C3 glomerulopathy and current dilemmas

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.

On the origin of proteins in human drusen: The meet, greet and stick hypothesis

“…AD is the biggest cause of dementia, affecting millions of people in the western world. DDD is a relatively rare juvenile disease characterized by kidney malfunction (Ito et al, 2017;Wang et al, 2017;Cunningham and Kotagiri, 2018). Despite the potential relevance for diseases, little is known about the composition of drusen and how and why biomaterials accumulate these deposits.…”

Clinical features and pathogenesis of membranoproliferative glomerulonephritis: a nationwide analysis of the Japan renal biopsy registry from 2007 to 2015

“…MPGN I, the most common form, is characterized by subendothelial deposits, and MPGN III has both subepithelial and subendothelial deposits, whereas MPGN type II is characterized by dense deposits in the glomerular basement membrane (dense deposit disease [DDD]) [1,2]. Together with DDD, this group of C3-positive immunoglobulinnegative glomerular diseases has been labeled as C3 glomerulopathies [7,8]. Furthermore, the MPGN has the strongest association with secondary causes, including viruses, autoimmune diseases, and paraproteins [1,9].…”

The role of the alternative pathway of complement activation in glomerular diseases

“…Clinically, it presents with hematuria (76-89%) and subnephrotic proteinuria, but acute nephritic or nephrotic syndrome may also occur. In most affected individuals, it leads to ESRD (in approximately half of the patients within 10 years from diagnosis) [81,84]. Features of (PD), diabetes mellitus type 1, and ocular drusen can accompany DDD, but they have not been reported in C3GN [84].…”

“…In most affected individuals, it leads to ESRD (in approximately half of the patients within 10 years from diagnosis) [81,84]. Features of (PD), diabetes mellitus type 1, and ocular drusen can accompany DDD, but they have not been reported in C3GN [84]. Drusen are whitish-yellow deposits of lipoproteins and complement components within the ocular Bruch's membrane, beneath the retinal pigment epithelium, which are similar to those seen in AMD.…”