A recent Core Curriculum by Noris and Remuzzi is on the timely topic of activation of the complement system in glomerular disease. This focuses on our evolving understanding of atypical hemolytic uremic syndrome (aHUS), membranoproliferative glomerulonephritis (MPGN), and C3 glomerulopathy.
The complement system may be activated by one of three pathways (alternative, classical, and lectin) with a common terminal pathway.
The alternative pathway (AP) continuously ticks over with low-grade activation via spontaneous cleavage of C3 by C3 convertase. This is beneficial for pathogen recognition, leukocyte attachment, and phagocytosis. AP regulators, either membrane bound or fluid phase, act as a braking mechanism for the system, and AP dysregulation via inherited or acquired defects in complement regulatory proteins is critical to the pathogenesis of several glomerular disorders.
aHUS refers to a rare cause of HUS which cannot be explained by Shiga toxin-producing E. coli or other secondary causes. It is notable that about 30% of cases of aHUS present with diarrhea, making clinical differentiation from Shiga toxin-related HUS difficult, even in very young children. Primary disorders of AP complement regulation are often to blame (about 60% of cases have a mutation identifiable). The authors describe mutations including CFH (and CFH-related 1-5 genes), CFI, MCP, CFB, C3, and thrombomodulin. Other interesting observations include:
- Cases of polygenic inheritance demonstrating alterations in >1 complement gene (might these patterns explain different phenotypes with similar mutations?).
- Incomplete penetrance with likely additional genetic or environmental ‘hits’ necessary to trigger disease.
- Normal C3 levels in many cases, which may be explained by the proteins preserved ability to regulate complement in the fluid phase (but not on host cells).
- Likelihood of unrecognized mutations inducing C5b-9 (membrane attack complex) endothelial deposits.
The discussion of MPGN includes the newer classification based on IF rather than EM. This splits cases into those with immune complexes (comprising most of what was previously termed MPGN type 1 & 3) and those with predominant complement deposition, named C3 glomerulopathy (dense deposit disease and C3 glomerulonephritis). Despite this guidance, tricky cases remain, particularly those with predominant C3 staining but with some Ig deposition, and cases of apparent post-infectious GN with isolated C3 staining.
The authors explain how chronic infection, autoimmune immune complexes, and paraproteins may activate the complement system in MPGN. Immune-complex MPGN may therefore remain part of the complement spectrum of glomerular disorders, even if complement activation is not the primary insult, since it represents a primary mechanism of injury. A more detailed pathophysiology of C3 glomerulopathy is described, including nuances of the C3 nephritic factor and other complement protein autoantibodies.
An issue which has always perplexed me is why some patients with certain complement gene mutations develop aHUS while others develop MPGN/C3 glomerulopathy. This remains unclear, but the review speculates that they may be part of a spectrum of complement-mediated glomerular disorders. They cite cases of different presentations with the same mutation, as well as patients who first developed aHUS but subsequently developed C3 glomerulonephritis post transplant. We have more to learn in this evolving story. However, our increasing understanding of the pathogenesis of these disorders is allowing directed treatments with the arrival of eculizumab and other novel anti-complement targeted therapies on the horizon.
Dr. Paul Phelan
AJKD Blog Contributor