Membranoproliferative glomerulonephritis and C3 glomerulopathy: Resolving the confusion

Membranoproliferative glomerulonephritis (MPGN) denotes a general pattern of glomerular injury that is easily recognized by light microscopy. With additional studies, MPGN subgrouping is possible. For example, electron microscopy resolves differences in electron-dense deposition that are classically referred to as MPGN type I (MPGN I), MPGN II, and MPGN III, while immunofluorescence typically detects immunoglobulins in MPGN I and MPGN III but not in MPGN II. All three MPGN types stain positive for complement component 3 (C3). Subgrouping has led to unnecessary confusion, primarily because immunoglobulin-negative MPGN I and MPGN III are more common than once recognized. Together with MPGN II, which is now called dense deposit disease, immunoglobulin-negative, C3-positive glomerular diseases fall under the umbrella of C3 glomerulopathies (C3G). The evaluation of immunoglobulin-positive MPGN should focus on identifying the underlying trigger driving the chronic antigenemia or circulating immune complexes in order to begin disease-specific treatment. The evaluation of C3G, in contrast, should focus on the complement cascade, as dysregulation of the alternative pathway and terminal complement cascade underlies pathogenesis. Although there are no disease-specific treatments currently available for C3G, a better understanding of their pathogenesis would set the stage for the possible use of anti-complement drugs.