Clinical and Experimental Nephrology

, Volume 19, Issue 5, pp 797–803 | Cite as

Clinicopathological characteristics of M-type phospholipase A2 receptor (PLA2R)-related membranous nephropathy in Japanese

  • Norifumi Hayashi
  • Shin’ichi Akiyama
  • Hiroshi Okuyama
  • Yuki Matsui
  • Hiroki Adachi
  • Hideki Yamaya
  • Shoichi Maruyama
  • Enyu Imai
  • Seiichi Matsuo
  • Hitoshi YokoyamaEmail author
Original Article



Recent studies have suggested that assessments of serum antibodies against M-type phospholipase A2 receptor (PLA2R) and the glomerular expression of PLA2R antigen in biopsy specimens are useful for the diagnosis of primary membranous nephropathy (MN). In this study, we assessed both of them and investigated the clinicopathological characteristics of PLA2R-related Japanese MN.


We retrospectively enrolled 22 primary and 3 secondary Japanese patients whose serum samples and renal specimens were collected before treatment. According to the findings of serum antibodies and antigen in glomeruli, the primary MN patients were classified into PLA2R-related or -unrelated MN. We compared their clinicopathological findings, including IgG subclass staining, and electron microscopic findings, and evaluated the predictors of proteinuria remission.


In primary MN, 16 patients (73 %) were classified into the PLA2R-related group, and 6 patients into the PLA2R-unrelated group. There was no significant difference in baseline laboratory data and electron microscopic findings, except for eGFR and serum IgG levels. IgG4-dominant deposition was more common in the related group (63 vs. 0 %). The 10 PLA2R-related patients with dominant IgG4 deposition had a lower rate and prolonged time in remission compared with the 6 PLA2R-related patients with non-dominant IgG4 (log-rank, p = 0.032). Furthermore, dominant IgG4 deposition was an unfavorable predictor of remission by multivariable Cox proportional hazard analysis.


Assessments of both serum PLA2R antibodies and PLA2R antigen in glomeruli were more sensitive for the diagnosis of PLA2R-related MN, and among affected Japanese patients, those with dominant IgG4 deposition had worse clinical outcomes.


Electron microscopic findings IgG subclass staining Membranous nephropathy Phospholipase A2 receptor Western blotting 



We are grateful to the staff members of the Division of Nephrology for their cooperation and support. This study was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; (C) No.25461237 (HY), (B) No.24406029 (HY), and (B) No.2530502 (HY, SM), and a Grant-in-Aid for Progressive Renal Disease Research and Intractable Renal Disease Research, Research on Rare and Intractable Diseases, and Health and Labour Sciences Research Grants from the Ministry of Health, Labour, and Welfare of Japan.

Conflict of interest

None of the authors has any competing interests.

Supplementary material

10157_2014_1064_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 kb)
10157_2014_1064_MOESM2_ESM.tif (986 kb)
Supplementary material 2 (TIFF 986 kb)
10157_2014_1064_MOESM3_ESM.tif (1.8 mb)
Supplementary material 3 (TIFF 1806 kb)
10157_2014_1064_MOESM4_ESM.tif (1014 kb)
Supplementary material 4 (TIFF 1013 kb)
10157_2014_1064_MOESM5_ESM.pdf (66 kb)
Supplementary material 5 (PDF 65 kb)


