Glomerular paramesangial deposits: association with hypocomplementemia in membranoproliferative glomerulonephritis types I and III.
Of 22 subjects previously reported with some form of factor H dysfunction, 12 had a glomerulonephritis that appeared to not be of immune complex origin. Factor H dysfunction results in elevated circulating levels of the C3b-dependent C3 convertase, C3b,Bb. Of the 12 cases with glomerulonephritis, the glomerular deposits in the six whose biopsy specimens were studied were predominately subepithelial on the paramesangial portion of the glomerular basement membrane. In a subsequent study, similar deposits were found in patients with membranoproliferative glomerulonephritis (MPGN) type II, also a nephritis that is probably not of immune complex origin. Paramesangial deposits were found in these patients only in biopsy specimens obtained when the C3 level was low, at which time convertase stabilized by nephritic factor would be present in the circulation. This association of paramesangial deposits with circulating convertase was further tested by correlating these deposits with the level of C3 at the time of biopsy in MPGN types I and III. The results in type III MPGN were similar to those in type II; paramesangial deposits were frequently present when the C3 level was low as a result of circulating nephritic factor of the terminal pathway, NFt, and were usually absent when the C3 level was in the upper two thirds of the normal range. Deposits persisted in those patients with C3 levels that had been low but that had increased during the year before biopsy to within the lower one third of the normal range. The persistence of paramesangial deposits in MPGN type III, as compared with MPGN type II, may be related to the differences in composition and function of the two NF stabilized convertases (C3bn,Bb,P,NFt and C3b,Bb,NFa, respectively) that circulate in these two disorders. In contrast to MPGN type III, the hypocomplementemia in MPGN type I is thought to be, for the most part, the result of classical pathway activation, which is not associated with elevated circulating convertase levels. In agreement with this, paramesangial deposits were found in only two of 34 biopsy specimens. At the time of those two biopsies, both patients had a complement profile indicating that the NFt was circulating, as in MPGN type III. In three other cases with profiles compatible with circulating NFt, paramesangial deposits were not found. In all patients with type I MPGN, electron microscopy and immunofluorescence of the glomeruli gave results typical of an immune complex nephritis. Thus, even though the complement profile in MPGN type I may at times indicate the presence of a nephritic factor, circulating immune complexes appear to be basic to pathogenesis. The observations support the hypothesis that elevated levels of the C3b-dependent convertase, as found in the "experiments of nature" with factor H dysfunction and in MPGN types II and III, are associated with paramesangial deposits. The nature of this association and the role of these deposits in producing the nephritis is not clear.
West
C D
CD
Children's Hospital Research Foundation and the Department of Pediatrics, College of Medicine, University of Cincinnati, OH, USA. howaj0@CHMCC.org
McAdams
A J
AJ
D001706:Biopsy; D051561:Complement C3 Convertase, Alternative Pathway; D003178:Complement C3 Nephritic Factor / Q000032:analysis; D050577:Complement C3-C5 Convertases / Q000032:analysis; D003179:Complement C3b / Q000032:analysis / Q000172:deficiency*; D005455:Fluorescent Antibody Technique; D005920:Glomerular Mesangium / Q000276:immunology / Q000473:pathology*; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008854:Microscopy, Electron; D010446:Peptide Fragments / Q000032:analysis
D003178:Complement C3 Nephritic Factor; D010446:Peptide Fragments; D003179:Complement C3b; D050577:Complement C3-C5 Convertases; D051561:Complement C3 Convertase, Alternative Pathway