Наследственный нефротический синдром у детей: особенности клинического фенотипа и генотипа, патогенеза, почечного прогноза изолированных и синдромальных форм

В обзоре литературы представлены клинический фенотип и генотип, патогенез, почечный прогноз наследственного нефротического синдрома изолированной и синдромальной с экстраренальной манифестацией форм у детей. Освещены клинико-генетические особенности наследственного стероидчувствительного и стероидрезистентного нефротического синдрома у детей, обусловленного мутациями генов, кодирующих основные компоненты щелевой диафрагмы, гломерулярной базальной мембраны, структурные и функциональные белки подоцита. Данные литературы демонстрируют неблагоприятный почечный прогноз у детей с наследственным стероидрезистентным нефротическим синдромом с фокально-сегментарным гломерулосклерозом и диффузным мезангиальным склерозом, с клинической манифестацией в возрасте 0–17 лет, прогрессированием в терминальную стадию почечной недостаточности в возрасте 0,4–18 лет. Замещающая функцию почек терапия с применением диализа и трансплантации почки повышает выживаемость и качество жизни детей с наследственным нефротическим синдромом.

1. OMIM: An online catalog of human genes and genetic disorders [Electronic resource]. Electronic data, Novemder 9, 2022. https://www.omim.org (Ссылка активирована на 01.11.2022.)

2. Gbadegesin R., Saleem М., Lipska-Ziętkiewicz B.S., Boyer O. Genetic Basis of Nephrotic Syndrome. Pediatric Nephrology Eighth Edition. Editors F. Emma, S.L. Goldstein, A. Bagga, C.M. Bates, R. Shroff. Springer Naturee Switzerland, 2022; 10: 261–284. DOI: 10.1007/978–3–030–52719–8_90

3. Jalanko H., Jahnukainen T., Hui Ng Kar. Congenital Nephrotic Syndrome. Editors F. Emma, S.L. Goldstein, A. Bagga, C.M. Bates, R. Shroff. Springer Naturee Switzerland, 2022; 11: 285– 300. DOI: 10.1007/978–3–030–52719–8_78

4. Boyer O., Gbadegesin R., Aoife Water A. Clinical Aspects of Genetic Forms of Nephrotic Syndrome. Editors F. Emma, S.L. Goldstein, Bagga A., Bates C.M., Shroff R. Springer Naturee Switzerland, 2022; 12: 301–326

5. Boyer О., Tory K., Machuca E., Antignac С. Idiopathic Nephrotic Syndrome in Children: Genetic Aspects. Editors E.D. Avner, W.E. Harmon, P. Niaudet, N. Yoshikawa, F. Emma, S.L. Goldstein. Springer, 2016; 1: 805–837. DOI: 10.1007/s00467–007–0633–9

6. Weber S. Hereditary Nephrotic Syndrome. Pediatric Kidney Disease. Editors D.F. Geary, F. Schaefer. Springer-Verlag Berlin Heidelberg 2016; 17. DOI: 10.1007/978–3–662–52972–0_17

7. Jalanko H., Holmberg C. Congenital Nephrotic Syndrome. Pediatric Nephrology. Editors E.D. Avner, W.E. Harmon, P. Niaudet, N. Yoshikawa, F. Emma, S.L. Goldstein. Springer, 2016; 1: 753–769. DOI: 10.1007/s00467–007–0633–9

8. Preston R., Stuart H.M., Lennon R. Genetic testing in steroid –resistant nephrotic syndrome: why, who, when and how? Pediatr Nephrol 2019; 34(2): 195–210. DOI: 10.1007/ s00467–017–3838–6

9. Kestilla M., Lenkkeri U., Mannikko M. Positionally cloned gene for a novel glomerular protein nephrin-is mutated in congenital nephrotic syndrome. Mol Cell 1998; 1(4): 575– 582. DOI: 10.1016/s1097–2765(00)80057-x

