C., Valйrio F.C., Vasconcelos M.A., Miranda D.M., Oliveira E.A. Interactions between cytokines, congenital anomalies
of kidney and urinary tract and chronic kidney disease. Clin. Dev. Immunol. 2013; 2013:597920. DOI: 10.1155/2013/597920.18.
18. Uwaezuoke S.N., Ayuk A.C., Muoneke V.U., Mbanefo N.R. Chronic kidney disease in children: Using novel biomarkers as predictors of
disease. Saudi J. Kidney Dis. Transplant. 2018; 29:775-84.
19. Lousa I., Reis F., Beirгo I., Alves, R., Belo L., Santos-Silva A. New Potential Biomarkers for Chronic Kidney Disease Management-A
Review of the Literature. Int. J. Mol. Sci. 2021; 22: 43. DOI: 10.3390/ ijms22010043.
20. Morohashi T., Wada N., Odaira S., Shimizu S., Takahashi S. β2- microglobulin measurement with dried urine spots for congenital
anomalies of the kidney and urinary tract screening in 3-year-old children. Pediatr Int. 2022; 64(1):e15077. DOI: 10.1111/ped.15077.
21. Radhakrishna V., Kumaravel S., Priyamvada P.S., Hanumanthappa N. Clinico-biochemical profile of children with congenital anomalies
of the kidney and urinary tract: a cross-sectional study. Kidney Dis. (Basel). 2019; 5(1):51-7. DOI: 10.1159/000493683.
22. Popykhova E.B., Ivanov A.N., Stepanova T.V., Lagutina D.D. Diabetic nephropathy – possibilities of early laboratory diagnostics and course
prediction (review of literature). Klinicheskaya Laboratornaya Diagnostika. 2021; 66 (10): 593-602. DOI: 10.51620/0869-2084-2021-66-10-593-602. (in Russian)
23. Jančič S.G., Močnik M., Marčun Varda N. Glomerular Filtration Rate Assessment in Children. Children (Basel). 2022; 9(12):1995. DOI: 10.3390/children9121995.
24. Anand S., Bajpai M., Khanna T., Kumar A. Urinary biomarkers as pointof-care tests for predicting progressive deterioration of kidney function
in congenital anomalies of kidney and urinary tract: trefoil family factors (TFFs) as the emerging biomarkers. Pediatric Nephrology (Berlin, Germany). 2021; 36(6):1465-72. DOI: 10.1007/s00467-020-04841-8.
25. Vel`kov V.V. Cystatin C and NGAL — the Markers of Preclinical Renal Dysfuction and Subclinical Acute Kidney Injury. Laboratornaya sluzhba. 2015; 2:38-43. DOI: 10.17116/labs20154238-43. (in Russian)
26. Gavrilovici C., Dusa C.P., Iliescu Halitchi C., Lupu V.V. The role of urinary NGAL in the management of primary vesicoureteral reflux
in children. Int. J. Mol. Sci. 2023; 24(9):7904. DOI: 10.3390/ ijms24097904.
27. Wasilewska A., Taranta-Janusz K., Dȩbek W., Zoch-Zwierz W., Kuroczycka-Saniutycz E. KIM-1 and NGAL: new markers of obstructive nephropathy. Pediatr. Nephrol. 2011; 26(4):579–86.
28. Greenberg J.H., Kakajiwala A., Parikh C.R., Furth S. Emerging biomarkers of chronic kidney disease in children. Pediatr. Nephrol. 2018; 33(6):925-33. DOI: 10.1007/s00467-017-3701-9.
29. Dцnmez O., Korkmaz H.A., Ediz B. Comparison of serum cystatin C and creatinine levels in determining glomerular filtration rate in
children with stage I to III chronic renal disease. Ren. Fail. 2015; 37(5): 784-90.
30. Abboud O., Adler S., Bertram K. KDIGO 2012 clinical practice guideline for the evaluation and managementof chronic kidney disease. Kidney Int. Suppl. 2013; 3(1):140-50.
31. Karmakova Т.А., Sergeeva N.S., Kanukoev К.Yu., Alekseev B.Ya., Kaprin А.D. Kidney injury molecule-1 (KIM-1): a multifunctional
glycoprotein and biological marker (review). Sovremennye tekhnologii v meditsine. 2021; 13(3): 64–80. DOI: 10.17691/ stm2021.13.3.08. (in Russian)
32. Andrianova N.V., Buyan M.I., Zorova L.D., Pevzner I.B., Popkov V.A., Babenko V.A. et al. Kidney cells regeneration: dedifferentiation of
tubular epithelium, resident stem cells and possible niches for renal progenitors. Int. J. Mol. Sci. 2019; 20(24): E6326. DOI: 10.3390/ijms20246326.
33. Karakus S., Oktar T., Kucukgergin C., Kalelioglu I., Seckin S., Atar A. et al. Urinary IL-10, MCP-1, NGAL, Cystatin C, and KIM-1 levels in
prenatally diagnosed unilateral hydronephrosis: the search for an ideal biomarker. Urology. 2016; 87:185-92.
