ESSENTIALS OF DIAGNOSIS
Characterized by persistent hypocomplementemia.
Disease is most often primary or idiopathic.
Disease can occur secondary to immunoglobulin-mediated activation of the complement cascade or acquired or genetic abnormalities in the alternate pathway of complement.
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 post-transplantation 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 rare but well recognized cause of serious glomerular disease in pediatric and adult patients throughout the world and represents an important cause of end-stage kidney disease (ESKD). 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).
In the last decade, the pivotal role of the alternate pathway of complement in this disorder has become increasingly evident. As a consequence, a new nomenclature, C3 glomerulopathy (C3G), has been introduced that overlaps with MPGN, types II and III. This is an evolving area and it is likely that terminology and definitions will become more standardized with time. MPGN is now classified into immune-complex (IC-GN) and complement C3G. For the purpose of this chapter, the new classification will be used namely, immunoglobulin (Ig) mediated MPGN I, C3 glomerulopathies, and Ig-mediated MPGN III.
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 29–1). 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 ...