Abstract
Autoantibody against phospholipase A2 receptor (anti-PLA2R) is a sensitive and specific biomarker of idiopathic membranous nephropathy (iMN), being found in approximately 70% of iMN patients and only occasionally in other glomerular diseases. However, whereas its diagnostic specificity vs. normal controls and other glomerulonephritides (GN) has been firmly established, its specificity vs. membranous nephropathy associated with various diseases (sMN) has given inconsistent results. The aim of our study was to evaluate the prevalence of anti-PLA2R antibodies in iMN in comparison with various control groups, including sMN. A total of 252 consecutive iMN patients, 184 pathological and 43 healthy controls were tested for anti-PLA2R antibody using indirect immunofluorescence (PLA2R IIFT, Euroimmun). Anti-PLA2R autoantibodies were detectable in 178/252 iMN patients, 1/80 primary GN, 0/72 secondary GN, 9/32 sMN and 0/43 healthy controls, with a diagnostic sensitivity of 70.6%. The diagnostic specificity of anti-PLA2R antibody vs. normal and pathological controls was 100 and 94.6% respectively. However, when the diagnostic specificity was calculated only vs. secondary forms of MN, it decreased considerably to 71.9%. Interestingly enough, 9 out of 10 anti-PLA2R positive patients in the disease control groups had membranous nephropathy associated with various diseases (7 cancer, 1 Crohn’s disease, 1 scleroderma). In conclusion, anti-PLA2R positivity in a patient with MN, should not be considered sufficient to abstain from seeking a secondary cause, especially in patients with risk factors for neoplasia. The causal relationship between tumors and anti-PLA2R-induced MN remains to be established, as well as the possible mechanisms through which malignancies provoke autoimmunity.
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References
Couser WG (2017) Primary membranous nephropathy. Clin J Am Soc Nephrol; 12(6):983–997
Sinico RA, Mezzina N, Trezzi B, Ghiggeri GM, Radice A (2016) Immunology of membranous nephropathy: from animal models to humans. Clin Exp Immunol 183(2):157 – 65
Kerjaschki D (2000) Pathogenetic concepts of membranous glomerulopathy (MGN). J Nephrol 13:S96–S100
Beck LH, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ (2009) M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 361(1):11–21
Hoxha E, Harendza S, Zahner G, Panzer U, Steinmetz O, Fechner K, Helmchen U, Stahl RA (2011) An immunofluorescence test for phospholipase-A2-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis. Nephrol Dial Transpl 26(8):2526–2532
Radice A, Trezzi B, Maggiore U, Pregnolato F, Stellato T, Napodano P, Rolla D, Pesce G, D’Amico M, Santoro D, Londrino F, Ravera F, Ortisi G, Sinico RA (2016) Clinical usefulness of autoantibodies to M-type phospholipase A2 receptor (PLA2R) for monitoring disease activity in idiopathic membranous nephropathy (IMN). Autoimmun Rev 15(2):146–154
Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, Suardi F, Gagliardini E, Orisio S, Benigni A, Ronco P, Remuzzi G (2015) Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol 26:2545–2558
Dai H, Zhang H, He Y (2015) Diagnostic accuracy of PLA2R autoantibodies and glomerular staining for the differentiation of idiopathic and secondary membranous nephropathy: an updated meta-analysis. Sci Rep 5:8803. doi:10.1038/srep08803
Ge YC, Jin B, Zeng CH, Zhang MC, Chen DC, Yin R, Le WB (2016) PLA2R antibodies and PLA2R glomerular deposits in psoriasis patients with membranous nephropathy. BMC Nephrol 22 17:185. doi:10.1186/s12882-016-0407-3
Qin W, Beck LH, Zeng C, Chen Z, Li S, Zuo K, Salant DJ, Liu Z (2011) Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol 22:1137–1143
Hihara K, Iyoda M, Tachibana S, Iseri K, Saito T, Yamamoto Y, Suzuki T, Wada Y, Matsumoto K, Shibata T (2016). Anti-phospholipase A2 receptor (PLA2R) antibody and glomerular PLA2R expression in Japanese patients with membranous nephropathy. PLoS One 11(6):doi:10.1371/journal.pone.0158154
Akiyama S, Akiyama M, Imai E, Ozaki T, Matsuo S, Maruyama S (2015) Prevalence of anti-phospholipase A2 receptor antibodies in Japanese patients with membranous nephropathy. Clin Exp Nephrol 19:653–660
Timmermans SA, Ayalon R, van Paassen P, Beck LH Jr, van Rie H, Wirtz JJ, Verseput GH, Frenken LA, Salant DJ, Cohen Tervaert JW; Limburg Renal Registry (2013). Anti-phospholipase A2 receptor antibodies and malignancy in membranous nephropathy. Am J Kidney Dis 62(6):1223–1225
Larsen CP, Messias NC, Silva FG, Messias E, Walker PD (2013) Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Modern Pathol 26:709–715
