Abstract
C3 dominant immunofluorescence staining is present in a subset of patients with idiopathic immune complex membranoproliferative glomerulonephritis (iMPGN). It is increasingly recognized that iMPGN may be complement driven, as are cases of “typical” C3 glomerulopathy (C3G). In both iMPGN and C3G, a frequent membranoproliferative pattern of glomerular injury may indicate common pathogenic mechanisms via complement activation and endothelial cell damage. Dysregulation of the alternative complement pathway and mutations in certain regulatory factors are highly implicated in C3 glomerulopathy (which encompasses C3 glomerulonephritis, dense deposit disease, and cases of C3 dominant MPGN). We report three cases that demonstrate that an initial biopsy diagnosis of iMPGN does not exclude complement alterations similar to the ones observed in patients with a diagnosis of C3G. The first patient is a 39-year-old woman with iMPGN and C3 dominant staining, with persistently low C3 levels throughout her course. The second case is a 22-year-old woman with elevated anti-factor H antibodies and C3 dominant iMPGN findings on biopsy. The third case is a 25-year-old woman with C3 dominant iMPGN, dense deposit disease, and a crescentic glomerulonephritis on biopsy. We present the varied phenotypic variations of C3 dominant MPGN and review clinical course, complement profiles, genetic testing, treatment course, and peri-transplantation plans. Testing for complement involvement in iMPGN is important given emerging treatment options and transplant planning.
Highlights
Complement Component 3 (C3) glomerulopathy (C3G) encompasses a group of diseases that result from abnormalities in the alternative pathway of complement regulation, and has been defined by C3 only or C3-dominant immunofluorescence staining seen on renal biopsy [1]
As the understanding of the pathogenesis of C3 glomerulopathy (C3G) evolved, it became clear that some cases of immune complex mediated membranoproliferative glomerulonephritis (MPGN), including those with C3 dominant immunofluorescence staining and cases where there was deposition of other immune complex deposits, were complement-mediated, and represented a subset of C3G [1, 8, 16, 17]
C3G includes dense deposit disease (DDD) [7, 33], C3 glomerulonephritis [34], and a subset of immune complex mediated MPGN which are thought to result from alternative pathway dysregulation
Summary
C3 glomerulopathy (C3G) encompasses a group of diseases that result from abnormalities in the alternative pathway of complement regulation, and has been defined by C3 only or C3-dominant immunofluorescence staining seen on renal biopsy [1]. C3G includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD); the latter of which is characterized ultra-structurally by the presence of highly osmiophilic intramembranous deposits [4] Both C3GN and DDD often present with a membranoproliferative pattern of glomerular injury, a finding that can be seen in thrombotic microangiopathy (TMA) [5]. As the understanding of the pathogenesis of C3G evolved, it became clear that some cases of immune complex mediated MPGN, including those with C3 dominant immunofluorescence staining and cases where there was deposition of other immune complex deposits, were complement-mediated, and represented a subset of C3G [1, 8, 16, 17]. Complement titers (CH 50) were near the lower limit of normal
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