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  • Characterized by persistent hypocomplementemia.
  • Disease is most often primary or idiopathic.
  • Fifty percent of patients progress to end-stage renal disease over 10–15 years.
  • Prednisone is effective in pediatric patients but there is no proven treatment in adults.
  • Disease recurs posttransplantation in approximately 25% of patients.

Membranoproliferative glomerulonephritis (MPGN) is the classic renal nomenclature monstrosity that spreads fear among house officers and practitioners. This disease was first described by Rene Habib in 1961 and was linked to decreased serum complement levels in 1965. Since then it has been a recognized cause of serious glomerular disease in pediatric and adult patients throughout the world and represents an important cause of end-stage renal disease. It is defined by a characteristic histopathologic appearance that consists of a lobulated shape to the glomerular tuft, glomerular hypercellularity, thickening of the capillary wall, and splitting of the glomerular basement membrane with a double contour (“tram tracking”). On ultrastructural examination of renal tissue, there are electron-dense deposits in the capillary wall and the distinctive localization of the deposits results in classification of MPGN into type I (subendothelial and mesangial), type II (intramembranous dense deposits), and type III (subendothelial, mesangial, and subepithelial).

The general mechanism of disease for the development of MPGN is dysregulated complement protein activation. Under normal circumstances complement activity, composed of various chemotactic factors and the membrane attack complex, is triggered either through the classical or alternative pathways. The third component of the cascade, C3, occupies a pivotal position in both pathways and is essential to the effector functions of the system. Therefore, a number of regulatory proteins are synthesized to modulate C3 convertase (C3bBb) activity and to prevent the deleterious consequences of uninterrupted complement activation. These include factors H and I, membrane cofactor protein (MCP), and decay accelerating factor.

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 ...

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