A pediatric case of C3 glomerulonephritis initially misclassified as IgA nephropathy with a favorable response to C3-targeted therapy

Abstract

C3 glomerulopathy is an ultra-rare kidney disease driven by dysregulation of the alternative complement pathway fluid phase C3 convertase. We report the case of a previously healthy 13-year-old girl who presented with concurrent nephrotic and nephritic syndrome and low complement C3. Her initial kidney biopsy surprisingly showed mesangioproliferative glomerulonephritis with dominating IgA deposits resulting in a diagnosis of IgA nephropathy. Despite standard immunosuppressive treatment with prednisone and mycophenolic acid plus angiotensin-converting enzyme inhibitors, she achieved only partial remission and subsequently relapsed, exhibiting severe, persistent C3 consumption (6-8 mg/dl) and sustained C5b9 activation (1059 ng/ml). A repeat biopsy 1.2 years later established the definitive diagnosis of C3 glomerulonephritis (C3GN) with a membranoproliferative pattern. C3NEF antibodies were negative, and no pathological variant was detected in the genetic study. After 1 year and 9 months without response to immunosuppressive treatment, the C3 inhibitor pegcetacoplan was initiated. The patient achieved rapid and complete remission within 3 months, marked by normalization of proteinuria, from 2747 mg/day (urine protein-to-creatinine ratio [UPCR] 2.66 mg/mg) pre-treatment to 19 mg/d (UPCR 0.02 mg/mg) and complement activation markers (from 1162 ng/ml pre-treatment to C5b9 92 ng/ml; reference value 30-150 ng/ml). This case highlights the inherent diagnostic complexity of C3GN, suggesting the critical role of repeat biopsies in treatment-refractory, complement-dysregulated glomerulonephritis. It strongly supports the potential efficacy of C3 inhibition as a targeted therapeutic approach for patients with C3GN.