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Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated
Paraskevas Iatropoulos1, Erica Daina2, Manuela Curreri1
1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy.
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.
Insights
This study reclassifies Membranoproliferative GN (MPGN) into four distinct patterns based on complement activation. Identifying these patterns aids in understanding C3 glomerulopathy (C3G) and immune complex-MPGN (IC-MPGN) etiology and improving patient risk assessment.
Area of Science:
- Nephrology
- Immunology
- Complement System Biology
Background:
- Membranoproliferative GN (MPGN) classification evolved to C3 glomerulopathy (C3G) and immune complex-MPGN (IC-MPGN).
- Alternative pathway complement abnormalities are implicated in both C3G and IC-MPGN.
- Distinct pathophysiologic mechanisms within MPGN subtypes require further elucidation.
Purpose of the Study:
- To identify distinct disease entities within C3G/IC-MPGN based on underlying pathophysiologic mechanisms.
- To stratify patients into clusters reflecting specific complement activation patterns.
- To develop an algorithm for patient classification and potential risk stratification.
Main Methods:
- Unsupervised hierarchical clustering of histologic, genetic, clinical, and serum/plasma complement data.
- Analysis of 173 patients diagnosed with C3G/IC-MPGN.
- Development of a classification algorithm for patient assignment.
Main Results:
- Four distinct patient clusters emerged, representing different pathogenetic patterns of complement activation.
- Clusters 1-3 showed fluid-phase complement activation with low C3 and high alternative pathway abnormalities.
- Cluster 4 demonstrated solid-phase complement activation with normal/mildly altered C3, late onset, and poor renal survival.
- Specific clusters were associated with alternative/terminal pathway activation, classic pathway involvement, or C3 convertase activation and distinct deposit types.
Conclusions:
- The findings support the existence of four distinct pathogenetic patterns within C3G/IC-MPGN.
- Patient stratification based on complement activation mechanisms can clarify disease etiology.
- This classification may improve risk assessment for end-stage renal disease (ESRD) and guide personalized treatment strategies.