10. Hölttä T., Bonthuis M., Van Stralen K.J., Bjerre A., Topaloglu R., Ozaltin F. et al. Timing of renal replacement therapy does not infl ence survival and growth in children with congenital nephrotic syndrome caused by mutations in NPHS1: data from the ESPN/ERA-EDTA Registry. Pediatr Nephrol 2016; 31(12): 2317–2325. DOI: 10.1007/s00467–016–3517-z

11. Hamasaki Y., Muramatsu M., Hamada R., Ishikura K., Hataya H. Long-term outcome of congenital nephrotic syndrome after kidney transplantation in Japan. Clin Exp Nephrol 2018; 22(3): 719–726. DOI: 10.1007/s10157–017–1508–4

12. Holmberg C., Jalanko H. Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation. Pediatr Nephrol 2014; 29: 2309–2317. DOI: 10.1007/s00467–014–2781-z

13. Rood I.M., Deegens J.K.J., Lugtenberg D., Bongers E.M., Wetzels J.F.M. Nephrotic Syndrome with Mutations in NPHS2: The Role of R229Q and Implications for Genetic Counseling. Am J Kidney Dis 2019; 73(3): 400–403. DOI: 10.1053/j.ajkd.2018.06.03

14. Boyer O., Benoit G., Gribouval O. Mutational analysis the PLCE1 gene in steroid resistant nephrotic syndrome. J Med Genet 2010; 47(7): 445–452. DOI: 10.1136/jmg.2009.076166

15. Ozaltin F., Ibsirlioglu T., Taskiran E.Z., Baydar D.E., Kaymaz F., Buyukcelik M. et al. Disruption of PTPRO causes childhood-onset nephrotic syndrome. Am J Hum Genet 2011; 89: 139–147. DOI: 10.1016/j.ajhg.2011.05.026

16. Ozaltin F., Li B., Rauhauser A., An S.W., Soylemezoglu O., Gonul I.I. et al. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol 2013; 24: 377–384. DOI: 10.1681/ASN.2012090903

17. Gupta I.R., Baldwin C., Auguste D., Ha K.C.H., El-Andalousi J., Fahiminiya S. et al. ARHGDIA: a novel gene implicated in nephrotic syndrome. J Med Genet 2013; 50: 330–338. DOI: 10.1136/JMEDGENET-2012–101442

18. Ashraf S., Gee H.Y., Woerner S., Xie L.X., Vega-Warner V., Lovric S. et al. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 2013; 123(12): 5179–5189. DOI: 10.1172/JCI69000

19. Wang F., Zhang Y., Mao J., Yu Z., Yi Z., YuL. et al. Spectrum of mutations in Chinese children with steroidresistant nephrotic syndrome. Pediatr Nephrol 2017; 32: 1181–1192. DOI: 10.1007/s00467–017–3590-y

20. Atmaca M., Gulhan B., Korkmaz E., Inozu M., Soylemezoglu O., Candan C. et al. Follow-up results of patients with ADCK4 mutations and the efficacy of CoQ10 treatment. Pediatr Nephrol 2017; 32: 1181–1192. DOI: 10.1007/s00467–017–3634–3

21. Gee H. Y, Ashraf S., Wan X., Vega-Warner V., Esteve-Rudd J, Lovric S. et al. Mutations in EMP2 cause childhood-onset nephrotic syndrome. Am J Hum Genet 2014; 94: 884–890. DOI: 10.1016/j.ajhg.2014.04.010

22. Dorval G., Gribouval O., Martinez-Barquero V., Machuka E., Tete M.-J. et al. Clinical and genetic heterogeneity in familial steroid-sensitive nephritic syndrome. Pediatr Nephrol 2018; 33(3): 473–483. DOI: 10.1007/s00467–017–3819–9

23. Karp A.M., Gbadegesin R. Genetics of childhood steroid-sensitive nephritic syndrome. Pediatr Nephrol 2017; 32(9): 1481–1488. DOI: 10.1007/s00467–016–3456–8

