Evolution in the understanding of idiopathic membranous nephropathy pathogenesis: from experimental models to the clinic

Cover Page


Cite item

Full Text

Abstract

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. This review describes a 60-year history of MN study and represents an evolution in the understanding of its pathogenesis from experimental models to the clinic. Due to the development in 1959 of an MN animal model (active and passive Heymann's nephritis) the renal autoantigen podocyte-related protein megalin was identified. Experimental studies confirmed that the immune deposits consisting of megalin with circulating antimegalin antibodies are formed in situ. That leads to the complement activation providing with the membrane attack complex formation in the subepithelial space which causes a  sub-lethal podocyte injury with a  reorganization of their actin cytoskeleton and a  dissociation of slit diaphragm proteins. As the result, the permeability of the filtration barrier increases leading to the proteinuria. Thus, the understanding of an idiopathic MN pathogenesis evolved from an immune complex-mediated damage into a podocytopathy so the pathway for the other podocyte-related antigens search was opened. Mechanisms of podocytes damage were considered to be the leading ones in the human idiopathic MN development. Nevertheless, the searching for antigenic targets different from the megalin was continued for many years, as human podocytes do not express this protein. In the first decade of the 21st century such autoantigens as neutral endopeptidase, M-type phospholipase A2 receptor, and thrombospondin type-1 domain-containing 7A were identified. Furthermore, the leading role of autoantibodies directed against these podocyte targets was confirmed. New knowledge formed the basis for modern diagnostics and treatment methods of MN. 

About the authors

I. N. Bobkova

I.M. Sechenov First Moscow State Medical University

Author for correspondence.
Email: irbo.mma@mail.ru

MD, PhD, Professor, Chair of Internal Medicine and Occupational Medicine, Faculty of Preventive Medicine

11а–23 Gagarina ul., Krasnoznamensk, Moscow Region, Moscow, 143090

Tel.: +7 (917) 559 71 43

8/2 Trubetskaya ul., 119991

Россия

P. A. Каkhsurueva

I.M. Sechenov First Moscow State Medical University

Email: fake@neicon.ru

MD, Postgraduate Student, Chair of Internal Medicine and Occupational Medicine, Faculty of Preventive Medicine

8/2 Trubetskaya ul., Moscow, 119991

Россия

E. V. Stavrovskaya

I.M. Sechenov First Moscow State Medical University

Email: fake@neicon.ru

MD, PhD, Associate Professor, Chair of Internal Medicine and Occupational Medicine, Faculty of Preventive Medicine

