Membranoproliferative glomerulonephritis and C3 nephropathy
MPGN is a rare form of chronic nephritis that occurs primarily in children and young adults and is characterized by diffuse proliferative lesions and widening of the capillary loops under light microscopy. Subgrouping of this condition is based on electron microscopy findings: type I is characterized by subendothelial deposits, type II by electron-dense deposits in the glomerular basement membrane, and type III by subendothelial and subepithelial deposits. All three types stain positive for complement component 3, however, immunoglobulin deposits are typically present in types I and II, but not in type II. To further add to the confusion, C3-positive but immunoglobulin-negative MPGN I and MPGN III have also been observed. Thus, a more recent classification differentiates immune complex-mediated MPGN (IC-MPGN), which is immunoglobulin-positive, and C3 glomerulopathies (C3G), encompassing dense deposit disease and C3 glomerulonephritis (C3GN), both characterized by C3 accumulation and absent or scarce immunoglobulin deposition (8). Still, these two entities share one common feature: a large majority of patients with either IC-MPGN or C3G have low serum C3 and normal C4 levels, indicating activation of the alternative complement pathway (9).
Mutations in genes encoding proteins pf the alternative pathway complement were found in both IC-MPGN and C3G. The most prevalent mutations are in the two components of the alternative pathway C3 convertase C3 and CFB (9).
In the majority of patients with C3G only antibodies against the C3 convertase, termed C3 Nephritic Factors (C3Nefs), can be found as a potential pathogenic factor. C3NeFs belong to a heterogeneous family of autoantibodies (NeFs) that stabilize the convertases complexes. C3NeFs bind to the assembled C3 convertase (C3bBb) and prevent its spontaneous and factor H mediated decay (10). Another nephritic factor has been characterized by the ability to stabilize the C5 convertase of the alternative pathway (C5NeF). C5NeFs bind to the assembled C5 convertase and prevent both its spontaneous and CFH mediated decay. Numerous studies have explored mechanisms of action of C3NeF on the C3bBb, but few have investigated the reactivity of patient IgG to C3bBb and to the C5 convertase (11).
Cluster analysis in patients with IC-MPGN and C3G
Acknowledging the limitations of the current MPGN/C3G classification, Iatropoulous et al. performed a cluster analysis in 173 patients with IC-MPGN and C3G (Figure 2). They distributed patients into four clusters, indicating the existence of four different pathogenetic patterns: clusters 1-3 included patients with fluid-phase complement activation, who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities; while cluster 4 included patients with solid-phase complement activation and normal or mildly altered serum C3, late disease onset, and poor renal survival. Patients 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. Patients 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 fluid phase activation of the alternative pathway but C3 convertase activity predominates over C5 convertase activity as documented by mostly normal sC5b9 levels, and show very dense deposits on electron microscopy (12). The authors also devised a simple algorithm to assign patients with IC-MPGN/C3G to specific clusters (Figure 2). Such an approach may facilitate clarification of disease etiology, improve risk assessment for progression to end-stage renal disease, and pave the way for personalized treatment (12). Furthermore, unlike the standard pathohistology classification, cluster analysis exhibits prognostic value and predicts response to therapy (13). All these findings were further confirmed in a study by Garam et al. (14).