  1. 1.
    Glassock RJ. The pathogenesis of idiopathic membranous nephropathy: a 50-year odyssey. Am J Kidney Dis. 2010;56:157–67.CrossRefPubMedGoogle Scholar
  2. 2.
    Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11–21.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Hofstra JM, Debiec H, Short CD, et al. Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy. J Am Soc Nephrol. 2012;23:1735–43.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Hofstra JM, Beck LH Jr, Beck DM, et al. Anti-phospholipase A(2) receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2011;6:1286–91.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Beck LH Jr, Fervenza FC, Beck DM, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol. 2011;22:1543–50.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Hoxha E, Kneissler U, Stege G, et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney Int. 2012;82:797–804.CrossRefPubMedGoogle Scholar
  7. 7.
    Svobodova B, Honsova E, Ronco P, et al. Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy. Nephrol Dial Transpl. 2013;28:1839–44.CrossRefGoogle Scholar
  8. 8.
    Shiiki H, Saito T, Nishitani Y, et al. Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan. Kidney Int. 2004;65:1400–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Yokoyama H, Goshima S, Wada T, et al. The short- and long-term outcomes of membranous nephropathy treated with intravenous immune globulin therapy. Nephrol Dial Transpl. 1999;14:2379–86.CrossRefGoogle Scholar
  10. 10.
    Yoshimoto K, Yokoyama H, Wada T, et al. Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy. Kidney Int. 2004;65:148–53.CrossRefPubMedGoogle Scholar
  11. 11.
    Ehrenreich T, Porush JG, Churg J, et al. Treatment of idiopathic membranous nephropathy. N Engl J Med. 1976;295:741–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Qin W, Beck LH Jr, Zeng C, et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol. 2011;22:1137–43.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Oh YJ, Yang SH, Kim DK, et al. Autoantibodies against phospholipase A2 receptor in Korean patients with membranous nephropathy. PLoS One. 2013;8:e62151.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. N Engl J Med. 2011;364:689–90.CrossRefPubMedGoogle Scholar
  15. 15.
    Larsen CP, Messias NC, Silva FG, et al. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol. 2013;26:709–15.CrossRefPubMedGoogle Scholar
  16. 16.
    Prunotto M, Carnevali ML, Candiano G, et al. Autoimmunity in membranous nephropathy targets aldose reductase and SOD2. J Am Soc Nephrol. 2010;21:507–19.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Qu Z, Liu G, Li J, et al. Absence of glomerular IgG4 deposition in patients with membranous nephropathy may indicate malignancy. Nephrol Dial Transpl. 2012;27:1931–7.CrossRefGoogle Scholar
  18. 18.
    Ohtani H, Wakui H, Komatsuda A, et al. Distribution of glomerular IgG subclass deposits in malignancy-associated membranous nephropathy. Nephrol Dial Transpl. 2004;19:574–9.CrossRefGoogle Scholar
  19. 19.
    Imai H, Hamai K, Komatsuda A, et al. IgG subclasses in patients with membranoproliferative glomerulonephritis, membranous nephropathy, and lupus nephritis. Kidney Int. 1997;51:270–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Debiec H, Hanoy M, Francois A, et al. Recurrent membranous nephropathy in an allograft caused by IgG3kappa targeting the PLA2 receptor. J Am Soc Nephrol. 2012;23:1949–54.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Salant DJ. Genetic variants in membranous nephropathy: perhaps a perfect storm rather than a straightforward conformeropathy? J Am Soc Nephrol. 2013;24:525–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Kuroki A, Iyoda M, Shibata T, et al. Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy. Kidney Int. 2005;68:302–10.CrossRefPubMedGoogle Scholar
  23. 23.
    Aalberse RC, Stapel SO, Schuurman J, et al. Immunoglobulin G4: an odd antibody. Clin Exp Allergy. 2009;39:469–77.CrossRefPubMedGoogle Scholar
  24. 24.
    Huang CC, Lehman A, Albawardi A, et al. IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression. Mod Pathol. 2013;26:799–805.CrossRefPubMedGoogle Scholar
  25. 25.
    Rahimi S, Qian Z, Layton J, et al. Non-complement- and complement-activating antibodies synergize to cause rejection of cardiac allografts. Am J Transpl. 2004;4:326–34.CrossRefGoogle Scholar
  26. 26.
    Hoxha E, Thiele I, Zahner G, et al. Phospholipase A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy. J Am Soc Nephrol. 2014;25:1357–66.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2014

Authors and Affiliations

  • Norifumi Hayashi
    • 1
  • Shin’ichi Akiyama
    • 2
  • Hiroshi Okuyama
    • 1
  • Yuki Matsui
    • 1
  • Hiroki Adachi
    • 1
  • Hideki Yamaya
    • 1
  • Shoichi Maruyama
    • 2
  • Enyu Imai
    • 2
  • Seiichi Matsuo
    • 2
  • Hitoshi Yokoyama
    • 1
    Email author
  1. 1.Division of NephrologyKanazawa Medical UniversityUchinadaJapan
  2. 2.Division of Nephrology, Department of Internal MedicineNagoya University Graduate School of MedicineNagoyaJapan

Personalised recommendations