Over the past 40 years, nephrologists and pathologists alike have consistently emphasized that membranoproliferative glomerulonephritis (MPGN) is not a diagnosis per se but rather a histopathologic pattern of injury that in turn requires the clinician to seek out potential underlying causes of injury. Until recently, the major clinical classification for MPGN divided patients into secondary cases, when an underlying aetiology could be identified (for example, systemic lupus erythematosus, hepatitis C virus infection, and cryoglobulinaemia), and idiopathic or primary cases, when no such aetiology was present. For primary disease with an MPGN pattern, a histopathologic classification of type I, type II, and type III was used, based largely on the ultrastructural appearance and location of electron-dense deposits. Neither classification scheme was founded on an understanding of the pathogenesis of the disease process. Therapy was largely empiric or selected on the basis of results from trials of patients whose biopsy samples looked similar by light microscopy despite the fact that the findings had the potential to have very different aetiologies. Some of the largest and most influential treatment trials of MPGN included patients with type I MPGN and those with type II MPGN (dense deposit disease [DDD]), despite strong sentiment that type II MPGN was a unique entity and unrelated to type I MPGN.
Over the past decade, improved understanding of the role of complement in the pathogenesis of a number of glomerular diseases has led to progress in disease classification and treatment. For example, in patients with a thrombotic microangiopathy on renal biopsy, clinicians now attempt to determine if the patient has thrombotic thrombocytopenic purpura (TTP) with a low level of ADAMTS13 (the von Willebrand factor cleaving protease), Shiga-toxin-positive haemolytic uremic syndrome (HUS), or atypical HUS in which persistent activation of the alternative complement pathway leads to the thrombotic microangiopathy. Understanding the role of the alternative complement pathway in MPGN has illuminated the entire field and led to a paradigm shift in classification. A proposed reclassification of MPGN into immunoglobulin-mediated disease, driven by classical complement pathway activation, versus non-immunoglobulin-mediated disease, fuelled by alternative complement pathway activation, has led to improved diagnostic algorithms and the emergence of a new grouping of diseases called the C3 glomerulopathies. This improved understanding of MPGN and, in particular, the heightened focus on the activity of the alternative complement pathway in the C3 glomerulopathies will, ideally, lead to improved outcomes in these diseases. (1)
C3 GN is part of the same family as dense deposit disease (DDD) and fall into the new classification of C3 glomerulopathy. Compared to C3 GN, DDD is characterized by extremely electro-dense intra-membranous deposits on EM. Both entities can present with features of MPGN, once significant chronic endothelium glomeruli damage occurs. These glomerular pathologies shared in common its pathogenesis, which involves complement dysregulation.
Classically, immunoglobulins that deposit in the glomeruli are the major triggers of glomeruli inflammation. In rare settings such as C3 GN, complement proteins are present in the glomerular lesions in the absence of immunoglobulins. Abnormal activation of the alternative pathway is implicated on this finding. Either an acquired or inherited defect in the control of alternative complement pathway should be investigated.
The following tests are generally recommended:
- Levels of C3 and complement factors B/H/I
- Presence of C3 nephritic factor (C3 NeF)
- Genotyping for certain complement mutations (common in children)
Circulating C3 nephritic factor is an IgG autoantibody that directly stabilizes the C3-convertase activating complex of the alternative pathway and thereby prevents the normal inhibitory action of complement factor H, leading to continuous activation of the complement cascade and consequent deposition of complement by-products in the glomeruli.
Although atypical hemolytic uremic syndrome (aHUS) is also strongly associated with a dysregulation of the alternative pathway, glomerular lesions in aHUS do not exhibit C3 deposits or electro-dense deposits on electron microscopy, differentiating from C3 glomerulopathies. How changes in complement regulation leads to very diverse presentations might be related to the underlying defect. Nonetheless, atypical HUS could be placed in one side of this spectrum of renal diseases associated with alternative complement dysregulation(2) (figure below; adapted from Servais et al. 2007).
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(1) Nature Reviews Nephrology 8, 634-642 (November 2012) | doi:10.1038/nrneph.2012.213 (2)