Table 4.

Acquired drivers of C3 glomerulopathy

Driver	Frequency in affected patients (%)	Function	Knowledge gaps	Refs.
C3 nephritic factors	50–80	Dysregulation of C3 convertase (C3bBb)	Diagnostic assays need standardization In vitro function of antibodies well characterized however well documented in vivo data supporting cause-and-effect relationship to disease needed Not known whether antibody characteristics change over disease course Unclear why antibody removal methods (plasma exchange or B-cell targeted agents) are generally not effective Defining the mechanism underlying complement dysregulation is often very difficult	56
C4 nephritic factors	2.4	Dysregulation of C3 and C5 convertases of the classical and lectin pathways (C4b2a and C4b2aC3b)		56
C5 nephritic factors	50	Dysregulation of C5 convertase (C3bBbC3b)		57
Factor H autoantibodies	~1	Affects factor I cofactor activity; not associated with CFHR3 or CFHR1 gene deletion		58
Factor B autoantibodies	~2.5	Recognizes the Bb fragment; binds C3 convertase; increases release of C3a and Bb; does not enhance C5 convertase activity		59
C3b autoantibodies	1.5	Recognizes C3b and C3c; stabilizes C3 convertase; reduces binding to complement receptor type 1; increases activity of C5 convertase		59
Monoclonal immunoglobulins	Sporadic cases of multiple myeloma or MGRS	Intact antibody and/or light chain fragments interfere with alternative pathway regulation		60-62

C, complement component; MGRS, monoclonal gammopathy of renal significance.