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Abstract: FR-PO724

Unravelling the Pathophysiology of C3G/IC-MPGN and How to Predict Disease Progression and Orient Therapies

Session Information

Category: Glomerular

  • 1004 Clinical/Diagnostic Renal Pathology and Lab Medicine

Authors

  • Iatropoulos, Paraskevas, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Daina, Erica, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Curreri, Manuela, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Piras, Rossella, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Valoti, Elisabetta, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Mele, Caterina, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Bresin, Elena, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Gamba, Sara, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Alberti, Marta, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Breno, Matteo, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Sabadini, Ettore, Ospedale Papa Giovanni XXIII, Bergamo, BG, Italy
  • Noris, Marina, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy
  • Remuzzi, Giuseppe, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy

Group or Team Name

  • Registry of Membranoproliferative Glomerulonephritis/C3 Glomerulopathy
Background

Membranoproliferative glomerulonephritis (MPGN) was recently reclassified into alternative pathway (AP) complement-mediated C3 glomerulopathy (C3G) and immune-complex-mediated MPGN (IC-MPGN). However, genetic and acquired AP abnormalities are also observed in IC-MPGN. Here, in patients with C3G/IC-MPGN, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms.

Methods

We performed unsupervised hierarchical clustering, a data-driven statistical approach not biased by operator hypotheses, on 163 C3G/IC-MPGN patients using histology, genetic, serum complement and clinical features.

Results

This approach divided C3G/IC-MPGN patients into four clusters, characterized by specific histology, clinical and complements features indicating the existence of four different pathogenetic patterns. Specifically, patients with fluid-phase complement activation, showing low serum C3 and a high prevalence of AP gene mutations and/or C3NeF (clusters 1-3), were separated from patients with solid-phase complement activation (cluster 4), showing likely normal serum C3, late onset and poor renal survival. In patients with fluid-phase complement activation, clusters 1 and 2 were characterized by massive AP activation as far as the terminal pathway and the highest prevalence of subendothelial deposits, but cluster 2 was characterized by the additional activation of the classical pathway and the highest prevalence of nephrotic syndrome at onset. Patients in cluster 3 were characterized by prevalent activation of the C3 convertase and highly electron-dense deposits.

Conclusion

These clusters of C3G/IC-MPGN patients may be useful for better clarifying disease etiology, defining the risk of ESRD and paving the way for personalized treatment.