Журнал «Почки» Том 12, №2, 2023

Мембранозна нефропатія (МН) — автоімунне захворювання ниркових клубочків, одна з провідних причин нефротичного синдрому. Захворювання характеризується гетерогенними наслідками, приблизно в 30 % випадків прогресує до термінальної стадії ниркової недостатності. Вивчення механізму розвитку МН неухильно вдосконалюється завдяки ідентифікації автоантитіл до рецептора фосфоліпази А2 (PLA2R) у 2009 р. та тромбоспондинового домена 7А (THSD7A) на поверхні пoдоцитів у 2014 р. Приблизно 50–80 і 3–5 % первинних випадків МН пов’язані з антитілами або PLA2R, або THSD7A відповідно. Наявність цих автоантитіл використовується для діагностики МН. Рівні антитіл корелюють із тяжкістю захворювання і мають значення як біомаркери при моніторингу прогресування захворювання та відповіді на лікування.

Membranous nephropathy (MN) is an autoimmune disease of the kidney glomeruli and one of the leading causes of nephrotic syndrome. The disease exhibits heterogenous outcomes with approximately 30 % of cases progressing to end-stage renal disease. The study of MN pathogenesis has steadily advanced owing to the identification of autoantibodies to the phospholipase A2 receptor (PLA2R) in 2009 and thrombospondin domain-containing 7A (THSD7A) on the podocyte surface in 2014. Approximately 50–80 and 3–5 % of primary MN cases are associated with either anti-PLA2R or anti-THSD7A antibodies, respectively. The presence of these autoantibodies is used for MN diagnosis; antibody levels correlate with disease severity and possess significant biomarker values in monitoring disease progression and treatment response.

мембранозна нефропатія; нефротичний синдром; базальна мембрана клубочка; протеїнурія; антитіла; PLA2R; THSD7A

membranous nephropathy; nephrotic syndrome; basement membrane of the glomerulus; proteinuria; antibodies; PLA2R; THSD7A; review