Xie Q, Li Y, Xue J, Xiong Z, Wang L, Sun Z, Ren Y, Zhu X, Hao CM (2015) Renal phospholipase A2 receptor in hepatitis B virus-associated membranous nephropathy. Am J Nephrol; 41:345–353
Li X, Wei D, Zhou Z, Wang B, Xu Y, Pan J, Yang C, Lu J, Qiu Y (2016) Anti-PLA2R antibodies in chinese patients with membranous nephropathy. Med Sci Monit 22:1630–1636
Kimura Y, Miura N, Debiec H, Morita H, Yamada H, Banno S, Ronco P, Imai H (2017) 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 21:117–126
Hill PA, McRae JL, Dwyer KM (2016) PLA2R and membranous nephropathy: a 3 year prospective Australian study. Nephrology (Carlton) 21:397–403
Dauvergne M, Moktefi A, Rabant M, Vigneau C, Kofman T, Burtey S, Corpechot C, Stehlé T, Desvaux D, Rioux-Leclercq N, Rouvier P, Knebelmann B, Boffa JJ, Frouget T, Daugas E, Jablonski M, Dahan K, Brocheriou I, Remy P, Grimbert P, Lang P, Chazouilleres O, Sahali D, Audard V (2015) Membranous nephropathy associated with immunological disorder-Related liver disease. A retrospective study of 10 cases. Medicine (Baltimore) 94(30):e1243. doi:10.1097/MD.0000000000001243
Stehlé T, Audard V, Ronco P, Debiec H (2015) Phospholipase A2 receptor and sarcoidosis-associated membranous nephropathy. Nephrol Dial Transpl 30:1047–1050
Oh YJ, Yang SH, Kim DK, Kang SW, Kim YS (2013). Autoantibodies against phospholipase A2 receptor in korean patients with membranous nephropathy. PLoS One 8(4):e62151.doi:10.1371/journal.pone
Svobodova B, Honsova E, Ronco P, Tesar V, Debiec H (2013) Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy. Nephrol Dial Transpl 28:1839–1844
Dähnrich C, Komorowski L, Probst C, Seitz-Polski B, Esnault V, Wetzels JF, Hofstra JM, Hoxha E, Stahl RA, Lambeau G, Stöcker W, Schlumberger W (2013) Development of a standardized ELISA for the determination of autoantibodies against human M-type phospholipase A2 receptor in primary membranous nephropathy. Clin Chim Acta 421:213–218
Gunnarsson I, Schlumberger W, Rönnelid J (2012) Antibodies to M-Type phospholipase A2 receptor (PLA2R) and membranous lupus nephritis. Am J Kidney Dis 59(4):585–586
Gopalakrishnan N, Abeesh P, Dineshkumar T, Murugananth S, Sakthirajan R, Raman GS, Dhanapriya J, Balasubramaniyan T, Haris M (2016). Prevalence of serum anti M-type phospholipase A2 receptor antibody in primary membranous nephropathy: a single center experience. Indian J Nephrol 26(4):257–261
Hu SL, Wang D, Gou WJ, Lei QF, Ma TA, Cheng JZ (2014) Diagnostic value of phospholipase A2 receptor in idiopathic membranous nephropathy: a systematic review and meta-analysis. J Nephrol 27(2):111–116
Cambier JF, Ronco P (2012) Onco-Nephrology: Glomerular Diseases with Cancer. Clin J Am Soc Nephrol; 7:1701–1712
Beck LH Jr (2010) Membranous nephropathy malignancy seminars Nephrol 30(6):635–644
Murtas C, Ghiggeri GM (2016). Membranous glomerulonephritis: histological and serological features to differentiate cancer-related and non-related forms. J Nephrol 29(4):469–478
Hoxha E, Wiech T, Stahl PR, Zahner G, Tomas NM, Meyer-Schwesinger C, Wenzel U, Janneck M, Steinmetz OM, Panzer U, Harendza S, Stahl RA (2016) A mechanism for cancer-associated membranous nephropathy. N Engl J Med 374(20):1995–1996
De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC (2017) A proposal for a serology-based approach to membranous nephropathy. J Am Soc Nephrol 28:421–430
Acknowledgements
The authors wish to thank Carlo De Maria, Angelo Battaglia, Antonio Amodeo and Salvatore Di Marco, with all their staff members, for their continuous technical support and assistance, and the “Biomedicale” clinical engineering services for the professional help.
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The study was approved by the local Ethics Committee (N. 150/ST/2014, 01.10.2014). Patient data were anonymously used under consideration of the latest version of the Helsinki Declaration of human research ethics.
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Informed consent was obtained for all participating patients for the treatment of data already collected for routine clinical use.
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Radice, A., Pieruzzi, F., Trezzi, B. et al. Diagnostic specificity of autoantibodies to M-type phospholipase A2 receptor (PLA2R) in differentiating idiopathic membranous nephropathy (IMN) from secondary forms and other glomerular diseases. J Nephrol 31, 271–278 (2018). https://doi.org/10.1007/s40620-017-0451-5
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DOI: https://doi.org/10.1007/s40620-017-0451-5