Abstract
Background
The prevalence of antibodies against M-type anti-phospholipase A2 receptor (PLA2R) was reported to be ~ 70–80% in early studies on idiopathic membranous nephropathy (iMN) cohorts from Western countries, China, and Korea, and ~ 50% in recent studies on two Japanese iMN cohorts.
Methods
We developed an in-house enzyme-linked immunosorbent assay (ELISA) for the detection of anti-PLA2R antibodies, and examined sera from 217 patients with iMN, 22 patients with secondary MN (sMN), and 50 healthy individuals. All patients and healthy individuals were Japanese. The relationships between levels of anti-PLA2R antibodies and clinical parameters were analyzed. Serum samples were also tested using a standardized commercial ELISA (Euroimmun, Germany).
Results
In our ELISA, OD values greater than the mean + 3 standard deviation of healthy subjects were considered to be positive for anti-PLA2R antibodies. Of the patients with iMN, 33.6% (73/217) were positive, but all sMN patients were negative. Our ELISA and the Euroimmun ELISA had a high concordance (93.5%). The proportion of patients with nephrotic syndrome was significantly higher in anti-PLA2R antibody-positive patients than in antibody-negative patients (65.8 vs. 37.5%, P < 0.001). Levels of anti-PLA2R antibodies were significantly correlated with levels of urinary protein and serum albumin (P = 0.004 and P < 0.001, respectively).
Conclusions
The prevalence of anti-PLA2R antibodies in our Japanese iMN cohort was lower than that in the previous studies from other countries and other Japanese institutes. The low prevalence of antibodies may be related with the characteristics of enrolled patients with mild proteinuria and undetectable antibody levels.
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References
Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care. Lancet. 2015;385:1983–92.
Francis JM, Beck LH Jr, Salant DJ. Membranous nephropathy: a journey from bench to bedside. Am J Kidney Dis. 2016;68:138–47.
Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11–21.
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;19:653–60.
Hihara K, Iyoda M, Tachibana S, Iseri K, Saito T, Yamamoto Y, et al. Anti-phospholipase A2 receptor (PLA2R) antibody and glomerular PLA2R expression in Japanese patients with membranous nephropathy. PLoS One. 2016;11:e0158154.
Dähnrich C, Komorowski L, Probst C, Seitz-Polski B, Esnault V, Wetzels JF, et al. Development of a standardized ELISA for the determination of autoantibodies against human M-type phospholipase A2 receptor in primary membranous nephropathy. Clin Chim Acta. 2013;421:213–8.
Timmermans SA, Damoiseaux JG, Heerings-Rewinkel PT, Ayalon R, Beck LH Jr, Schlumberger W, et al. Evaluation of anti-PLA2R1 as measured by a novel ELISA in patients with idiopathic membranous nephropathy. Am J Clin Pathol. 2014;142:29–34.
Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revised. J Am Soc Nephrol. 2004;15:241–50.
Nagahama K, Matsushita H, Hara M, Ubara Y, Hara S, Yamada A. Bucillamine induces membranous glomerulonephritis. Am J Kidney Dis. 2002;39:706–12.
Matsuo A, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.
Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol. 2015;26:2545–58.
Kim YG, Choi YW, Kim SY, Moon JY, Ihm CG, Lee TW, et al. Anti-phospholipase A2 receptor antibody as prognostic indicator in idiopathic membranous nephropathy. Am J Nephrol. 2015;42:250–7.
Dou Y, Zhang L, Liu D, Wang C, Quan S, Ma S, et al. The accuracy of the anti-phospholipase A2 receptor antibody in the diagnosis of idiopathic membranous nephropathy: a comparison of different cutoff values as measured by the ELISA method. Int Urol Nephrol. 2016:48; 845–9.
Qin W, Beck LH Jr, Zeng C, Chen Z, Li S, Zuo K, et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol. 2011;22:1137–43.
Hoxha E, Harendza S, Zahner G, Panzer U, Steinmetz O, Fechner K. e al. An immunofluorescence test for phospholipase-A2-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis. Nephrol Dial Transpl. 2011;26:2526–32.
Hofstra JM, Debiec H, Short CD, Pellé T, Kleta R, Mathieson PW, et al. Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy. J Am Soc Nephrol. 2012;23:1735–43.
Oh YJ, Yang SH, Kim DK, Kang SW, Kim YS. Autoantibodies against phospholipase A2 receptor in Korean patients with membranous nephropathy. PLoS One. 2013;8:e62151.
Behnert A, Fritzler MJ, Teng B, Zhang M, Bollig F, Haller H, et al. An anti-phospholipase A2 receptor quantitative immunoassay and epitope analysis in membranous nephropathy reveals different antigenic domains of the receptor. PLoS One. 2013;8:e61669.
Kanigcherla D, Gummadova J, McKenzie EA, Roberts AS, Harris S, Nikam M, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney Int. 2013;83:940–8.
Behnert A, Schiffer M, Müller-Deile J, Beck LH Jr, Mahler M, Fritzler M. Antiphospholipase A2 receptor antibodies: a comparison of three different immunoassays for the diagnosis of idiopathic membranous nephropathy. J Immunol Res. 2014; 2014:143274.
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;25:1357–66.
Seiz-Polski B, Dolla G, Payré C, Tomas NM, Lochouarn M, Jeammet L, et al. Cross-reactivity of anto-PLA2R autoantibodies to rabbit and mouse PLA2R1 antigens and development of two novel ELISAs with different diagnostic performances in idiopathic membranous nephropathy. Biochimie. 2015;118:104–15.
Ong L, Silvestrini R, Chapman J, Fulcher DA, Lin MW. Validation of a phospholipase A2 receptor antibody ELISA in an Australian cohort with membranous nephropathy. Pathology. 2016;48:242–6.
Wei SY, Wang YX, Li JS, Zhao SL, Diao TT, Wang Y, et al. Serum anti-PLA2R antibody predicts treatment outcome in idiopathic membranous nephropathy. Am J Nephrol. 2016;43:129–40.
Li X, Wei D, Zhou Z, Wang B, Xu Y, Pan J, et al. Anti-PLA2R antibodies in Chinese patients with membranous nephropathy. Ned Sci Monit. 2016;22:1630–6.
Jullien P, Seiz Polski B, Maillard N, Thibaudin D, Laurent B, Ollier E, et al. Anti-phospholipase A2 receptor antibody levels at diagnosis predicts spontaneous remission of idiopathic membranous nephropathy. Clin Kidney J. 2017;10:209–14.
Pang L, Zhang AM, Li HX, Du JL, Jiao LL, Duan N, et al. Serum anti-PLA2R antibody and glomerular PLA2R deposition in Chinese patients with membranous nephropathy: a cross-sectional study. Medicine (Baltimore). 2017;96:e7218.
Acknowledgements
This work was supported in part by a research grant from Cosmic Corporation, Tokyo, Japan.
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Kaga, H., Komatsuda, A., Yamamoto, S. et al. Comparison of measurements of anti-PLA2R antibodies in Japanese patients with membranous nephropathy using in-house and commercial ELISA. Clin Exp Nephrol 23, 465–473 (2019). https://doi.org/10.1007/s10157-019-01712-x
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DOI: https://doi.org/10.1007/s10157-019-01712-x