Update on C3 Glomerulopathy: A Complement-Mediated Disease

Abstract

C3 glomerulopathy (C3G) is a clinicopathologic entity secondary to dysregulation of the alternative complement pathway in plasma and the glomerular microenvironment. The current consensus definition of C3G relies on immunofluorescence staining criteria. However, due to its high clinical variability, these criteria may not be accurate enough in some clinical scenarios. Thus, a new pathogenic classification based on a cluster analysis of clinical, histologic, and genetic data has recently been proposed, which could also help identify patients at higher risk of progression. Several pathogenic abnormalities in complement genes have been described, and the role of autoantibodies in the disease is increasingly recognized, but still the genotype-phenotype correlations in C3G are poorly understood. C3G may be diagnosed in both children and adults. The spectrum of clinical manifestations is wide, although one of the most common clinical presentations is proteinuria with relatively preserved kidney function. In order to standardize the evaluation of kidney biopsies from these patients, a histopathologic index was recently proposed, including both parameters of activity and chronicity. However, this index has not yet been val-idated in independent cohorts. Currently, no targeted therapies are available in clinical settings for the treatment of C3G, although several new molecules are under investigation. Treatment with corticosteroids plus mycophenolate mofetil has been shown to be associated with improved renal outcomes, as compared to other immunosuppressive regimens. Yet, the main determinants of treatment response with this regimen and the influence of the underlying pathogenic drivers have not been extensively studied. The therapeutic response to eculizumab, an anti-C5 monoclonal antibody, has been shown to be highly heterogeneous. Thus, its current clinical indication in C3G is restricted to rapidly progressive forms of the disease. To summarize, in recent years, several important advances have taken place in the understanding of C3G, but still further studies are warranted to elucidate the best therapeutic strategies that could improve prognosis of this entity.

Characterising COVID-19 as a Viral Clotting Fever: A Mixed Methods Scoping Review

“…Collapsing glomerulopathy as a morphological variant of focal segmental glomerulosclerosis is in turn associated both with thrombotic microangiopathy (Buob et al, 2016) and alternative complement pathway activation (Thurman et al, 2015). C3 glomerulopathy is another condition involving the kidneys and resulting from a dysregulated alternative complement pathway activation (Caravaca-Fontán et al, 2020).…”

Complement Factor D (adipsin) Levels Are Elevated in Acquired Partial Lipodystrophy (Barraquer–Simons syndrome)

“…Twenty-two patients with biopsy-proven C3G were selected for inclusion in this study based on standardized criteria [ 6 , 46 , 47 ]. Additionally, 50 healthy subjects were recruited as controls.…”

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

“…In contrast to aHUS patients, these patients are characterized by C3 deposits in glomeruli, which leads to disruption of kidney function, but the disease is not associated with thrombocytopenia, anemia, or other systemic involvement (93). The pathophysiology of disease is not always clear, but in some cases it is known to be caused by autoantibody formation against C3bBb, which stabilizes the convertase and thus increases its activity, or by mutations in C3 or the complement regulatory proteins FH or FI (94)(95)(96). Another kidney disease where an FH polymorphism increases susceptibility is IgA nephropathy, a form of glomerulonephritis where C3 depositions are found on affected kidney tissue, together with IgA.…”