Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN

J Am Soc Nephrol. 2018 Jan;29(1):283-294. doi: 10.1681/ASN.2017030258. Epub 2017 Oct 13.


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.

Keywords: C3 glomerulonephritis; C3 glomerulopathy; Complement system; Dense Deposit Disease; Rare diseases; membranoproliferative glomerulonephritis (MPGN).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Algorithms
  • Child
  • Child, Preschool
  • Cluster Analysis
  • Complement Activation*
  • Complement C3 / metabolism*
  • Complement C3 Nephritic Factor / metabolism*
  • Complement C3-C5 Convertases / metabolism
  • Female
  • Glomerulonephritis, Membranoproliferative / blood
  • Glomerulonephritis, Membranoproliferative / genetics*
  • Glomerulonephritis, Membranoproliferative / immunology*
  • Humans
  • Immune Complex Diseases / blood
  • Immune Complex Diseases / complications*
  • Male
  • Nephrotic Syndrome / immunology
  • Young Adult


  • Complement C3
  • Complement C3 Nephritic Factor
  • Complement C3-C5 Convertases