34. Noyan A., Parmaksiz G., Dursun H., Ezer S.S., Anarat R., Cengiz N. Urinary NGAL, KIM-1 and L-FABP concentrations in antenatal hydronephrosis. J. Pediatr. Urol. 2015; 11:249.e1-6.
35. Paraboschi I., Mantica G., Dalton N.R., Turner C., Garriboli M. Urinary biomarkers in pelvic-ureteric junction obstruction: a systematic
review. Transl. Androl. Urol. 2020; 9(2):722-42. DOI: 10.21037/ tau.2020.01.01.
36. Magalhгes P., Schanstra J.P., Carrick E., Mischak H., Zьrbig P. Urinary biomarkers for renal tract malformations. Expert. Rev. Proteomics.
2016; 13(12): 1121–9.
37. Bobkova I.N., Chebotareva N.V., Kozlovskaya L.V., Varshavsky V.A., Golitsina E.P. Determination of urinary excretion of monocyte
chemotactic protein-1 (MCP-1) and transforming growth factor-β1 (TGF-β1) is an invasive method of assessment of tubulointerstitial
fibrosis with chronic glomerulonephritis. Nefrologiya. 2006; 10(4):49-55. DOI: 10.24884/1561-6274-2006-10-4-49-55. (in Russian)
38. Simхes e Silva A.C., Pereira A.B., Teixeira M.M., Teixeira A. L. Chemokines as Potential Markers in Pediatric Renal Diseases. Disease
Markers. 2014; 2014. Article ID 278715: 9. DOI: 10.1155/2014/278715.
39. Sandokji I., Greenberg J.H. Plasma and urine biomarkers of CKD: a review of findings in the CKiD study. Semin. Nephrol. 2021; 41(5):416-
26. DOI: 10.1016/j.semnephrol.2021.09.003.
40. Gu Y.-Y., Liu X.-S., Huang X.-R., Yu X.-Q., Lan H.-Y. Diverse Role of TGF-β in kidney disease. Front. Cell Dev. Biol. 2020; 8:123. DOI: 10.3389/fcell.2020.00123.
41. Zaikova N.M., Dlin V.V., Sinitsyna L.V., Eremeeva A.V. Markers of collagenopathy and sclerosis in the diagnosis of the progression of
reflux nephropathy in children. Nefrologiya. 2018; 22 (3): 33-42. DOI: 10.24884/1561-6274-2018-22-3-33-42. (in Russian)
42. Ma T.T., Meng X.M. TGF-β/Smad and Renal Fibrosis. Adv. Exp. Med. Biol. 2019; 1165:347-64. DOI: 10.1007/978-981-13-8871-2_16.
43. Rнos-Silva M., Huertaet M., Mendoza-Cano O. Urinary epidermal growth factor in kidney disease: a systematic review. Nefrologia. 2023; 43(4):413-426. DOI:10.1016/j.nefro.2022.10.003.
44. Musial K, Zwolinska D. Matrix metalloproteinases (MMP-2,9) and their tissue inhibitors (TIMP-1,2) as novel markers of stress response and atherogenesis in children with chronic kidney disease (CKD) on conservative treatment. Cell Stress Chaperones. 2011; 16:97-103.
45. Morozova O.L., Morozov D.A., Lakomova D.Y. Reflux nephropathy in children: early diagnosis and monitoring. Urologiya. 2017; (4):107–12. DOI: 10.18565/urol.2017.4.107-112. (in Russian)
46. Bates C., Ho J., Sims-Lucas S., Reidy K. Pre-natal Development of the Kidneys and Urinary Tract. In: Emma F., Goldstein S., Bagga A.,
Bates C.M., Shroff R. et al. Pediatric Nephrology. Heidelberg, Springer Berlin; 2021. DOI: 10.1007/978-3-642-27843-3_1-2.
47. Zaikova N.M., Dlin V.V. Diagnosis of reflux nephropathy in young children. Praktika pediatra. 2021; 2:54-9. (in Russian)
48. Zhao M., Wang L., Wang M. Targeting fibrosis: mechanisms and clinical trials. Sig Transduct Target Ther. 2022; 7:206. DOI: 10.1038/ s41392-022-01070-3.
49. Morozov D.A., Krasnova E.I., Deryugina L.A., Zakharova N.B., Il’icheva Yu.A. The diagnostic value of biomarkers of
inflammation, angiogenesis and fibrogenesis to assess the severity of urodynamic obstruction in children with congenital megaureter.
Saratovskiy nauchno-meditsinskiy zhurnal. 2012; 8(4):996–1001. (in Russian)
50. Lakomova D.Yu. Index of early renal damage in children with vesicoureteral reflux. Saratovskiy nauchno-meditsinskiy zhurnal. 2012;8(2):318–24. (in Russian)