8/2 Trubetskaya ul., Moscow, 119991

Россия

E. E. Filatova

I.M. Sechenov First Moscow State Medical University

Email: fake@neicon.ru

Student

8/2 Trubetskaya ul., Moscow, 119991

Россия

References

  1. Jones DB. Nephrotic glomerulonephritis. Am J Pathol. 1957;33(2):313–29.
  2. Movat HZ, McGregor DD. The fine structure of the glomerulus in membranous glomerulonephritis (lipoid nephrosis) in adults. Am J Clin Pathol. 1959;32(2):109–27. doi: 10.1093/ ajcp/32.2.109.
  3. Mellors RC, Ortega LG, Holman HR. Role of gamma globulins in pathogenesis of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation on the lupus erythematosus cell reaction. J Exp Med. 1957;106(2): 191–202. doi: 10.1084/jem.106.2.191.
  4. Heymann W, Hackel DB, Harwood S, Wilson SG, Hunter J. Production of nephrotic syndrome in rats by Freund's adjuvants and rat kidney suspensions. Proc Soc Exp Biol Med. 1959;100(4): 660–4.
  5. Feenstra K, van den Lee R, Greben HA, Arends A, Hoedemaeker PJ. Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens. I. The natural history: a histologic and immunohistologic study at the light microscopic and the ultrastructural level. Lab Invest. 1975;32(2): 235–42.
  6. Edgington TS, Glassock RJ, Dixon FJ. Autologous immune complex nephritis induced with renal tubular antigen. I. Identification and isolation of the pathogenetic antigen. J Exp Med. 1968;127(3):555–72. doi: 10.1084/ jem.127.3.555.
  7. Van Damme BJ, Fleuren GJ, Bakker WW, Vernier RL, Hoedemaeker PJ. Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens. V. Fixed glomerular antigens in the pathogenesis of heterologous immune complex glomerulonephritis. Lab Invest. 1978;38(4):502–10.
  8. Couser WG, Steinmuller DR, Stilmant MM, Salant DJ, Lowenstein LM. J Clin Invest. Experimental glomerulonephritis in the isolated perfused rat kidney. 1978;62(6):1275–87. doi: 10.1172/JCI109248.
  9. Kerjaschki D, Farquhar MG. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci U S A. 1982;79(18): 5557–61.
  10. Farquhar MG, Saito A, Kerjaschki D, Orlando RA. The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol. 1995;6(1):35–47.
  11. Oleinikov AV, Feliz BJ, Makker SP. A small N-terminal 60-kD fragment of gp600 (megalin), the major autoantigen of active Heymann nephritis, can induce a full-blown disease. J Am Soc Nephrol. 2000;11(1):57–64.
  12. Ronco P, Debiec H. Molecular dissection of target antigens and nephritogenic antibodies in membranous nephropathy: towards epitope-driven therapies. J Am Soc Nephrol. 2006;17(7):1772–4.
  13. Tramontano A, Knight T, Vizzuso D, Makker SP. Nested N-terminal megalin fragments induce high-titer autoantibody and attenuated Heymann nephritis. J Am Soc Nephrol. 2006;17(7):1979–85. doi: 10.1681/ ASN.2005101144.
  14. Shah P, Tramontano A, Makker SP. Intramolecular epitope spreading in Heymann nephritis. J Am Soc Nephrol. 2007;18(12):3060–6. doi: 10.1681/ASN.2007030342.
  15. Batsford S, Oite T, Takamiya H, Vogt A. Anionic binding sites in the glomerular basement membrane: possible role in the pathogenesis of immune complex glomerulonephritis. Ren Physiol. 1980;3(1–6):336–40.
  16. Border WA, Kamil ES, Ward HJ, Cohen AH. Antigenic changes as a determinant of immune complex localization in the rat glomerulus. Lab Invest. 1981;45(5):442–9.
  17. Nangaku M, Shankland SJ, Couser WG. Cellular response to injury in membranous nephropathy. J Am Soc Nephrol. 2005;16(5):1195–204. doi: 10.1681/ASN.2004121098.
  18. Glassock RJ. The pathogenesis of idiopathic membranous nephropathy: a 50-year odyssey. Am J Kidney Dis. 2010;56(1):157–67. doi: 10.1053/j.ajkd.2010.01.008.
  19. Borza DB. Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy. Front Immunol. 2016;7:157. doi: 10.3389/fimmu.2016.00157.
  20. Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: an update. Semin Immunopathol. 2014;36(4):381–97. doi: 10.1007/s00281-014-0423-y.
  21. Schulze M, Pruchno CJ, Burns M, Baker PJ, Johnson RJ, Couser WG. Glomerular C3c localization indicates ongoing immune deposit formation and complement activation in experimental glomerulonephritis. Am J Pathol. 1993;142(1): 179–87.
  22. Perkinson DT, Baker PJ, Couser WG, Johnson RJ, Adler S. Membrane attack complex deposition in experimental glomerular injury. Am J Pathol. 1985;120(1):121–8.
  23. Salant DJ, Belok S, Madaio MP, Couser WG. A new role for complement in experimental membranous nephropathy in rats. J Clin Invest. 1980;66(6):1339–50. doi: 10.1172/JCI109987.
