Glomerular C4d Staining Does Not Exclude a C3 Glomerulopathy

Abstract

Introduction C4d, an early product in the classical/lectin complement pathway has shown potential in the evaluation of C3 glomerulopathy where its absence would support an alternative pathway abnormality. As autoimmune/genetic complement testing is not readily available to most parts of the world, glomerular C4d staining may serve as a useful additional step toward the diagnosis. Methods To test this hypothesis, C4d staining was performed on a large cohort of C3 glomerulopathy. Archival cases from 2011 to 2017 were reviewed and immunohistochemistry for C4d was performed, scored (scale of 0 to 3+), and correlated with the immunofluorescence and ultrastructural findings. Paraffin immunofluorescence was performed in cases of “discordant C4d” to unmask Igs. Results Twenty-seven cases of dense deposit disease (DDD) and 14 cases of C3 glomerulonephritis (C3GN) were retrieved. C4d demonstrated a range of staining intensities with negative/traces in only 22% of DDD and 64% of C3GN. Lower-intensity C4d staining (1 to 2+) was mostly concordant with similar amounts of Igs/C1q. Discordant 3+ staining was noted in approximately 50% of cases of DDD and 20% of cases of C3GN. Among them, paraffin immunofluorescence unmasked polyclonal Igs in 2 of 5 cases of DDD and 1 of 3 cases of C3GN. Conclusion This observational study suggests that the presence of glomerular C4d should not exclude a C3 glomerulopathy. In lower intensities, it appears to represent overlying classical/lectin pathway activation with concordant Ig/C1q deposits. A subset of cases, however, displays intense and discordant C4d staining, which raises the possibility of an associated lectin pathway abnormality, a potential future area of study.

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties

“…33 C4d staining was positive in 14 secondary and 4 primary Ig-MPGN cases but negative or not significant in 30 C3G cases. Nevertheless, a more recent report 34 challenges the use of C4d as a diagnostic tool to exclude C3G.…”

“…r e v i e w with C3G and Ig-MPGN. The limitations of C4d staining, notably for the distinction between C3G and primary Ig-MPGN 33,34 and for the assessment of CP activation, have already been discussed.…”

C4d in Proliferative Glomerulonephritis

“…From Bansode et al . [ 4 ] and our own experience,[ 6 ] the value of the lack of C4d is significant in indicating a potential abnormality in the AP in proliferative glomerulonephritis, however, its presence should not give false reassurance. In our practice, based on a combination of clinical and pathology features including C4d, the first step is to perform electron microscopy in suspect cases and at the very least advise a close clinical follow-up with serial serum C3/C4 estimation.…”

A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease

“…The absence of C4d in the kidney biopsy from proliferative GN has been found to be helpful, as noted by Sethi et al [43], in distinguishing C3 GP from Ig complex-mediated and postinfection glomerulonephritis. Although helpful, this feature has been questioned by other studies [44].…”