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Clinical Research
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Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex–Mediated Membranoproliferative GN

Paraskevas Iatropoulos, Erica Daina, Manuela Curreri, Rossella Piras, Elisabetta Valoti, Caterina Mele, Elena Bresin, Sara Gamba, Marta Alberti, Matteo Breno, Annalisa Perna, Serena Bettoni, Ettore Sabadini, Luisa Murer, Marina Vivarelli, Marina Noris and Giuseppe Remuzzi; for the Registry of Membranoproliferative Glomerulonephritis/C3 Glomerulopathy
JASN January 2018, 29 (1) 283-294; DOI: https://doi.org/10.1681/ASN.2017030258
Paraskevas Iatropoulos
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Erica Daina
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Manuela Curreri
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Rossella Piras
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Elisabetta Valoti
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Caterina Mele
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Elena Bresin
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Sara Gamba
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Marta Alberti
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Matteo Breno
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Annalisa Perna
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Serena Bettoni
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Ettore Sabadini
2Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy;
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Luisa Murer
3Unit of Pediatric Nephrology, Dialysis and Transplantation, Azienda Ospedaliera of Padova, Padua, Italy;
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Marina Vivarelli
4Division of Nephrology and Dialysis, Children’s Hospital Bambino Gesù, IRCCS, Rome, Italy; and
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Marina Noris
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
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Giuseppe Remuzzi
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy;
2Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy;
5Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
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Abstract

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement–mediated C3 glomerulopathy (C3G) and immune complex–mediated 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 1–3) 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.

  • C3 glomerulopathy
  • C3 glomerulonephritis
  • Dense Deposit Disease
  • membranoproliferative glomerulonephritis (MPGN)
  • Complement system
  • Rare diseases
  • Copyright © 2018 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 29 (1)
Journal of the American Society of Nephrology
Vol. 29, Issue 1
January 2018
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Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex–Mediated Membranoproliferative GN
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Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex–Mediated Membranoproliferative GN
Paraskevas Iatropoulos, Erica Daina, Manuela Curreri, Rossella Piras, Elisabetta Valoti, Caterina Mele, Elena Bresin, Sara Gamba, Marta Alberti, Matteo Breno, Annalisa Perna, Serena Bettoni, Ettore Sabadini, Luisa Murer, Marina Vivarelli, Marina Noris, Giuseppe Remuzzi
JASN Jan 2018, 29 (1) 283-294; DOI: 10.1681/ASN.2017030258

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Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex–Mediated Membranoproliferative GN
Paraskevas Iatropoulos, Erica Daina, Manuela Curreri, Rossella Piras, Elisabetta Valoti, Caterina Mele, Elena Bresin, Sara Gamba, Marta Alberti, Matteo Breno, Annalisa Perna, Serena Bettoni, Ettore Sabadini, Luisa Murer, Marina Vivarelli, Marina Noris, Giuseppe Remuzzi
JASN Jan 2018, 29 (1) 283-294; DOI: 10.1681/ASN.2017030258
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Keywords

  • C3 glomerulopathy
  • C3 glomerulonephritis
  • Dense Deposit Disease
  • membranoproliferative glomerulonephritis (MPGN)
  • Complement system
  • Rare diseases

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