24. Gee H.Y., Zhang F., Ashraf S., Kohl S., Sadowski C., Vega – Warner V. et al. KANK deficiency leads to podocyte disfunction an Nephrotic syndrome. J Clin Invest 2015; 125: 2375– 2384. DOI: 10.1172/JCI79504

25. Dorval G., Kuzmuk V., Gribouval O., Welsh G.I., Bierzynska A., Schmitt A. et al. TBC1D8B loss-of-function mutations lead to X-linked nephrotic syndrome via defective trafficking pathways. Am J Hum Genet 2019; 104(2): 348–355. DOI: 10.1016/j.ajhg.2018.12.016

26. Ebarasi L., Ashraf S., Bierzynska A., Gee H.Y., McCarthy H.J., Lovric S. et al. Defects of CRB2 cause steroid-resistant nephrotic syndrome. Am J Hum Genet 2015; 96(1): 153–161. DOI: 10.1016/j.ajhg.2014.11.014

27. Vivante A., Chacham O.S., Shril S., Schreiber R., Mane S.M., Pode-Shakked B. et al. Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children. Pediatr Nephrol 2019; 34(9): 1607–1613. DOI: 10.1007/s00467-019-042560

28. Harita Y., Kitanaka S., Isojima T., Ashida A., Hattori M. Spectrum of LMX1B mutations: from Nail-Patella syndrome to isolated nephropathy. Pediatr Nephrol 2017; 32(10): 1845– 1850. DOI: 10.1007/s00467–016–3462-x

29. Andeen N.K., Schleit J., Blosser C.D., Dorschner M.O., Hisama F.M., Smith K.D. LMX1B-associated nephropathy with type III Collagen Deposition in the Glomerular and Tubular Basement Membranes. Am J Kidney Dis 2018; 72(2): 296– 301. DOI: 10.1053/j.ajkd.2017.09.023

30. Gee H.Y., Sadovski C.E., Aggarwal P.K., Porath J.D., Yakulov T.A., Schuele M. et al. FAT1 mutations cause a glomerulotubular nephropaty. Nat Commun 2016; 7: 10822. DOI: 10.1038/ncomms10822

31. Fabretti F., Tschernoster N., Erger F., Hedergott A., Anja K., Buescher A.K. et al. Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling. Kidney Int Rep 2021; 6(5): 1368–1378. DOI: 10.1016/j.ekir.2021.01.023

32. Janecke A.R., Xu R., Steichen-Gersdorf E., Waldegger S., Entenmann A., Giner T. et al. Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications. Hum Mutat 2017; 38(4): 365–372. DOI: 10.1002/humu.23192

33. Lovric S., Goncalves S., Gee H.Y., Oskouian B., Srinivas H., Choi W.-I. et al. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency J Clin Invest 2017; 127: 912–928. DOI: 10.1172/JCI89626

34. Prasad R., Hadjidemetriou I., Maharaj A., Meimaridou E., Buonocore F., Salee, M. et al. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Inves 2017; 127: 942–953. DOI: 10.1172/JCI90171

35. Arima M., Tsukamoto S., Akiyama R., Nishiyama K., Kohno R.I., Takashi Tachibana T. et al. Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ß2 gene. J AAPOS 2018; 22(5): 401–403. DOI: 10.1016/j.jaapos.2018.03.016

36. Zhang H., Cui J., Wang F., Xiao H., Ding J., Yao Y. LAMB2 mutation with different phenotypes in China. Clin Nephrol 2017; 87(1): 33–38. DOI: 10.5414/CN108979

37. Nishi K., Inoguchi T., Kamei K., Hamada R., Hataya H., Ogura M. et al. Detailed clinical manifestations at onset and prognosis of neonatal-onset Denys-Drash syndrome and congenital nephrotic syndrome of the Finnish type. Clin Exp Nephrol 2019. DOI: 10.1007/s10157–019–01732–7

38. Коша П., Харамба Ж., Леклерк Ф.-Л. Рекуррентные заболевания в педиатрической нефрологии. Нефрология.2013;17(3):9–16.

