Abstract
C3 glomerulopathy (C3G) is a recently identified disease entity caused by dysregulation of the alternative complement pathway, and dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are its components. Because laboratory detection of complement dysregulation is still uncommon in practice, “dominant C3 deposition by two orders greater than that of immunoglobulins in the glomeruli by immunofluorescence”, as stated in the consensus report, defines C3G. However, this morphological definition possibly includes the cases with glomerular diseases of different mechanisms such as post-infectious glomerulonephritis. In addition, the differential diagnosis between DDD and C3GN is often difficult because the distinction between these two diseases is based solely on electron microscopic features. Recent molecular and genetic advances provide information to characterize C3G. Some C3G cases are found with genetic abnormalities in complement regulatory factors, but majority of cases seem to be associated with acquired factors that dysregulate the alternative complement pathway. Because clinical courses and prognoses among glomerular diseases with dominant C3 deposition differ, further understanding the background mechanism, particularly complement dysregulation in C3G, is needed. This may resolve current dilemmas in practice and shed light on novel targeted therapies to remedy the dysregulated alternative complement pathway in C3G.
Highlights
C3 glomerulopathy (C3G) is an emerging kidney disease caused by dysregulation of the alternative complement pathway [1,2,3,4,5]
C3 glomerulopathy (C3G) is a recently identified disease entity caused by dysregulation of the alternative complement pathway, and dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are its components
We review the current status of C3G and dilemmas that may bring a more distinct definition and accurate therapies for patients with alternative complement dysregulation
Summary
C3 glomerulopathy (C3G) is an emerging kidney disease caused by dysregulation of the alternative complement pathway [1,2,3,4,5]. C3G reveal various histological patterns of glomerular injury by LM, including mesangial proliferative, diffuse endocapillary proliferative, and crescentic glomerulonephritis [7, 19, 20] This indicates that discrimination of C3GN and DDD is difficult by LM, except in cases with the typical features of DDD such as intensely Periodic acid-Schiff (PAS) staining positive, ribbon-like intramembranous deposits with thickened GBM [13, 51]. According to the current consensus report, the term ‘‘isolated’’ was replaced by ‘‘dominant staining of C3 defined as at least two orders of C3 intensity greater than that of any other immune reactant’’ [6] This extended definition was derived from the fact that 47.6% of DDD cases show various amounts of glomerular immunoglobulin deposits even though they are caused by alternative complement activation [21]. There are still many missing pieces that must be assembled to determine pathophysiology-based therapies for C3G, and further investigations are certainly warranted
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