{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T23:12:31Z","timestamp":1784761951663,"version":"3.55.0"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"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>Membranous nephropathy (MN) is a disease with an etiology and pathogenesis that are still not fully understood, and it represents a great challenge. It is characterized by a variable course, spontaneous remissions and relapses. The inability to rely entirely on antibodies and the continuous threat of a malignant disease make the differentiation of MN types extremely difficult. Data of twelve patients with membranous nephropathy, ranging in age between 28 and 67 years, are presented; in total, seven men and five women were observed for a period of 2 to 10 years. In all patients, the diagnosis was confirmed through kidney biopsy and laboratory tests, including immunological, histopathological, and immunohistochemical tests. Histopathological and immunohistochemical tests were applied on available material from the thyroid gland in two patients and the gallbladder in two patients with MN. Data of 102 patients with MN and their comorbidities are evaluated in order to establish correlations. These and other data are used to build a hypothetical pathogenetic model that explains the etiology and the likely pattern of disease occurrence. We found a connection between chronic cholecystitis, thyroiditis, hepatitis, and other diseases in the occurrence of MN and disease course. From our practice and cases, we drew the conclusion that chronic inflammation in sites that express PLA2R leads to the formation of antibodies against PLA2R. These antibodies occur as a preformed immune complex or separately and are deposited in the subepithelial space, leading to MN appearance.<\/jats:p>","DOI":"10.3390\/ijms26052206","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T10:12:33Z","timestamp":1740737553000},"page":"2206","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hypothetical Pathogenetic Model of Membranous Nephropathy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1362-0121","authenticated-orcid":false,"given":"Irina","family":"Zdravkova","sequence":"first","affiliation":[{"name":"Department of Propaedeutics of Internal Diseases, Medical Faculty, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"},{"name":"Nephrology Clinic, University Hospital \u201cKaspela\u201d, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4091-4312","authenticated-orcid":false,"given":"Eduard","family":"Tilkiyan","sequence":"additional","affiliation":[{"name":"Nephrology Clinic, University Hospital \u201cKaspela\u201d, 4000 Plovdiv, Bulgaria"},{"name":"Second Department of Internal Diseases, Section \u201cNephrology\u201d, Medical Faculty, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7802-0576","authenticated-orcid":false,"given":"Desislava","family":"Bozhkova","sequence":"additional","affiliation":[{"name":"Department of General and Clinical Pathology, Faculty of Medicine, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"},{"name":"Department of General and Clinical Pathology, Kaspela University Hospital, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1745-3579","authenticated-orcid":false,"given":"Teodor","family":"Kuskunov","sequence":"additional","affiliation":[{"name":"Department of Propaedeutics of Internal Diseases, Medical Faculty, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"},{"name":"Hemodialysis Unit, University Hospital \u201cKaspela\u201d, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yovko","family":"Ronchev","sequence":"additional","affiliation":[{"name":"Clinical Laboratory, University Hospital \u201cKaspela\u201d, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Kirilov","sequence":"additional","affiliation":[{"name":"Internal Diseases Unit, Department of Emergency Medicine, University Hospital \u201cSveti Georgi\u201d, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pozdzik, A., Broch\u00e9riou, I., David, C., Touzani, F., Goujon, J.M., and Wissing, K.M. (2018). Membranous Nephropathy and Anti-Podocytes Antibodies: Implications for the Diagnostic Workup and Disease Management. BioMed Res. Int., 2018.","DOI":"10.1155\/2018\/6281054"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"983","DOI":"10.2215\/CJN.11761116","article-title":"Primary Membranous Nephropathy","volume":"12","author":"William","year":"2017","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_3","unstructured":"Coffman, T.M., Falk, R.J., Molitoris, B.A., and Schrier, R.W. (2011). Diseases of the Kidney, Elsevier Health Sciences. [9th ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.1681\/ASN.2016010093","article-title":"Long-Term Exposure to Air Pollution and Increased Risk of Membranous Nephropathy in China","volume":"27","author":"Xu","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/nep.12739","article-title":"Increasing Prevalence of Membranous Nephropathy in Patients with Primary Glomerular Diseases: A Cross-sectional Study in China","volume":"22","author":"Tang","year":"2017","journal-title":"Nephrology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"660","DOI":"10.3181\/00379727-100-24736","article-title":"Production of Nephrotic Syndrome in Rats by Freund\u2019s Adjuvants and Rat Kidney Suspensions","volume":"100","author":"Heymann","year":"1959","journal-title":"Exp. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3181\/00379727-163-40729","article-title":"Evidence That the Antigen of Autologous Immune Complex Glomerulonephritis of Rats Is a Mannose- or Glu-cose-Containing Glycoprotein","volume":"163","author":"Makker","year":"1980","journal-title":"Exp. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1681\/ASN.V6135","article-title":"The Heymann Nephritis Antigenic Complex: Megalin (Gp330) and RAP","volume":"6","author":"Farquhar","year":"1995","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1681\/ASN.V11157","article-title":"A Small N-Terminal 60-kD Fragment of Gp600 (Megalin), the Major Autoantigen of Active Heymann Nephritis, Can Induce a Full-Blown Disease","volume":"11","author":"Oleinikov","year":"2000","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1681\/ASN.2005101144","article-title":"Nested N-Terminal Megalin Fragments Induce High-Titer Autoantibody and Attenuated Heymann Nephritis","volume":"17","author":"Tramontano","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.4049\/jimmunol.172.4.2367","article-title":"Conformation and Glycosylation of a Megalin Fragment Correlate with Nephritogenicity in Heymann Nephritis","volume":"172","author":"Tramontano","year":"2004","journal-title":"J. Immunol."},{"key":"ref_12","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_13","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_14","doi-asserted-by":"crossref","unstructured":"Iwakura, T., Ohashi, N., Kato, A., Baba, S., and Yasuda, H. (2015). Prevalence of Enhanced Granular Expression of Thrombospondin Type-1 Domain-Containing 7A in the Glomeruli of Japanese Patients with Idiopathic Membranous Nephropathy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138841"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s10157-014-1054-2","article-title":"Prevalence of Anti-Phospholipase A2 Receptor An-tibodies in Japanese Patients with Membranous Nephropathy","volume":"19","author":"Akiyama","year":"2015","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1681\/ASN.2018080852","article-title":"Exostosin 1\/Exostosin 2\u2013Associated Membranous Nephropathy","volume":"30","author":"Sethi","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1097\/MNH.0000000000000697","article-title":"Membranous Nephropathy: Current Understanding of Various Causes in Light of New Target Antigens","volume":"30","author":"Ronco","year":"2021","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3060","DOI":"10.1681\/ASN.2007030342","article-title":"Intramolecular Epitope Spreading in Heymann Nephritis","volume":"18","author":"Shah","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1681\/ASN.2014111061","article-title":"Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy","volume":"27","author":"Dolla","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1681\/ASN.2019030273","article-title":"Clinical Relevance of Domain-Specific Phos-pholipase A2 Receptor 1 Antibody Levels in Patients with Membranous Nephropathy","volume":"31","author":"Reinhard","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tang, H., Zhu, R., Waldman, M., and Zhu, Q. (2022). Structural Determinants of the Dominant Conformational Epitopes of Phospholipase A2 Receptor in Primary Membranous Nephropathy. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101605"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.2215\/CJN.05880614","article-title":"Antiphospholipase A2 Receptor Autoantibody Guided Diagnosis and Treatment of Membranous Nephropathy: A New Personalized Medical Approach","volume":"9","author":"Glassock","year":"2014","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s40620-022-01528-1","article-title":"Accuracy of Serum PLA2R Antibody Detected by Indirect Immunofluorescence in Diagnosing Biopsy-Proven Primary Membranous Nephropathy: A Single-Center Experience and a Systematic Review of the Literature","volume":"36","author":"Allinovi","year":"2022","journal-title":"J. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1159\/000520399","article-title":"Malignancy-Associated Membranous Nephropathy with Positive Anti-PLA2R Autoantibodies: Coincidence or Connection","volume":"11","author":"Baker","year":"2021","journal-title":"Case. Rep. Nephrol. Dial."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e140453","DOI":"10.1172\/JCI140453","article-title":"Altered Glycosylation of IgG4 Promotes Lectin Complement Pathway Activation in Anti-PLA2R1\u2013Associated Membranous Nephropathy","volume":"131","author":"Haddad","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nm0395-237","article-title":"Glycosylation Changes of IgG Associated with Rheumatooid Arthritis Can Activate Complement via the Mannose-Binding Protein","volume":"1","author":"Malhotra","year":"1995","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Radovani, B., and Gudelj, I. (2022). N-Glycosylation and Inflammation; the Not-So-Sweet Relation. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.893365"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Tissue-Based Map of the Human Proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_30","unstructured":"(2024, December 08). Single Cell Type\u2014PLA2R1\u2014The Human Protein Atlas. Available online: https:\/\/www.proteinatlas.org\/ENSG00000153246-PLA2R1\/single+cell#single_cell_type_summary."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1042\/CS20120543","article-title":"Celecoxib Modifies Glomerular Basement Membrane, Mesangium and Podocytes in OVE26 Mice, but Ibuprofen Is More Detrimental","volume":"124","author":"Nasrallah","year":"2013","journal-title":"Clin. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, W., Gao, C., Dai, H., Zheng, Y., Dong, Z., Gao, Y., Liu, F., Zhang, Z., Liu, Z., and Liu, W. (2019). Immunological Pathogenesis of Membranous Nephropathy: Focus on PLA2R1 and Its Role. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01809"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2206\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:44:55Z","timestamp":1760028295000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,28]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26052206"],"URL":"https:\/\/doi.org\/10.3390\/ijms26052206","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,28]]}}}