  24. Baker PJ, Ochi RF, Schulze M, Johnson RJ, Campbell C, Couser WG. Depletion of C6 prevents development of proteinuria in experimental membranous nephropathy in rats. Am J Pathol. 1989;135(1):185–94.
  25. Ma H, Sandor DG, Beck LH Jr. The role of complement in membranous nephropathy. Semin Nephrol. 2013;33(6):531–42. doi: 10.1016/j. semnephrol.2013.08.004.
  26. Арьев АЛ, Изотова АБ. Современные представления о патогенезе идиопатического мембранозного гломерулонефрита. Нефрология. 2004;8(4):92–5.
  27. Cattran DC, Brenchley PE. Membranous nephropathy: integrating basic science into improved clinical management. Kidney Int. 2017;91(3):566–74. doi: 10.1016/j. kint.2016.09.048.
  28. Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient's care. Lancet. 2015;385(9981):1983–92. doi: 10.1016/S0140- 6736(15)60731-0.
  29. Смирнов АВ. Лечение гломерулопатий циклоспорином: правильный подход с неверным обоснованием. Нефрология. 2010;14(4): 9–22.
  30. Козловская ЛВ. Хронический гломерулонефрит: аргументы в пользу применения циклоспорина. Клиническая нефрология. 2010;(3):56–61.
  31. Penny MJ, Boyd RA, Hall BM. Permanent CD8(+) T cell depletion prevents proteinuria in active Heymann nephritis. J Exp Med. 1998;188(10): 1775–84. doi: 10.1084/jem.188.10.1775.
  32. Salant DJ, Madaio MP, Adler S, Stilmant MM, Couser WG. Altered glomerular permeability induced by F(ab')2 and Fab' antibodies to rat renal tubular epithelial antigen. Kidney Int. 1982;21(1):36–43. doi: 10.1038/ki.1982.6.
  33. Bomback AS, Derebail VK, McGregor JG, Kshirsagar AV, Falk RJ, Nachman PH. Rituximab therapy for membranous nephropathy: a systematic review. Clin J Am Soc Nephrol. 2009;4(4):734–44. doi: 10.2215/CJN.05231008.
  34. Debiec H, Guigonis V, Mougenot B, Decobert F, Haymann JP, Bensman A, Deschênes G, Ronco PM. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N Engl J Med. 2002;346(26):2053–60. doi: 10.1056/NEJMoa012895.
  35. Ronco P, Debiec H. Advances in membranous nephropathy: success stories of a long journey. Clin Exp Pharmacol Physiol. 2011;38(7):460–6. doi: 10.1111/j.1440-1681.2011.05506.x.
  36. Ronco P, Debiec H. Target antigens and nephritogenic antibodies in membranous nephropathy: of rats and men. Semin Immunopathol. 2007;29(4):445–58. doi: 10.1007/s00281-007- 0091-2.
  37. Kerjaschki D. Pathomechanisms and molecular basis of membranous glomerulopathy. Lancet. 2004;364(9441):1194–6. doi: 10.1016/S0140- 6736(04)17154-7.
  38. Behnert A, Fritzler MJ, Teng B, Zhang M, Bollig F, Haller H, Skoberne A, Mahler M, Schiffer M. An anti-phospholipase A2 receptor quantitative immunoassay and epitope analysis in membranous nephropathy reveals different antigenic domains of the receptor. PLoS One. 2013;8(4):e61669. doi: 10.1371/journal. pone.0061669.
  39. Kao L, Lam V, Waldman M, Glassock RJ, Zhu Q. Identification of the immunodominant epitope region in phospholipase A2 receptor-mediating autoantibody binding in idiopathic membranous nephropathy. J Am Soc Nephrol. 2015;26(2):291–301. doi: 10.1681/ ASN.2013121315.
  40. Fresquet M, Jowitt TA, Gummadova J, Collins R, O'Cualain R, McKenzie EA, Lennon R, Brenchley PE. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. J Am Soc Nephrol. 2015;26(2):302–13. doi: 10.1681/ ASN.2014050502.
  41. Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11–21. doi: 10.1056/NEJMoa0810457.
  42. Hoxha E, Harendza S, Zahner G, Panzer U, Steinmetz O, Fechner K, Helmchen U, Stahl RA. An immunofluorescence test for phospholipase-A2-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis. Nephrol Dial Transplant. 2011;26(8):2526–32. doi: 10.1093/ ndt/gfr247.
  43. Dai H, Zhang H, He Y. Diagnostic accuracy of PLA2R autoantibodies and glomerular staining for the differentiation of idiopathic and secondary membranous nephropathy: an updated meta-analysis. Sci Rep. 2015;5:8803. doi: 10.1038/srep08803.
  44. Kimura Y, Miura N, Debiec H, Morita H, Yamada H, Banno S, Ronco P, Imai H. Circulating antibodies to α-enolase and phospholipase A2 receptor and composition of glomerular deposits in Japanese patients with primary or secondary membranous nephropathy. Clin Exp Nephrol. 2017;21(1):117–26. doi: 10.1007/ s10157-016-1235-2.
  45. Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. N Engl J Med. 2011;364(7):689– 90. doi: 10.1056/NEJMc1011678.
