{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T18:22:19Z","timestamp":1770142939390,"version":"3.49.0"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T00:00:00Z","timestamp":1716940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Following the discovery of podocyte phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A, various potential target antigens for membranous nephropathy (MN) have been reported one after another. MN target antigens have now been identified in a significant proportion of patients, and a new classification framework classifies patients with MN based on the detected antigen and associated disease phenotype. A serology-based approach that does not require a histological diagnosis for patients suspected of having MN has also been proposed. However, there have been cases in which dual positivity for MN antigens and\/or corresponding antibodies has been shown. Importantly, some of them showed a transition of the affected patient\u2019s immune responses to MN antigens, suggesting that serological diagnosis changes depending on the timing of the analysis. In this review, we provide detailed information on these cases and present an overview of our recent understanding of their putative mechanisms involved in these cases. Greater awareness is required to adequately recognize and develop appropriate therapeutic strategies for this condition.<\/jats:p>","DOI":"10.3390\/ijms25115931","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T10:42:34Z","timestamp":1717065754000},"page":"5931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Prevalence, Characteristics, and Putative Mechanisms of Dual Antigen-Positive Membranous Nephropathy: The Underestimated Condition"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5852-9690","authenticated-orcid":false,"given":"Takahiro","family":"Uchida","sequence":"first","affiliation":[{"name":"Department of Nephrology and Blood Purification, Kidney Disease Center, Tokyo Medical University Hachioji Medical Center, Hachioji 193-0998, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6131-7752","authenticated-orcid":false,"given":"Takashi","family":"Oda","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Blood Purification, Kidney Disease Center, Tokyo Medical University Hachioji Medical Center, Hachioji 193-0998, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"983","DOI":"10.2215\/CJN.11761116","article-title":"Primary Membranous Nephropathy","volume":"12","author":"Couser","year":"2017","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"611317","DOI":"10.3389\/fmed.2020.611317","article-title":"Secondary Membranous Nephropathy. A Narrative Review","volume":"7","author":"Moroni","year":"2020","journal-title":"Front. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1681\/ASN.2016070776","article-title":"A Proposal for a Serology-Based Approach to Membranous Nephropathy","volume":"28","author":"Glassock","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa0810457","article-title":"M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy","volume":"361","author":"Beck","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Du, Y., Li, J., He, F., Lv, Y., Liu, W., Wu, P., Huang, J., Wei, S., and Gao, H. (2014). The diagnosis accuracy of PLA2R-AB in the diagnosis of idiopathic membranous nephropathy: A meta-analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104936"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.kint.2021.05.015","article-title":"Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases","volume":"100","author":"Rovin","year":"2021","journal-title":"Kidney Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1056\/NEJMoa1409354","article-title":"Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy","volume":"371","author":"Tomas","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.kint.2023.06.032","article-title":"Mayo Clinic consensus report on membranous nephropathy: Proposal for a novel classification","volume":"104","author":"Sethi","year":"2023","journal-title":"Kidney Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/s41581-022-00564-1","article-title":"Membranous nephropathy: New pathogenic mechanisms and their clinical implications","volume":"18","author":"Hoxha","year":"2022","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5414\/CN108602","article-title":"Anti-PLA2R-associated membranous nephropathy: A review with emphasis on diagnostic testing methods","volume":"84","author":"VanBeek","year":"2015","journal-title":"Clin. Nephrol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/modpathol.2016.32","article-title":"THSD7A staining of membranous glomerulopathy in clinical practice reveals cases with dual autoantibody positivity","volume":"29","author":"Larsen","year":"2016","journal-title":"Mod. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1681\/ASN.2020071082","article-title":"New \u2018Antigens\u2019 in Membranous Nephropathy","volume":"32","author":"Sethi","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"962502","DOI":"10.3389\/fimmu.2022.962502","article-title":"Pediatric membranous nephropathy: In the novel antigens era","volume":"13","author":"Huang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100625","DOI":"10.1016\/j.xkme.2023.100625","article-title":"Anti-PLA(2)R Antibody Development During NELL1-Associated Membranous Glomerulonephritis Treatment: A Case Report","volume":"5","author":"Inoue","year":"2023","journal-title":"Kidney Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Miyasaka, R., Wada, Y., Takeuchi, K., Abe, T., Uchitsubo, R., Kawamura, S., Sakurabayashi, S., Naito, S., Aoyama, T., and Shimizu, A. (CEN Case Rep., 2024). Lupus-like membranous nephropathy during the postpartum period expressing glomerular antigens exostosin 1\/exostosin 2 and phospholipase A2 receptor: A case report, CEN Case Rep., online ahead of print.","DOI":"10.1007\/s13730-023-00848-w"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.2215\/CJN.01460217","article-title":"Circulating Antibodies against Thrombospondin Type-I Domain-Containing 7A in Chinese Patients with Idiopathic Membranous Nephropathy","volume":"12","author":"Wang","year":"2017","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.kint.2018.10.024","article-title":"Novel ELISA for thrombospondin type 1 domain-containing 7A autoantibodies in membranous nephropathy","volume":"95","author":"Zaghrini","year":"2019","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1007\/s11255-019-02146-w","article-title":"Circulating antibodies against M-type phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A in Chinese patients with membranous nephropathy","volume":"51","author":"Tian","year":"2019","journal-title":"Int. Urol. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s00428-019-02558-0","article-title":"Clinicopathological characteristics of thrombospondin type 1 domain-containing 7A-associated membranous nephropathy","volume":"474","author":"Hara","year":"2019","journal-title":"Virchows Arch."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1016\/j.ekir.2020.06.024","article-title":"Profile of Indian Patients With Membranous Nephropathy","volume":"5","author":"Subramanian","year":"2020","journal-title":"Kidney Int. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.2215\/CJN.02500220","article-title":"Multi-Autoantibody Signature and Clinical Outcome in Membranous Nephropathy","volume":"15","author":"Ghiggeri","year":"2020","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e13855","DOI":"10.1111\/ijcp.13855","article-title":"Renal expression of PLA2R, THSD7A, and IgG4 in patients with membranous nephropathy and correlation with clinical findings","volume":"75","author":"Kaya","year":"2021","journal-title":"Int. J. Clin. Pract."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102308","DOI":"10.1016\/j.jaut.2019.102308","article-title":"Autoantigens PLA2R and THSD7A in membranous nephropathy share a common epitope motif in the N-terminal domain","volume":"106","author":"Fresquet","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"727","DOI":"10.2215\/CJN.11860720","article-title":"Neural Epidermal Growth Factor-Like 1 Protein-Positive Membranous Nephropathy in Chinese Patients","volume":"16","author":"Wang","year":"2021","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.kint.2019.09.014","article-title":"Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy","volume":"97","author":"Sethi","year":"2020","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1297107","DOI":"10.3389\/fimmu.2023.1297107","article-title":"Clinicopathological and prognostic characteristics of idiopathic membranous nephropathy with dual antigen positivity","volume":"14","author":"Yang","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2215\/CJN.04060808","article-title":"Membranous glomerulonephritis with ANCA-associated necrotizing and crescentic glomerulonephritis","volume":"4","author":"Nasr","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_28","first-page":"461","article-title":"MPO-ANCA crescentic glomerulonephritis complicated by membranous nephropathy: MPO demonstrated in epimembranous deposits","volume":"2","author":"Matsumoto","year":"2009","journal-title":"NDT Plus"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.humpath.2010.08.020","article-title":"Detection of myeloperoxidase in membranous nephropathy-like deposits in patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis","volume":"42","author":"Hanamura","year":"2011","journal-title":"Hum. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1093\/ckj\/sfr149","article-title":"Coexistence of ANCA-associated glomerulonephritis and anti-phospholipase A(2) receptor antibody-positive membranous nephropathy","volume":"5","author":"Surindran","year":"2012","journal-title":"Clin. Kidney J."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tominaga, K., Uchida, T., Imakiire, T., Itoh, K., Shimazaki, H., Nakanishi, K., Kumagai, H., and Oshima, N. (2018). Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis with detection of myeloperoxidase and phospholipase A(2) receptor in membranous nephropathy-lesions: Report of two patients with microscopic polyangiitis. BMC Nephrol., 19.","DOI":"10.1186\/s12882-018-0922-5"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1681\/ASN.2014050502","article-title":"Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy","volume":"26","author":"Fresquet","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1681\/ASN.2015080953","article-title":"Combined Assessment of Phospholipase A2 Receptor Autoantibodies and Glomerular Deposits in Membranous Nephropathy","volume":"27","author":"Qin","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"145","DOI":"10.2169\/internalmedicine.4752-20","article-title":"Membranous Nephropathy with Proteinase 3-ANCA-associated Vasculitis Successfully Treated with Rituximab","volume":"60","author":"Yoshida","year":"2021","journal-title":"Intern. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1159\/000431331","article-title":"Renal phospholipase A2 receptor in hepatitis B virus-associated membranous nephropathy","volume":"41","author":"Xie","year":"2015","journal-title":"Am. J. Nephrol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chen, R., Wang, J., Xie, Q., Zheng, J., Liu, S., Xue, J., and Hao, C. (2022). Favorable outcome in PLA2R positive HBV-associated membranous nephropathy. BMC Nephrol., 23.","DOI":"10.1186\/s12882-022-02871-y"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1681\/ASN.2018080852","article-title":"Exostosin 1\/Exostosin 2-Associated Membranous Nephropathy","volume":"30","author":"Sethi","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s40620-023-01779-6","article-title":"Distribution spectrum and clinical significance of glomerular exostosin (EXT1) deposits in PLA2R-positive membranous nephropathy","volume":"37","author":"Liu","year":"2023","journal-title":"J. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.xkme.2021.03.013","article-title":"Primary Membranous Nephropathy with Enhanced Staining of Exostosin 1\/Exostosin 2 in the Glomeruli: A Report of 2 Cases","volume":"3","author":"Iwakura","year":"2021","journal-title":"Kidney Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1038\/s41598-022-07037-2","article-title":"Prevalence of neural epidermal growth factor-like 1- and exostosin 1\/exostosin 2-associated membranous nephropathy: A single-center retrospective study in Japan","volume":"12","author":"Iwakura","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.kint.2020.05.030","article-title":"Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients","volume":"98","author":"Sethi","year":"2020","journal-title":"Kidney Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1681\/ASN.2020081165","article-title":"Protocadherin 7-Associated Membranous Nephropathy","volume":"32","author":"Sethi","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Fu, N., Yuan, S., Yang, G., Li, H., and Wang, T. (CEN Case Rep., 2023). Concurrent glomerular PCDH7 deposits in PLA2R-associated membranous nephropathy, CEN Case Rep., online ahead of print.","DOI":"10.1007\/s13730-023-00842-2"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1007\/s00467-022-05503-7","article-title":"Clinicopathologic features of non-lupus membranous nephropathy in a pediatric population","volume":"37","author":"Miller","year":"2022","journal-title":"Pediatr. Nephrol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1007\/s10157-021-02098-5","article-title":"A digest of the Evidence-Based Clinical Practice Guideline for Nephrotic Syndrome 2020","volume":"25","author":"Wada","year":"2021","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1080\/0886022X.2022.2039705","article-title":"Anti-phospholipase A2 receptor antibodies directly induced podocyte damage in vitro","volume":"44","author":"Li","year":"2022","journal-title":"Ren. Fail."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41581-018-0077-4","article-title":"The evaluation of monoclonal gammopathy of renal significance: A consensus report of the International Kidney and Monoclonal Gammopathy Research Group","volume":"15","author":"Leung","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1093\/ndt\/gfn363","article-title":"Monoclonal immunoglobulin deposition disease associated with membranous features","volume":"23","author":"Komatsuda","year":"2008","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1681\/ASN.2009010110","article-title":"Proliferative glomerulonephritis with monoclonal IgG deposits","volume":"20","author":"Nasr","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1681\/ASN.2012060577","article-title":"Recurrent membranous nephropathy in an allograft caused by IgG3kappa targeting the PLA2 receptor","volume":"23","author":"Debiec","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"608741","DOI":"10.3389\/fmed.2021.608741","article-title":"Membranous Nephropathy with Monoclonal IgM Lambda Deposits in a Patient with IgM Monoclonal Gammopathy: A Case Report","volume":"8","author":"Hirose","year":"2021","journal-title":"Front. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e35470","DOI":"10.1097\/MD.0000000000035470","article-title":"Histological transition from minimal change disease to THSD7A-associated membranous nephropathy in a patient receiving long-term steroid treatment: A case report","volume":"102","author":"Kojima","year":"2023","journal-title":"Medicine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1038\/sj.ki.5000289","article-title":"Renal pathology in idiopathic membranous nephropathy: A new perspective","volume":"69","author":"Troyanov","year":"2006","journal-title":"Kidney Int."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1056\/NEJMoa1814427","article-title":"Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy","volume":"381","author":"Fervenza","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1110355","DOI":"10.3389\/fneph.2023.1110355","article-title":"Treatment of membranous nephropathy: Perspectives on current and future therapies","volume":"3","author":"Shah","year":"2023","journal-title":"Front. Nephrol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.ekir.2020.01.018","article-title":"Proteomic Analysis of Complement Proteins in Membranous Nephropathy","volume":"5","author":"Ravindran","year":"2020","journal-title":"Kidney Int. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1681\/ASN.0000000000000221","article-title":"From Patterns to Proteins: Mass Spectrometry Comes of Age in Glomerular Disease","volume":"35","author":"Sethi","year":"2024","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/jcp.23.7.629","article-title":"Elution of antibodies from biopsy tissue","volume":"23","author":"Feltkamp","year":"1970","journal-title":"J. Clin. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/j.kint.2021.08.014","article-title":"Contactin-1 is a novel target antigen in membranous nephropathy associated with chronic inflammatory demyelinating polyneuropathy","volume":"100","author":"Teisseyre","year":"2021","journal-title":"Kidney Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5931\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:05Z","timestamp":1760107805000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,29]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25115931"],"URL":"https:\/\/doi.org\/10.3390\/ijms25115931","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,29]]}}}