#3764 An unusually aggressive case C3 glomerulonephritis

Abstract Background and Aims Complement factor 3 glomerulonephritis (C3GN) is a rare glomerular disorder characterized by predominant C3 deposition and the absence of other immune complexes in renal biopsy findings. The most common histological presentation of C3GN on light microscopy (LM) is membranoproliferative glomerulonephritis (MPGN), though crescents may occasionally be observed. MPGN can result from various pathological processes, including inherited or acquired abnormalities in the alternative complement pathway, mutations in complement regulatory proteins (CFH, CFI, CFHR5, C3, CFB), autoimmune conditions, post-infectious glomerulonephritis, and exposure to biological therapies or certain anticancer agents. This case report describes a severe crescentic C3GN presentation, highlighting its diagnostic complexity and therapeutic challenges. Method We present the case of a 78-year-old male with acute kidney injury (AKI) following a five-day diarrheal illness. His medical history included type 2 diabetes mellitus, hypertension, and metastatic bladder cancer, for which he had completed two years of pembrolizumab therapy with good clinical and radiological response. He had no recent exposure to PPIs, anticoagulants, antibiotics, NSAIDs, or IV contrast agents. On admission, his serum creatinine was 9.58 mg/dL, and urea 220 mg/dL, with no electrolyte abnormalities. A urinary tract infection (E. faecalis, Klebsiella pneumoniae) was diagnosed, but renal ultrasound was unremarkable. Despite fluid rehydration, his renal function did not improve, and he required hemodialysis. His serum C3 and C4 levels were normal, and he tested negative for Anti-dsDNA, ANA, ENA, ANCA (MPO, PR3), and anti-GBM antibodies. Serum electrophoresis was also unremarkable. Due to ongoing urosepsis, a kidney biopsy was initially deferred, and he was started on IV methylprednisolone two weeks into admission. However, steroids were discontinued due to gastrointestinal bleeding, and a renal biopsy was eventually performed. Results LM revealed 100% crescentic glomerulonephritis (10 glomeruli: 3 globally sclerosed, 5 cellular crescents, 2 fibrocellular crescents, 2 with fibrinoid necrosis). There was 30% interstitial fibrosis and tubular atrophy, with red cell casts in many tubules and hyalinized arterioles. Immunofluorescence showed C3 (2+), negative IgG and C4, and weakly positive IgA, IgM, and C1q. Electron microscopy demonstrated collapsed capillary loops, subendothelial and mesangial electron-dense deposits, thickened basement membranes, and extensive podocyte foot process effacement. Autoimmune screening was positive for anti-CFB antibodies, while CFH, CFI autoantibodies, C3 nephritic factor, and genetic testing were negative. Despite intensive therapy—16 plasma exchange (PEX) sessions, corticosteroids, cyclophosphamide, and 3 months of eculizumab—his condition failed to improve, and he remained dialysis-dependent. Conclusion This case represents an aggressive form of RPGN with predominant C3 deposition and complement alternative pathway activation in the presence of anti-FB antibodies. Although post-infectious GN (PIGN) could be considered, anti-FB antibodies are usually associated with better prognosis, which was not the case here. The potential role of PD-1 inhibitors in triggering this pathology warrants further investigation, as red cell casts have been linked to poor outcomes, consistent with our patient's case. Sharing such experiences enhances our understanding of C3GN pathogenesis and treatment responses.