A Complement of Errors: When C3 Glomerulonephritis Masquerades as Infection-Related Glomerulonephritis

Introduction: Complement 3 Glomerulonephritis (C3GN) is a rare cause of renal dysfunction, making it a difficult diagnosis to make. Other glomerular lesions similar to C3GN, like infection-related glomerulonephritis (IRGN), can make the diagnosis of C3GN even more difficult and thereby delay treatment. We present a case of C3GN that was mistaken for IRGN. Case Description: A 56 year old man with no known PMHx first presented to the hospital for 3 weeks of edema, fevers, shortness of breath, and arthralgias. Workup was significant for hypertensive emergency, microscopic hematuria, massive proteinuria (28g in 24hr), hypoalbuminemia, hyperlipidemia, and elevated Cr to 2.18 (unknown baseline) – concerning for nephritic/nephrotic syndrome. Serologic workup was unrevealing. Renal biopsy revealed active cellular crescent formation, C3 dominant deposits, C1q deposits, and endocapillary proliferation with subendothelial and subepithelial deposits, thought to be consistent with IRGN. An extensive infectious workup was unrevealing, so he was treated as post-infectious GN with pulse dose steroids with taper. Hemodialysis was initiated for anasarca refractory to diuretics. Two years later, he presented to the hospital after missing dialysis for 40 days. Labs notable for Cr 2.6, BUN 55, K 4.6, HCO3 23, and phos 6.4. A repeat renal biopsy showed increased glomerular sclerosis and persistent C3 dominant deposits, deemed consistent with C3GN. Discussion: C3GN is a rare cause of renal dysfunction caused by dysregulation of the alternative complement pathway, characterized by dominant C3 staining on IF and evidence of mesangial, subepithelial or subendothelial electron-dense deposits. Clinically, it presents as proteinuria, hematuria, and progressive renal dysfunction. Pathomorphological findings of IRGN and C3GN are similar, which makes differentiating between the two difficult. Apparent evidence of infection is not required for the diagnosis of IRGN, which further complicates making the correct diagnosis. Diagnostic Comparison of C3GN and IRGN - C3 Glomerulonephritis Infection-Related Glomerulonephritis Etiology Alternative complement pathway dysregulation Immune complex-mediated due to recent/ongoing infection Complement Levels Persistently low C3; normal C4 Transiently low C3 and C4, C3 often lower than C4 Immunofluorescence Dominant C3 staining; minimal or no immunoglobulin Dominant C3 staining; immunoglobulins can be present Electron Microscopy Mesangial, subepithelial, and/or subendothelial dense deposits Classic subepithelial "humps" Light Microscopy Mesangial ± endocapillary hypercellularity; possible crescents Diffuse endocapillary proliferation +/- neutrophilic infiltrates Clinical Presentation Hematuria, proteinuria, edema, hypertension, chronic and progressive renal dysfunction Hematuria, proteinuria, edema, hypertension, recent or current infection