Pathology

MPGN is defined by the histologic pattern of glomeruli as seen by light, immunofluorescence, and electron microscopy. Two subtypes have been defined on histologic criteria and are associated with different clinical phenotypes. Type I MPGN is most common. Glomeruli have an accentuated lobular pattern from diffuse mesangial expansion, endocapillary proliferation, and an increase in mesangial cells and matrix. The glomerular capillary walls are thickened, often with splitting from interposition of the mesangium. Crescents, if present, indicate a poor prognosis. Immunofluorescence microscopy reveals C3 and lesser amounts of immunoglobulin in the mesangium and along the peripheral capillary walls in a lobular pattern. Electron microscopy confirms numerous deposits in the mesangial and subendothelial regions.

Far less common is type II MPGN, also called dense deposit disease, which has similar light microscopic findings as type I MPGN. Differentiation from type I disease is by immunofluorescence and electron microscopy. In type II disease, C3 immunofluorescence typically is prominent without concomitant immunoglobulin. By electron microscopy, the lamina densa in the GBM undergoes a very dense transformation, without evident immune complex–type deposits.

Pathogenesis

Because the histology of type I MPGN produced by primary and secondary forms is indistinguishable, it appears that this form occurs because circulating immune complexes become trapped in the glomerular subendothelial space, which then causes injury, resulting in the characteristic proliferative response and mesangial expansion. Further evidence confirming this pathway to glomerular injury is the finding of complement activation through the classical pathway in as many as 50% of affected patients.

Type II MPGN appears to not be mediated by the immune complex. The pathogenesis of the disease is not known, but the characteristic finding of severely depressed serum complement levels suggests that deranged complement regulation might play a major role in disease. A typical finding is markedly depressed serum C3 complement levels, with normal levels of other complement components. In many patients with type II MPGN, C3 nephritic factor is present. This factor activates the alternative complement pathway. In unusual cases, patients with type II MPGN demonstrate an associated systemic disease called partial lipodystrophy, where there is diffuse loss of adipose tissue and decreased complement in the presence of C3 nephritic factor. Correlation among the presence of C3 nephritic factor, complement levels, and disease presence or severity is not uniform or tightly associated, indicating that the complement abnormalities alone are not sufficient to cause the disease.

Clinical Manifestations

MPGN is most common in the 2nd decade of life. Systemic features could provide clues to which type of MPGN may be present in the secondary forms of the disease, but the 2 histologic types of idiopathic MPGN are indistinguishable on clinical grounds. Patients present in equal proportions with nephrotic syndrome, acute nephritic syndrome (hematuria, hypertension, and some level of renal insufficiency), or persistent asymptomatic microscopic hematuria and proteinuria. Serum C3 complement levels are low in the majority of cases (see Fig 505-3).

Differential Diagnosis

The differential diagnosis includes all forms of acute and chronic glomerulonephritis, including idiopathic and secondary forms, along with postinfectious glomerulonephritis. Postinfectious glomerulonephritis, far more common than MPGN, usually does not have nephrotic features but typically has hematuria, hypertension, renal insufficiency, and transient low C3 complement levels, all features that may be seen with MPGN. In contrast to MPGN, where C3 levels usually remain persistently low, C3 returns to normal within 2 months after the onset of postinfectious glomerulonephritis (Chapter 505 and Fig. 505-3). The diagnosis of MPGN is made by renal biopsy. Indications for biopsy include nephrotic syndrome in an older child, significant proteinuria with microscopic hematuria, and hypocomplementemia lasting >2 mo in a child with acute nephritis.

Prognosis and Treatment

It is important to determine whether MPGN is idiopathic or secondary to a systemic disease, particularly lupus or chronic infection, because treatment of the causative disease can result in resolution of MPGN. Untreated, idiopathic MPGN, regardless of type, has a poor prognosis. By 10 yr after onset, 50% of patients with MPGN have progressed to end-stage renal disease. By 20 yr after onset, up to 90% have lost renal function. Those with nephrotic syndrome at the time of presentation progress to renal failure more rapidly. No definitive therapy exists, but several reports, including a randomized, controlled trial, indicate that extended courses for years of alternate-day prednisone provide benefit. Some patients treated with steroids enter complete remission of their disease, but many have ongoing disease activity. Nevertheless, an extended course of prednisone is associated with significant preservation of renal function compared with patients receiving no such treatment.