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Published on: November 1, 2018
Toward a working definition of C3 glomerulopathy by immunofluorescence
Jean Hou1, Glen S Markowitz1, Andrew S Bomback2
1Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Insights
Defining C3 glomerulopathy requires precise immunofluorescence criteria. A proposed definition of C3 dominant deposits, significantly more intense than other immune reactants, aids in identifying patients for complement pathway evaluation.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Precise immunofluorescence (IF) criteria for C3 glomerulopathy (C3G) are undefined.
- Dense deposit disease (DDD) serves as a gold standard for C3G diagnosis.
- Membranoproliferative glomerulonephritis (MPGN) types 1 and 3 are common mimics of C3G.
Purpose of the Study:
- To test hierarchical IF criteria for C3G with varying stringency.
- To determine the incidence of C3G in MPGN types 1 and 3.
- To propose refined diagnostic criteria for C3G.
Main Methods:
- Retrospective coding of IF reports from 319 MPGN cases (types 1-3).
- Hierarchical criteria included 'C3 only', 'C3 dominant with trace/1+ IgM only', and 'C3 dominant and at least two orders of magnitude stronger than other Ig.'
- Analysis of DDD cases as the gold standard for C3G.
Main Results:
- The most restrictive 'C3 only' criteria identified only 50% of DDD cases.
- The most liberal criteria identified 88% of DDD cases, compared to 31-39% in MPGN types 1 and 3.
- A proposed definition of C3 dominant and significantly more intense than other immune reactants identified 88% of DDD cases.
Conclusions:
- 'C3 only' is an impractical definition for C3 glomerulopathy.
- A proposed definition requires C3 to be dominant and at least two orders of magnitude more intense than other immune reactants.
- These criteria may help identify patients for alternative complement pathway investigations.
Abstract:
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.
