As such, C3G is less likely than aHUS to present clinically as a systemically active and rapidly progressive disease (3). 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. strong class=”kwd-title” Keywords: complement mutations, membranoproliferative glomerulonephritis, alternative pathway, C3 glomerulonephritis, proteinuria Introduction 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). In contrast to atypical Hemolytic Uremic Syndrome (aHUS) (2), the clinical course of C3G is more indolent. As such, C3G is less likely than aHUS to present clinically as a systemically active and rapidly progressive disease (3). The term C3G was introduced to differentiate glomerular diseases which result ML-323 from alternative pathway dysregulation from other immune complex mediated glomerular diseases. 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 also be Mouse monoclonal to TIP60 seen in thrombotic microangiopathy (TMA) (5). Also included under the umbrella term of C3G are a subset of cases which were historically diagnosed as immune complex mediated membranoproliferative glomerulonephritis (MPGN) of unknown etiology, but showed dominant staining for C3 by immunofluorescence staining, with lesser deposition of typical immune complex deposits such as IgG or IgA. The pathogenic mechanism underlying C3G is uncontrolled production and deposition of the C3 breakdown product, C3b, along glomerular and sometimes tubular basement membranes (the latter which is most often ML-323 seen in ML-323 DDD) (6). While histologically the disease can appear quite heterogenous (7), pathogenically, there is a final common pathway leading to glomerular injury (8). There are important acquired forms of the disease such as autoantibodies against the regulatory proteins factor H (FH) and ML-323 factor B (FB), as well as autoantibodies against the C3 convertases of the alternative and classical pathways (C3Nef and C4Nef, respectively)that can phenotypically mimic genetically acquired disorders (9C11). Patients with C5 nephritic factors (C5Nef) against downstream effectors in the final common pathway have also been reported (12). C3-5Nef and factor B antibodies have been observed in C3G patients with DDD as well as MPGN patterns on renal biopsy (9, 12C14), and can be treated with C3 and C5 blocking pharmacotherapy (15, 16). 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 also deposition of other immune complex deposits, were in fact complement-mediated, and represented a subset of C3G (1, 8, 16, 17). These cases could therefore be distinguished from cases displaying the more typical mixed complement and immunoglobulin deposition seen in MPGN secondary to infections and autoimmune disease, or MPGN associated with plasma cell dyscrasias and monoclonal immunoglobulin deposition disease (MIDD) (1, 10, 15, 16). In some cases, histologic features of TMA may co-exist with diagnostic features of C3G, also suggestive of abnormal complement regulation and activation as the source of glomerular disease. Inherited or genetic causes of C3G include loss of function mutations that result in impaired self-protection from innate immunity (20), or uncontrolled activation of the alternative pathway (21C23). Mutations in Factor H, Factor I, C3, Factor B, Membrane cofactor protein (MCP), thrombomodulin (THBD), diacylglycerol kinase epsilon (DGKE) (24), and plasminogen are the more common mutations associated with DDD, C3GN, and C3 dominant iMPGN that form C3 GN (24). Table 1 summarizes the pathological findings seen in C3G and idiopathic immune complex MPGN. Table 1 Pathological findings in each subtype of C3 glomerulopathy and three cases of C3 dominant idiopathic MPGN. thead th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Type /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Age /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Gender ML-323 /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Ethnicity /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ LM findings /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ IF findings /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ EM findings /th th valign=”top” align=”still left” rowspan=”1″ colspan=”1″ Supplement profile /th th valign=”best” align=”still left” rowspan=”1″ colspan=”1″ Hereditary mutations linked /th th valign=”best”.
As such, C3G is less likely than aHUS to present clinically as a systemically active and rapidly progressive disease (3)