39. Colin E., Huynh Cong E., Mollet G., Guichet A., Gribouval O., Arrondel C. et al. Loss-of-function mutations in WDR 73 are responsible for microcephaly and steroid resistant nephrotic syndrome: Galloway-Mowat syndrome. Am J Hum Genet 2014; 95(6): 637–648. DOI: 10.1016/j.ajhg.2014.10.011

40. Hyun H.S., Kim S.H., Park E., Cho M.H., Kang H.G. Lee H.S. et al. A familial case of GallowayMowat syndrome due to a novel TP53RK mutation: a case report. BMC Med Genet 2018; 19(1): 131. DOI: 10.1186/s12881–018–0649-y

41. Ghoumid J., Petit F., Holder-Espinasse M., Jourdain A.S., Guerra J., Dieux-Coeslier A. et al. Nail-Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity. Eur J Hum Genet 2016; 24(1): 44–50. DOI: 10.1038/ejhg.2015.77

42. Harita Y., Urae S., Akashio R., Isojima T., Miura K., Yamada T., Yamamoto K.. Clinical and genetic characterization of nephropathy in patients with Nail-Patella syndrome. Eur J Hum Genet 2020; 28(10): 1414–1421. DOI: 10.1038/ s41431–020–0655–3

43. Sarin S., Javidan A., Boivin F., Alexopoulou I., Lukic D., Svajger B. et al. Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis. Histochem Cytochem 2015; 63(1): 32–44. DOI: 10.1369/0022155414558335

44. Castellano-Martinez A., Acuñas-Soto S., Varga-Martinez R., Rodriguez-Gonzalez M., Mora-Lopez F., Iriarte-Gahete M., Roldan-Cano V. Different Phenotypes of Schimke Immuno-Osseous Dysplasia (SIOD) in Two Sisters with the Same Mutation in the SMARCAL1 Gene. Endocr Metab Immune Disord Drug Targets 2022; 22(8): 888–894. DOI: 10.2174/1871530322666220223154028

45. Heeringa S.F., Chernin G., Chaki M., Zhou W., Sloan A.J., Ji Z. et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 2011; 121: 2013–2024. DOI: 10.1172/JCI45693

46. Park E., Ahn Y. H., Kang H. G., Yoo K. H., Won N. H., Lee K.B. et al. COQ6 mutations in children with steroid-resistant focal segmental glomerulosclerosis and sensorineural hearing loss. Am J Kidney Dis 2017; 70: 139–144. DOI: 10.1053/j.ajkd.2016.10.040

47. Yavuz S., Altunoglu U., Turkkan O. N., Sevinc B, Gokcay G., Gunes D. K. et al. Primary coenzyme Q10 deficiency –6(COQ10D6): two siblings with variable expressivity of the renal phenotype. Eur J Med Genet 2020; 63: 103621. DOI: 10.1016/j.ejmg.2019.01.011

48. Савенкова Н.Д., Левиашвили Ж.Г., Андреева Э.Ф., Семенова О.А., Папаян К.А. Наследственные болезни почек у детей. Руководство для врачей под ред. Н.Д. Савенковой. Ст-Петербург: Левша, 2020; 299–309.

49. Длин В.В., Морозов С.Л. Персонализированная терапия в детской нефрологии; проблемы и перспективы. Рос вестн перинатол педиатр 2021; 66(2): 6–12. DOI: 10.21508/1027–4065–2021–66–2–6–12

50. Приходина Л.C., Папиж С.В., Столяревич Е.С., Повилайтите П.Е., Щаталов П.А. Инфантильный нефротический синдром: клинико-морфологическая характеристика, генетическая гетерогенность, исходы. Опыт одного центра. Нефрология и диализ 2019; 21(2): 234–242. DOI: 10.28996/2618–9801–2019–2–342–242

51. Савенкова Н.Д. Наследственный врожденный и инфантильный нефротический синдром у детей: стратегия ведения с новыми возможностями генетической диагностики и терапии. Рос вестн перинатол педиатр 2020; 66(2): 6–12. DOI: 10.21508/1027–4065–2020–65–6–12–21