C3 Confusion: When Infection-Related Glomerulonephritis (GN) Imitates C3GN

Introduction: Infection-related glomerulonephritis (IRGN) can closely mimic complement-mediated membranoproliferative glomerulonephritis (C3 Glomerulonephritis, or C3GN). Both conditions may present with hypocomplementemia, particularly low serum C3, making them difficult to distinguish clinically. We present a rare case of C3GN following Serratia marcescens tricuspid endocarditis in a patient with chronic hepatitis C virus (HCV) infection. Case Description: A 41-year-old man with a history of intravenous drug use, chronic HCV, and NSAID use presented with bilateral leg edema and a non-blanching purpuric rash. Laboratory evaluation revealed anemia (Hb 6.6 g/dL), AKI (creatinine 1.2 → 2.4 mg/dL), hematuria, and subnephrotic-range proteinuria (2.5 g/day). Complement testing showed low C3 (64 mg/dL) with normal C4. HCV RNA was detectable; HIV, ANA, ANCA, and cryoglobulins were negative. Blood cultures grew Serratia marcescens, and transthoracic echocardiography revealed tricuspid valve vegetation. A skin biopsy showed leukocytoclastic vasculitis, and immunofixation of the cryoprecipitate confirmed type II cryoglobulinemia. Renal biopsy demonstrated a membranoproliferative pattern with diffuse endocapillary hypercellularity. Immunofluorescence revealed dominant C3 staining in the absence of immunoglobulin deposits, consistent with C3-dominant glomerulonephritis. The patient received IV antibiotics for S. marcescens bacteremia and diuretics for volume overload, with a plan to initiate HCV treatment after stabilization. Unfortunately, he left the hospital against medical advice and was lost to follow-up. Discussion: IRGN is typically associated with a known infection either at the time of presentation or within the preceding weeks. Differentiating IRGN from C3GN is clinically challenging due to overlapping features, including low C3 levels and similar histopathology. However, the persistence of glomerulonephritis and sustained C3 hypocomplementemia suggest an underlying complement dysregulation, raising suspicion for C3GN either as a primary diagnosis or as an infection-triggered entity. This case underscores the diagnostic complexity of C3-dominant GN in the setting of infection. A persistent glomerular inflammation with ongoing C3 consumption should prompt evaluation for C3GN, even in the presence of an inciting infection. Early recognition is critical for guiding appropriate management.