Abstract
BackgroundAcquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors.ResultsOne hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF.ConclusionsIn conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10–15% of IC-MPGN/C3G patients.
Highlights
Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well
In conclusion, C4 nephritic factor (C4NeF) may be a possible cause of complement dysregulation in approximately 10– 15% of IC-MPGN/C3 glomerulopathy (C3G) patients
C3G is characterized by more than two magnitude higher C3 staining in immunofluorescence microscopy than any other immune reactant and it is divided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), where osmophil dense deposits are present within the basement membrane on electronmicroscopy [3]
Summary
Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Mutations in the genes encoding the regulators or components of the complement system, such as Factor H (CFH), Factor H-related protein 5 (CFHR5), Factor I (CFI), membrane cofactor protein (CD46), thrombomodulin (THBD), or Factor B (CFB) and complement C3 protein (C3) are present in about 30% of C3 glomerulopathy patients [4,5,6,7,8], whereas acquired factors (autoantibodies) may be identified as well in a significant subgroup (40–80%)of these cases [9,10,11] The latter include several different autoantibodies that can be detected in the patients’ sera such as anti-Factor H, anti-C3b, anti-Factor B [4, 12,13,14,15,16] and C3- or C4 nephritic factors which are present mostly in patients with complement-mediated renal diseases. As in many cases there is no strict border between the two entities we included both diseases in our study [2, 3, 17, 18]
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