The Case Of Frozen-Section C4d-Positive, C1q-Negative C3 Glomerulopathy Indicating Lectin Pathway Involvement

C3 glomerulopathy is defined by C3-dominant glomerular deposits on immunofluorescence (IF) together with electron-dense deposits on electron microscopy (EM), and is driven by dysregulated activation of the alternative pathway. C4d commonly appears in immune–complex–mediated MPGN, but it is not specific. In some C3 glomerulopathy, C4d is also present. In the setting of C3 dominance with negative C1q and immunoglobulins, this points to lectin pathway co-activation. Notably, most reports have documented C4d positivity using paraffin-based antigen-retrieval methods; our case demonstrates C4d positivity on direct frozen-section IF.

Case Presentation
A 34-year-old man with a 6-year history of biopsy-proven C3 glomerulopathy re-presented with persistent proteinuria and microscopic hematuria. He had nephrotic-range proteinuria and hypoalbuminemia at entry; renal function was mildly reduced. Serology for ANA/ANCA, hepatitis B/C, and M-protein was negative. Complement testing showed low/borderline C3 with reduced CH50 and elevated activation fragments (Ba, C5a, sC5b-9). Prior records noted normal factor H and factor I levels with a positive anti–factor H antibody. On biopsy, PAS showed diffuse global mesangial expansion with capillary-wall thickening and double contours; PAM highlighted spikes/segmental stippling. Direct frozen-section IF demonstrated strong C3c/C3d with negative IgG/IgA/IgM and C1q, but robust C4d. EM revealed amorphous, discontinuous EDD in mesangial and intramembranous locations with focal outer lamina rara disruption, consistent with C3 glomerulonephritis. These findings suggested sustained lectin activation with concomitant alternative pathway amplification.

Treatment & Clinical Course
Prednisolone (20 mg/day) plus mycophenolate mofetil (2,000 mg/day) started in December 2023. Within two weeks, UPCR fell from 4.86 g/g to 2.98 g/g and remained in the 2–3 g/g range, indicating ~50% reduction and partial remission. Serum creatinine stayed between 1.30–1.49 mg/dL, showing stable kidney function. Despite clinical response, C3 (~51 mg/dL) and CH50 (~30 U/mL) remained low, indicating persistent complement activation.

Discussion
The findings of C4d-positive, C1q-negative in our case suggest the involvement of lectin pathway and alternative pathway without a classical pathway activation. This case indicates a disease archetype within the C3 glomerulopathy spectrum in which pattern-recognition via mannose-binding lectin/ficolins initiates lectin pathway activation at the glomerular surface, leaving a C4d footprint, while the alternative pathway amplifies injury through C3 deposition, anaphylatoxins, and sublytic C5b-9. This framework may be well explained by C4d positivity on direct frozen IF, as presented in our case. Glomerular C4d deposition in C3 glomerulopathy has been reported on paraffin sections (Singh G et al Kidney Int Rep, 2019). They described that C4d staining was noted in approximately 50% of cases of DDD and 20% of cases of C3 glomerulonephritis suggesting overlying activation of lectin pathway. The C4d-positive C3 glomerulopathy case provides an opportunity to reconsider the definition of C3 glomerulopathy.

Conclusion
This case demonstrates C4d-positive, C1q-negative C3 glomerulopathy on frozen-section IF, providing evidence of lectin pathway involvement. This suggests a broader pathophysiological spectrum than the traditional alternative pathway-only model of C3 glomerulopathy.