1. Ronco P., Debiec H. Molecular pathogenesis of membranous nephropathy. Ann. Rev. Pathol. Mech. Dis. 2020. 15. 287-313.
2. Alsharhan L., Beck L.H. Membranous Nephropathy: Core Curriculum 2021. Am. J. Kidney Dis. 2020. XX(XX). 1-14. doi: 10.1053/j.ajkd.2020.10.009.
3. Johnson R.J., Feehally J., Floege J. Comprehensive Clinical Nephrology. 6th ed. Edinburgh: Elsevier; 2019.
4. Özer H., Baloğlu I., Fervenza F.C., Türkmen K. Membranous Nephropathy: Current Understanding in The Light of New Advances. Turk. J. Nephrol. 2023. 32(2). 103-111.
5. Ozturk S., Sumnu A., Seyahi N. et al. Demographic and clinical characteristics of primary glomerular diseases in Turkey. Int. Urol. Nephrol. 2014. 46(12). 2347-2355. doi: 10.1007/s11255-014-0838-3.
6. United States Renal Data System. USRDS annual data report: epidemiology of kidney disease in the United States. NIDDK, 2018.
7. Ayalon R., Beck L.H. Jr. Membranous nephropathy: not just a disease for adults. Pediatr. Nephrol. 2015. 30(1). 31-39.
8. Hofstra J.M., Wetzels J.F. Introduction of a cyclophosphamide-based strategy and the risk of ESRD in patients with idiopathic membranous nephropathy: a nationwide survey in the Netherlands. Nephrol. Dial. Transplant. 2008. 23. 3534-810. doi: 10.1093/ndt/gfn350.
9. Li L.S., Liu Z.H. Epidemiologic data of renal diseases from a single unit in China: analysis based on 13519 renal biopsies. Kidney Int. 2004. 66. 920-923. doi: 10.1111/j.1523-1755.2004.00837.x.
10. Dobronravov V.A., Majer D.A., Berezhnaja O.V. et al. Membranous nephropathy in a Russian population. Ter. arkhiv. 2017. 89(6). 21-29. doi: 10.17116/terarkh201789621-29 (in Russian).
11. Hu R., Quan S., Wang Y. et al. Spectrum of biopsy proven renal diseases in Central China: a 10-year retrospective study based on 34,630 cases. Sci. Rep. 2020. 10(1). 10994. doi: 10.1038/s41598-020-67910-w.
12. Couser W.G. Primary Membranous Nephropathy. Clinical Journal of the American Society of Nephrology. 2017 June. 12(6). 983-997. doi: 10.2215/CJN.11761116.
13. Heymann W., Hackel D.B., Harwood S., Wilson S.G., Hun–ter J.L. Production of nephrotic syndrome in rats by Freund’s adjuvants and rat kidney suspensions. Proc. Soc. Exp. Biol. Med. 1959. 100. 660-664.
14. Kerjaschki D., Farquhar M.G. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc. Natl Acad. Sci. USA 1982. 79. 5557-5561.
15. Beck L.H. Jr., Bonegio R.G., Lambeau G., Beck D.M., Powell D.W. et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 2009. 361. 11-21.
16. Tomas N.M., Beck L.H. Jr., Meyer-Schwesinger C., Seitz-Polski B., Ma H. et al. Thrombospondin type-1 domain-containing 7a in idiopathic membranous nephropathy. N. Engl. J. Med. 2014. 371. 2277-2287.
17. Du Y., Li J., He F., Lv Y., Liu W. et al. The diagnosis accuracy of pla2r-ab in the diagnosis of idiopathic membranous nephropathy: a meta-analysis. PLoS One. 2014. 9. e104936.
18. Akiyama S., Akiyama M., Imai E., Ozaki T., Matsuo S., Maruyama S. Prevalence of anti-phospholipase A2 receptor antibodies in Japanese patients with membranous nephropathy. Clin. Exp. Nephrol. 2015. 19. 653-660.
19. Hofstra J.M., Wetzels J.F. Anti-pla(2)r antibodies in membranous nephropathy: ready for routine clinical practice? Neth. J. Med. 2012. 70. 109-113.
20. Iwakura T., Ohashi N., Kato A., Baba S., Yasuda H. Prevalence of enhanced granular expression of thrombospondin type-1 domain-containing 7a in the glomeruli of Japanese patients with idiopathic membranous nephropathy. PLoS One. 2015. 10. e0138841.
21. Akiyama S., Imai E., Maruyama S. Immunology of membranous nephropathy. F1000Research. 2019. 8. f1000.
22. Yamaguchi M., Ando M., Yamamoto R. et al. Patient age and the prognosis of idiopathic membranous nephropathy. PLoS One. 2014. 9(10). e110376 doi: 10.1371/journal.pone.0110376.
23. Wang Y., Wang G.P., Li B.M., Chen Q.K. Clinicopathological analysis of idiopathic membranous nephropathy in young adults. Gen. Mol. Res. 2015. 14(2). 4541-4548 doi: 10.4238/2015.
24. Xu Z., Chen L., Xiang H. et al. Advances in Pathogenesis of Idiopathic Membranous Nephropathy. Kidney Dis. 2020. Sep 6(5). 330-345. doi: 10.1159/00050770.
25. Xian L., Dong D., Luo J. et al. Expression of THSD7A in neoplasm tissues and its relationship with proteinuria. BMC Nephrol. 2019. 20. 332 doi: 10.1186/s12882-019-1489-5.
26. Sethi S., Debiec H., Madden B. et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int. 2020. 97(1). 163-174. doi: 10.1016/j.kint.2019.09.014.
27. Sethi S., Debiec H., Madden B. et al. Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients. Kidney Int. 2020. 98(5). 1253-1264. doi: 10.1016/j.kint.2020.05.030.
28. Hayashi N., Beck L.H. Jr. Moore’s law for membranous nephropathy. Kidney Int. 2020. 98(5). 1081-1084. doi: 10.1016/j.kint.2020.06.020.
29. Caza T.N., Hassen S.I., Kuperman M. et al. Neural cell adhesion molecule 1 is a novel autoantigen in membranous lupus nephritis. Kidney Int. 2021 Jul. 100(1). 171-181. doi: 10.1016/j.kint.2020.09.016.