  46. Qin HZ, Zhang MC, Le WB, Ren Q, Chen DC, Zeng CH, Liu L, Zuo K, Xu F, Liu ZH. Combined Assessment of Phospholipase A2 Receptor Autoantibodies and Glomerular Deposits in Membranous Nephropathy. J Am Soc Nephrol. 2016;27(10):3195–203. doi: 10.1681/ ASN.2015080953.
  47. Beck LH Jr, Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson SB, Cosio FG, Cattran DC, Salant DJ. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol. 2011;22(8):1543–50. doi: 10.1681/ ASN.2010111125.
  48. Hofstra JM, Beck LH Jr, Beck DM, Wetzels JF, Salant DJ. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2011;6(6):1286–91. doi: 10.2215/ CJN.07210810.
  49. Stahl R, Hoxha E, Fechner K. PLA2R autoantibodies and recurrent membranous nephropathy after transplantation. N Engl J Med. 2010;363(5):496–8. doi: 10.1056/NEJMc1003066.
  50. Kim YG, Choi YW, Kim SY, Moon JY, Ihm CG, Lee TW, Jeong KH, Yang SH, Kim YS, Oh YJ, Lee SH. Anti-Phospholipase A2 Receptor Antibody as Prognostic Indicator in Idiopathic Membranous Nephropathy. Am J Nephrol. 2015;42(3):250–7. doi: 10.1159/000440983.
  51. Bech AP, Hofstra JM, Brenchley PE, Wetzels JF. Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2014;9(8):1386–92. doi: 10.2215/ CJN.10471013.
  52. Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, Poulton K, McWilliam L, Short CD, Venning M, Brenchley PE. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney Int. 2013;83(5):940–8. doi: 10.1038/ki.2012.486.
  53. Hoxha E, Thiele I, Zahner G, Panzer U, Harendza S, Stahl RA. Phospholipase A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy. J Am Soc Nephrol. 2014;25(6):1357–66. doi: 10.1681/ASN.2013040430.
  54. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, Voinescu C, Patel N, Pearce K, Hubank M, Stephens HA, Laundy V, Padmanabhan S, Zawadzka A, Hofstra JM, Coenen MJ, den Heijer M, Kiemeney LA, Bacq-Daian D, Stengel B, Powis SH, Brenchley P, Feehally J, Rees AJ, Debiec H, Wetzels JF, Ronco P, Mathieson PW, Kleta R. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011;364(7):616–26. doi: 10.1056/NEJMoa1009742.
  55. Bullich G, Ballarín J, Oliver A, Ayasreh N, Silva I, Santín S, Díaz-Encarnación MM, Torra R, Ars E. HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2014;9(2):335–43. doi: 10.2215/CJN.05310513.
  56. Lv J, Hou W, Zhou X, Liu G, Zhou F, Zhao N, Hou P, Zhao M, Zhang H. Interaction between PLA2R1 and HLA-DQA1 variants associates with anti-PLA2R antibodies and membranous nephropathy. J Am Soc Nephrol. 2013;24(8): 1323–9. doi: 10.1681/ASN.2012080771.
  57. Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, Dolla G, Hoxha E, Helmchen U, Dabert-Gay AS, Debayle D, Merchant M, Klein J, Salant DJ, Stahl RAK, Lambeau G. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371(24):2277–87. doi: 10.1056/NEJMoa1409354.
  58. Tomas NM, Hoxha E, Reinicke AT, Fester L, Helmchen U, Gerth J, Bachmann F, Budde K, Koch-Nolte F, Zahner G, Rune G, Lambeau G, Meyer-Schwesinger C, Stahl RA. Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy. J Clin Invest. 2016;126(7):2519–32. doi: 10.1172/JCI85265.
  59. Wang CH, Su PT, Du XY, Kuo MW, Lin CY, Yang CC, Chan HS, Chang SJ, Kuo C, Seo K, Leung LL, Chuang YJ. Thrombospondin type I domain containing 7A (THSD7A) mediates endothelial cell migration and tube formation. J Cell Physiol. 2010;222(3):685–94. doi: 10.1002/jcp.21990.
  60. 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(9):e0138841. doi: 10.1371/ journal.pone.0138841.
  61. Larsen CP, Cossey LN, Beck LH. THSD7A staining of membranous glomerulopathy in clinical practice reveals cases with dual autoantibody positivity. Mod Pathol. 2016;29(4):421–6. doi: 10.1038/modpathol.2016.32.
  62. Prunotto M, Carnevali ML, Candiano G, Murtas C, Bruschi M, Corradini E, Trivelli A, Magnasco A, Petretto A, Santucci L, Mattei S, Gatti R, Scolari F, Kador P, Allegri L, Ghiggeri GM. Autoimmunity in membranous nephropathy targets aldose reductase and SOD2. J Am Soc Nephrol. 2010;21(3): 507–19. doi: 10.1681/ASN.2008121259.
  63. Neale TJ, Ojha PP, Exner M, Poczewski H, Rüger B, Witztum JL, Davis P, Kerjaschki D. Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen. J Clin Invest. 1994;94(4):1577–84. doi: 10.1172/JCI117499.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2017 Bobkova I.N., Каkhsurueva P.A., Stavrovskaya E.V., Filatova E.E.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies