RT Journal Article
SR Electronic
T1 Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex–Mediated Membranoproliferative GN
JF Journal of the American Society of Nephrology
JO J. Am. Soc. Nephrol.
FD American Society of Nephrology
SP 283
OP 294
DO 10.1681/ASN.2017030258
VO 29
IS 1
A1 Iatropoulos, Paraskevas
A1 Daina, Erica
A1 Curreri, Manuela
A1 Piras, Rossella
A1 Valoti, Elisabetta
A1 Mele, Caterina
A1 Bresin, Elena
A1 Gamba, Sara
A1 Alberti, Marta
A1 Breno, Matteo
A1 Perna, Annalisa
A1 Bettoni, Serena
A1 Sabadini, Ettore
A1 Murer, Luisa
A1 Vivarelli, Marina
A1 Noris, Marina
A1 Remuzzi, Giuseppe
YR 2018
UL http://jasn.asnjournals.org/content/29/1/283.abstract
AB 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.