An Unexpected Case of C3 Glomerulopathy in the Setting of Monoclonal Gammopathy and Cryoglobulinemic Vasculitis

Introduction: Membranoproliferative glomerulonephritis (MPGN) can be associated with cryoglobulinemia, monoclonal gammopathy of renal significance (MGRS), C3 glomerulonephritis (C3GN), and vasculitis. MGRS has rarely been associated with C3GN via monoclonal immunoglobulin impairment of regulation of the complement alternative pathway (CAP). We present a case of C3GN due to MGRS in a patient with Type I cryoglobulinemia, monoclonal gammopathy of undetermined significance (MGUS), and granulomatosis with polyangiitis (GPA). Case Description: A 57-year-old female with history of Type 1 cryoglobulinemic vasculitis (livedo on bilateral legs, ulcers, fatigue in 2022), IgG lambda MGUS, recurrent ulcerative chronic sinusitis and nasal septal perforation suggestive of GPA, was referred to Nephrology in April 2023 for proteinuria and microscopic hematuria. She was on methotrexate and intermittent prednisone for vasculitis. Hepatitis B and C were negative. Bone marrow biopsy (BMBx) in 2019 showed normocellular bone marrow (30-40%), 2% blasts and <5% monoclonal lambda plasma cells (PC). In July 2022, Kappa/Lambda ratio: 0.36, M protein: 1.2, urine M-protein: detectable but not measurable. In April 2023, urine protein/Cr ratio (UPCR) was 1.6. Kidney biopsy showed MPGN with C3-dominant deposits consistent with C3GN (Congo red negative). In May 2023, CAP functional assay confirmed overactivity, and genetic test for CAP mutations was negative, confirming acquired dysregulation of CAP from monoclonal gammopathy. Repeat BMBx in June 2023 showed 12% monoclonal PC. She was started on bortezomib (Velcade) and dexamethasone (Vd), then switched to daratumumab in Oct 2023 due to neuropathy from Velcade. Creatinine is preserved and UPCR <0.5 since July 2023. Discussion: This case illustrates a rare and distinct subtype of C3GN associated with monoclonal IgG lambda, which can cause dysregulation of the CAP via enhancement of C3 convertase by acting as anti-complement factor H (CFH) autoantibody, thus interfering with normal CFH regulation of C3 convertase. Although MPGN is commonly associated with cryoglobulinemia and vasculitis, this case highlights the role of monoclonal gammopathy as a potential etiology of C3GN and MGRS. Recognition of this entity is important as clone-directed treatment may improve outcomes and differs greatly from treatment for vasculitis.