Membranoproliferative Glomerulonephritis and C3 Glomerulopathy in Children

Abstract

Membranoproliferative glomerulonephritis (MPGN) and C3 glomerulopathy (C3G) define a disease pattern characterized by proteinuria, hypertension, and impaired kidney function with a significant risk of disease progression to end-stage kidney disease (ESKD) despite all current treatment efforts. While historically morphological criteria were applied to classify MPGN, recent advances in the understanding of disease pathogenesis with the appreciation of predominant glomerular C3 deposition and the identification of a key role for the complement alternative pathway (AP) resulted in disease reclassification. Today, C3G characterizes a glomerulopathy with predominant C3 deposition. It can be subdivided by electron microscopy into dense deposit disease (DDD) with electron-dense deposits located in the lamina densa of the glomerular basement membrane (GBM), and C3 glomerulonephritis (C3GN) with deposits in subendothelial, subepithelial, and/or mesangial localization. By contrast, cases with coappearance of C3 and immunoglobulins are classified as idiopathic immune-complex MPGN (IC-MPGN). Interestingly, complement mutations and C3 nephritic factor (C3NeF)-an IgG antibody binding to and stabilizing the AP C3 convertase-are found in about 20 and 80% of C3G cases, respectively, but can also be found in IC-MPGN patients. Current treatment recommendations include conservative measures in all cases, and in some immunosuppression with corticosteroids and mycophenolate mofetil (MMF). While milder in children compared to adults, overall prognosis is poor, with roughly 20% of children reaching end-stage kidney disease (ESKD) within 10-15 years. Future treatment strategies are expected to include therapies that block the AP and thereby reduce glomerular C3 accumulation.