MPGN is classified into primary and secondary forms. The pathogenesis of MPGN is linked to the underlying etiology of the glomerulopathy (Table 28–1). In the primary forms of MPGN, the mechanism of disease centers around abnormal activation of the complement cascade. In-depth studies of all components of the complement cascade suggest that there are three distinct patterns of complement activation in the three types of MPGN. Thus, in type I disease, the process is initiated by immune complex deposition within the glomerulus and involvement of the classical pathway. The source of the immune complexes is unknown in the idiopathic form of the disease. These patients have low levels of C3, C4, C6, C7, and/or C9. MPGN type I is sometimes associated with the presence of a circulating immunoglobulin (Ig)G or IgM autoantibody that stabilizes the C3 convertase (eg, C3 nephritic factor), thus engendering low C3 levels. A C4 nephritic factor has also been described. In the type II variant, the continuous overactivity of the complement cascade involves an amplification loop in the alternative pathway, characterized mainly by markedly depressed C3 levels. Abnormal complement activation in MPGN can also occur as a consequence of genetic mutations that result in reduced levels of endogenous inhibitors of the process, such as factor H, or because of the presence of C3 nephritic factor, the latter occurring in the majority of patients with MPGN type II (also called dense deposit disease). Animal models in mice and pigs demonstrate the importance of factor H in regulating complement activation and the occurrence of MPGN when circulating levels of this protein are reduced. It is worth noting that unlike hemolytic uremic syndrome, which can develop in patients who have heterozygous genetic defects in factor H, MPGN occurs only in patients who carry homozygous mutations. Other genetic causes of MPGN include isolated C4 deficiency. Finally, the pathogenesis of MPGN type III appears to have features in common with type I disease as well as evidence of activation of the terminal complement pathway with low C3, C5, and properdin levels. In adults, the type III form frequently occurs in association with systemic infection, inflammation, or neoplasm. The presence of MGPN type III in adults should stimulate a search for an underlying systemic process causing it.