{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:39:46Z","timestamp":1792643986471,"version":"4.5.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement\u2013mediated C3 glomerulopathy (C3G) and immune complex\u2013mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum\/plasma complement parameters from 173 patients with C3G\/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1\u20133) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G\/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment.<\/jats:p>","DOI":"10.1681\/asn.2017030258","type":"journal-article","created":{"date-parts":[[2017,10,13]],"date-time":"2017-10-13T20:25:34Z","timestamp":1507926334000},"page":"283-294","source":"Crossref","is-referenced-by-count":145,"title":["Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies\/Immune Complex\u2013Mediated Membranoproliferative GN"],"prefix":"10.1681","volume":"29","author":[{"given":"Paraskevas","family":"Iatropoulos","sequence":"first","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Daina","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Curreri","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Piras","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Valoti","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Mele","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Bresin","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gamba","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Alberti","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Breno","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Perna","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Bettoni","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Sabadini","sequence":"additional","affiliation":[{"name":"Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Murer","sequence":"additional","affiliation":[{"name":"Unit of Pediatric Nephrology, Dialysis and Transplantation, Azienda Ospedaliera of Padova, Padua, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Vivarelli","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Dialysis, Children\u2019s Hospital Bambino Ges\u00f9, IRCCS, Rome, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Noris","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Remuzzi","sequence":"additional","affiliation":[{"name":"IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2, Ranica Bergamo, Italy;"},{"name":"Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy;"},{"name":"Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Registry of Membranoproliferative Glomerulonephritis\/C3 Glomerulopathy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,10,13]]},"reference":[{"key":"B1-20230819","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/nrneph.2014.217","article-title":"Histopathology of MPGN and C3 glomerulopathies.","volume":"11","author":"Cook","year":"2015","journal-title":"Nat Rev Nephrol"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.semnephrol.2011.06.005","article-title":"Membranoproliferative glomerulonephritis: Pathogenetic heterogeneity and proposal for a new classification.","volume":"31","author":"Sethi","year":"2011","journal-title":"Semin Nephrol"},{"key":"B3-20230819","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/ki.2013.377","article-title":"C3 glomerulopathy: Consensus report.","volume":"84","author":"Pickering","year":"2013","journal-title":"Kidney 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