30. Ahmad S.B., Appel G.B. Antigens, antibodies, and membranous nephropathy: a decade of progress. Kidney Int. 2020 Jan. 97(1). 29-31. doi: 10.1016/j.kint.2019.10.009.
31. Stehlе T., Audard V., Ronco P., Debiec Н. Phospholipase A2 receptor and sarcoidosis-associated membranous nephropathy. Nephrol. Dial. Transplant. 2015. 30. 1047-1050. doi: 10.1093/ndt/gfv080.
32. Xie Q., Li Y., Xue J. et al. Renal phospholipase A2 receptor in hepatitis B virus-associated membranous nephropathy. Am. J. Nephrol. 2015. 41(4–5). 345-353. doi: 10.1159/000431331.
33. Larsen C.P., Messias N.C., Silva F.G. et al. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod. Pathol. 2013. 26. 709-715. doi: 10.1038/modpathol.2012.207.
34. Debiec H., Guigonis V., Mougenot B., Decobert F., Haymann J.P., Bensman A., Deschênes G., Ronco P.M. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N. Engl. J. Med. 2002. 346. 2053-2060.
35. Polanco N., Gutiérrez E., Covarsí A. et al.; Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Española de Nefrología. spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J. Am. Soc. Nephrol. 2010. 21. 697-704.
36. Hofstra J.M., Beck L.H. Jr, Beck D.M. et al. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin. J. Am. Soc. Nephrol. 2011. 6. 1286-1291.
37. Hoxha E., Harendza S., Pinnschmidt H. et al. PLA2R antibody levels and clinical outcome in patients with membranous nephro–pathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system. PLoS One. 2014. 9. e110681.
38. Beck L.H. Jr, Salant D.J. Membranous nephropathy: recent travels and new roads ahead. Kidney Int. 2010. 77. 765-770.
39. Li S.J., Guo J.Z., Zuo K. et al. Thromboembolic complications in membranous nephropathy patients with nephrotic syndrome — a prospective study. Thromb. Res. 2012. 130. 501-505.
40. Rankin A.J., McQuarrie E.P., Fox J.G. et al. Scottish Renal Biopsy Registry: venous thromboembolism in primary nephrotic syndrome — is the risk high enough to justify prophylactic anticoagulation? Nephron. 2017. 135. 39-45.
41. Lee T., Biddle A.K., Lionaki S. et al. Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy. Kidney Int. 2014. 85. 1412-1420.
42. Leeaphorn N., Kue-A-Pai P., Thamcharoen N. et al. Prevalence of cancer in membranous nephropathy: a systematic review and meta-analysis of observational studies. Am. J. Nephrol. 2014. 40. 29-35.
43. Hoxha E., Wiech T., Stahl P.R. et al. A mechanism for cancer-associated membranous nephropathy. N. Engl. J. Med. 2016. 374. 1995-1996.
44. Timmermans S.A., Ayalon R., van Paassen P. et al., Limburg Renal Registry. Anti-phospholipase A2 receptor antibodies and malignancy in membranous nephropathy. Am. J. Kidney Dis. 2013. 62. 1223-1225.
45. Stahl P.R., Hoxha E., Wiech T. et al. THSD7A expression in human cancer. Genes Chromosomes Cancer. 2017. 56. 314-327.
46. Cattran D.C., Brenchley P.E. Membranous nephropathy: integrating basic science into improved clinical management. Kidney Int. 2017. 91. 566-574.
47. Salant D.J., Cattran D.C. Membranous nephropathy. Ch. 20. In: Comprehensive Clinical Nephrology. 5th ed. Floege J., Johnson R.J., Feehally J. (eds). St. Louis, MI, Saunders, an imprint of Elsevier Inc., 2015. 239-251.
48. Brad H. Rovin, Sharon G. Adler, Jonathan Barratt et al. Exe–cutive summary of the KDIGO 2021 guideline for the management of glomerular diseases. Nephrologу and Dialуsis. 2022. 24(1). 21-51. doi: 10.28996/2618-9801-2022-1-21-51.
49. Seitz-Polski B., Payre C., Ambrosetti D. et al. Prediction of membranous nephropathy recurrence after transplantation by monitoring of anti-PLA2R1 (M-type phospholipase A2 receptor) autoantibodies: a case series of 15 patients. Nephrol. Dial. Transplant. 2014. 29(12). 2334-2342.
50. Kattah A., Ayalon R., Beck L.H. Jr. et al. Anti-phospholipase A(2) receptor antibodies in recurrent membranous nephropathy. Am. J. Transplant. 2015. 15(5). 1349-1359.
51. Quintana L.F., Blasco M., Seras M. et al. Antiphospholipase A2 receptor antibody levels predict the risk of posttransplantation recurrence of membranous nephropathy. Transplantation. 2015. 99(8). 1709-1714.
52. Andrew Howman, Tracey L. Chapman, Maria M. Langdon et al. Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial. Lancet. 2013. 381(9868). 744-751.
53. Cattran D.C., Kim E.D., Reich H. et al.; Toronto Glomerulonephritis Registry group. Membranous nephropathy: quantifying remission duration on outcome. J. Am. Soc. Nephrol. 2017. 28(3). 995-1003.
54. Troyanov S., Wall C.A., Miller J.A. et al. Idiopathic membranous nephropathy: definition and relevance of a partial remission. Kidney Int. 2004. 66(3). 1199-1205.
55. Thompson A., Cattran D.C., Blank M., Nachman P.H. Complete and partial remission as surrogate end points in membranous nephropathy. J. Am. Soc. Nephrol. 2015. 26(12). 2930-2937.