Toward a working definition of C3 glomerulopathy by immunofluorescence.
Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1-3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of 'C3 only' captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, 'C3 only' is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation.
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Jean
J
Hou
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Glen S
GS
Markowitz
Division of Nephrology, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Andrew S
AS
Bomback
Division of Nephrology, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Gerald B
GB
Appel
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Leal C
LC
Herlitz
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
M
M
Barry Stokes
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Vivette D
VD
D'Agati
D000328:Adult; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D015922:Complement C1q / Q000032:analysis; D003176:Complement C3 / Q000032:analysis*; D005260:Female; D005455:Fluorescent Antibody Technique; D015432:Glomerulonephritis, Membranoproliferative / Q000145:classification* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology; D008297:Male; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D009626:Terminology as Topic
D015415:Biomarkers; C038245:C3 protein, human; D003176:Complement C3; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015922:Complement C1q