• 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 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.

Secondary forms of MPGN can occur as a result of various infections including hepatitis B and C, bacterial endocarditis, mixed cryoglobulinemia, malignancies, collagen vascular disease, and chronic liver disease (including specific entities such as α1-antitrypsin deficiency). Indeed, most cases of MPGN, particularly in adults, are attributable to hepatitis C. The genetic forms of MPGN are rarely seen in adults. There are other entities that occur in rare association with MPGN such as Lyme disease and autoimmune thyroiditis. Moreover, the use of some newer medications has been linked to the occurrence of MPGN type I such as granulocyte colony-stimulating factor. Under these various circumstances, it is presumed that there is immune complex-mediated activation of the complement cascade. In animal models of cryoglobulinemia, overexpression of the membrane complement inhibitor, complement receptor 1-related gene/protein y (Crry), does not prevent the development of MPGN.

MPGN is either idiopathic or secondary to an underlying condition. The former category of diseases cannot be prevented. Secondary causes can be avoided by minimizing exposure to the etiologic agent or by primary prevention of the underlying disease.

Symptoms and Signs

The incidence of MPGN is low and accounts for 5–30% of patients with new-onset nephrotic syndrome. It is lower in adults than in children. Several reports suggest that the incidence of MPGN has been declining over the past 10–20 years. Further epidemiologic studies are needed to clarify this issue. The disease is generally sporadic and familial cases are rare. Overall, the disease is equally prevalent in male and female patients but appears to be more common in white compared to black patients.

MPGN can present in a variety of fashions ranging from asymptomatic hematuria to a severe acute glomerulonephritis. In children, MPGN most often presents either as idiopathic nephrotic syndrome or an acute glomerulonephritis that closely resembles acute postinfectious nephritis. It accounts for 5–10% of pediatric cases of new-onset nephrotic syndrome. The profile of MPGN is distinct from minimal change disease and focal segmental glomerulonephritis, which occur more frequently in younger boys, because it is more common in female patients over 8 years of age. The clinical suspicion of MPGN in a child with acute nephritis rises when the C3 levels fail to normalize during the standard 8–12 week observation period or the C4 level is decreased at the onset of disease because it is only rarely decreased in acute postinfectious glomerulonephritis. Cases such as these account for nearly 30% of all instances of MPGN and may have concomitant reduction in the glomerular filtration rate (GFR). Hypertension is present in 50–80% of cases of MPGN and can be severe. Because of concern that corticosteroid therapy may exacerbate the elevation in blood pressure and trigger malignant hypertension, it is advisable to rule out MPGN in a high-risk patient such as an older female child before initiation of daily treatment with steroids, in cases where steroids might otherwise be indicated.