Membranoproliferative glomerulonephritis classification
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ali Poyan Mehr, M.D. [2]
Overview
Like many forms of glomerulopathies, membranoproliferative glomerulonephritis (glomerulopathy) has been a diagnosis of tissue pathology rather the diagnosis of a specific disease entity. Therefore the term membranoploriferative glomerulonephritis (MPGN) relates to a pattern of glomerular injury which can be caused by many disease states. Historically the nephropathologists divided MPGN into 3 distinctive categories to shed light into what may be causing this type of kidney injury: MPGN type 1: mesangial and subendothelial electron dense deposits MPGN type 2: electron dense material in the glomerular basement membrane MPGN type 3: subepithelial deposits with basement membrane spikes
This categorization, however is now obsolete. The recognition of several new disorders as the underlying cause of MPGN, and the lack of clinical, prognostic, or therapeutic relevance made this categorization less useful. For completeness and to help better accommodate the transition from old to new classification, below both classifications are reviewed.
Classification
There are three types of MPGN.
Type I
The most common type.
Circulating immune complexes are present in approximately 33% of patients with MPGN type I. In all patients with type I, immune complexes are found in the mesangium and subendothelial spaces, and they trigger complement activation and the release of cytokines and chemokines. The release of inflammatory mediators causes an influx of inflammatory cells and leads to mesangial and endothelial cell proliferation. Most patients with circulating immune complexes do not develop MPGN; thus, additional pathogenic factors (eg, nature of the antigen, size of complexes, type and charge on antibodies, local glomerular factors) must play a role. In addition to circulating immune complexes becoming entrapped in the glomerular basement membrane (GBM), experimental evidence indicates that complexes may be formed in situ when antigens adhere to the GBM and antibodies subsequently bind to these antigens. Formation of such immune complexes triggers the same cascade as described above.
Activation of complement and the resulting hypocomplementemia may cause defective clearance of circulating immune complexes. The nephritic factor of the classic pathway (ie, NFc or C4NeF) is found in approximately 15% of patients. This nephritic factor stabilizes the classic pathway C3 convertase C4b,2a and potentiates C3 activation and consumption. The role of this nephritic factor in the pathogenesis of MPGN type I is unclear. Approximately 20% of patients have the nephritic factor of the terminal pathway.
Type II
Type II (dense deposit disease) is very similar, except the material deposited is not immune complexes and is not yet known. MPGN type II (or dense deposit disease) is a separate entity that has been conventionally classified with MPGN because of the similarities of light microscopic appearance. The pathogenesis of MPGN type II is not known. This disease is systemic, as evidenced by dense deposits in the kidney, splenic sinusoids, and Bruch membrane of the retina. This disease also has a high incidence of recurrence in renal allografts. The chemical composition and origin of the dense deposits are not known. No circulating immune complexes are observed in MPGN type II.
Dense deposit disease is associated with multiple complement abnormalities, including a persistent reduction of C3 levels. One hypothesis is that the dense deposits cause complement activation. This hypothesis is supported by the tram-track distribution of C3 deposits along the basement membrane.
NFa is present in 80% of patients with dense deposit disease. NFa stabilizes the alternative pathway convertase and results in complement activation and chronic C3 consumption. Deficiencies of factor H or resistance to factor H, described in MPGN, may lead to an accumulation of the alternative pathway convertase and chronic C3 consumption.
Partial lipoid dystrophy (PLD) is associated commonly with MPGN type II and the presence of NFa. Adipocytes produce adipsin, which is identical to complement factor D and is responsible for activating the preconvertase C3b,Bb. NFa causes a lysis of adipocytes that produce adipsin, and the distribution of fat atrophy in PLD follows variations in the amount of adipsin produced by adipocytes. By analogy, NFa may cause damage to glomerular cells that produce complement.
Type III
Type III is very rare, it is characterized by a mixture of subepithelial deposits and the typical pathological findings of Type I disease.
The glomerular deposits contain C3, C5, and properdin, indicating activation of the alternative complement pathway. Signs of activation of the classic pathway are minimal, and circulating immune complexes do not appear to play a role in the genesis of this variant.
Changes in the capillary wall are hypothesized to be the primary event leading to activation of the complement pathway. This hypothesis is supported by the deposition of C3Bb2,Bb convertase components in the basement membrane. The deposits of convertase and membrane attack complex may lyse the basement membrane and stimulate new membrane formation. NFt is present in 60-80% of patients with MPGN type III. NFt stabilizes the alternative pathway properdin-dependent C3/C5 convertase (C3Bb2,Bb,P) and also activates the terminal complement components, forming C5b-C9 (ie, the membrane attack complex).
A familial form of MPGN type III with an autosomal dominant pattern of inheritance has been identified with genetic linkage to band 1q31-32. Genes in this area of chromosome 1 code for proteins that regulate the C3 convertase activity.