#5076 MONOCLONAL GAMMOPATHY IN C3 GLOMERULOPATHY: DOES THE BUCKET STOP THERE?
Authors: Fragoso Pedro , Rodrigues Luís , Borges Andreia , Belmira Ana , Alves Rui 
Published: June 2023

Background and Aims

C3 glomerulopathy (C3G) is a rare diagnosis, characterized by dysregulation of the alternative pathway of complement, classically presenting in children and young adults. Recently, it has been reported the association between the production of a monoclonal protein and the development of C3G, affecting a larger age span.

Method

We report the case of a 53-year-old male patient, that attended the emergency department due to persistent holocranial headache. He was an IV drug abuser with a history of treated Hepatitis C infection and free lambda light chain monoclonal protein, being studied by the Haematology Department. On admission, he was hypertensive (187/98 mmHg), and labs showed an acute on chronic kidney disease (serum creatinine 2.35 mg/dL from a basal of 1.5 mg/dL) with an active urinary sediment (38 erythrocytes/field, with dysmorphia), a urinary protein/creatinine ratio of 626 mg/g, and C3 consumption (0.52 g/L). The patient was admitted, and a kidney biopsy was performed.

Results

Further lab results confirmed a serum IgG Lambda monoclonal protein. Autoantibodies screening (ANCAs, ANAs, Anti-GBM), ASLO and Rheumatoid Factor were negative. Cryoglobulinemia was detected, and the cryoprecipitate's immunofixation revealed monoclonal proteins IgG Lambda and IgM Kappa. HCV viral load was negative. Bone marrow biopsy revealed a small population (&lt; 3%) of plasma cells with Lambda light chain restriction. Kidney biopsy's light microscopy showed increased mesangial matrix and cells, endocapillary hypercellularity, and some glomeruli with lobulated appearance. Five out of 15 glomeruli presented fibrocellular crescents. Immunofluorescence showed C3 dominant staining on capillary walls and in the mesangium, with absent IgG and light chain deposits. A presumptive diagnosis of C3 glomerulopathy was made and the patient was empirically started on corticosteroids (3 pulses of intravenous methylprednisolone, followed by oral prednisolone 1mg/Kg/day), which was followed by paraprotein-directed chemotherapy with bortezomib, cyclophosphamide and dexamethasone (VCD). The patient is currently on the third VCD cycle, presenting both renal and haematological responses: recovery of serum creatinine to basal levels (1.54 mg/dL), resolution of haematuria and proteinuria, normalisation of C3 levels. Serum immunofixation is currently negative for monoclonal protein, with normal serum immunoglobulin levels. Electron microscopy revealed electron-dense deposits in the mesangium, and mesangium-capillary transition, supporting the diagnosis of C3 glomerulonephritis. Genetic testing of complement-related genes revealed a rare missense variation of unknown significance (c.4855A&gt;C) on the C3 gene, that has been previously reported in association with C3 glomerulopathy and atypical Haemolytic-Uremic syndrome.

Conclusion

This case represents a monoclonal gammopathy associated-C3 glomerulonephritis with a favourable response to paraprotein-directed chemotherapy. Although the association between monoclonal gammopathy and C3G rests on epidemiologic findings, experimental evidence suggests that several monoclonal proteins have complement dysregulation features, which may enhance alternate complement pathway activation.

Our patient's response is in line with observational data that have shown improved renal outcomes in patients who achieve a haematological response following clone-directed chemotherapy, which further supports the role of monoclonal gammopathy in C3G pathogenesis [1].

Interestingly, the genetic variation identified in our patient might have provided a favourable genetic background for the development of C3G, which is thought to rely upon a complex interaction of triggering events, such as a monoclonal gammopathy, and underlying complement abnormalities, such as genetic variants in complement genes.