C3G Differential Diagnosis and Subtypes

DISCLOSURES

Disclosure: Andrew S. Bomback, MD, MPH, has disclosed the following relevant financial relationships:Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Novartis; Apellis; Q32; Amgen

Complement 3 glomerulopathy (C3G) is a rare, complement-mediated kidney disease with two major subtypes: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). These conditions, which likely represent a continuum, are driven by dysregulation of the alternative pathway of the complement system; the underlying cause can be acquired or genetic. C3G often affects young people and pediatric patients, with a slight male predominance; however, its overall incidence is rare, estimated at 1-3 cases per 1,000,000 people in the United States and 0.2-1.0 case per 1,000,000 people in Europe.

The clinical presentation of C3G varies, and the disease is associated with a poor prognosis. Approximately 50% of adults with C3G will progress to end-stage kidney disease within 10 years of diagnosis. C3G is also notorious for recurrence after kidney transplantation, contributing to poor allograft survival rates.

Recent advancements in understanding C3G have opened the door to new therapeutic strategies aimed at improving patient outcomes. Differential diagnosis in C3G is crucial for guiding treatment, but it poses significant challenges owing to overlapping clinical features with other glomerular diseases and requires precise histopathologic and immunofluorescence analysis.

Microhematuria is a common feature in multiple glomerular diseases, including C3G and immune complex–mediated glomerulonephritis, making it insufficient to distinguish between the two conditions. The hallmark of C3G is predominant C3 deposition in kidney biopsy samples with minimal or no immunoglobulin deposits. This distinct immunofluorescence finding is essential for accurate diagnosis and differentiates C3G from immune complex–mediated diseases such as lupus nephritis and membranoproliferative glomerulonephritis.

Gross hematuria during upper respiratory tract infections is not unique to C3G; it is also a hallmark feature of immunoglobulin A (IgA) nephropathy. The distinction lies in the underlying pathology: C3G is characterized by predominant C3 deposition with minimal or no immunoglobulin deposits, whereas IgA nephropathy is characterized by significant IgA deposition in kidney biopsy samples.

C3G frequently presents with low serum C3 levels and normal C4 levels, reflecting activation of the alternative complement pathway, whereas the classical and lectin pathways are not primarily involved. This serologic pattern is observed in approximately 50% of patients with C3G and helps to distinguish it from conditions such as lupus nephritis, where both C3 and C4 levels are usually decreased.

Although subepithelial “hump-like” deposits are characteristic of infection-related glomerulonephritis, they can also be observed in C3G, particularly in cases with an underlying membranoproliferative pattern. Further immunofluorescence studies may be needed to differentiate between these conditions.

DDD and C3GN are the major subtypes of C3G. DDD is uniquely characterized by dense, ribbon-like electron-dense material within the lamina densa of the glomerular basement membrane, a feature not seen in C3GN. In contrast, C3GN typically shows mesangial and subendothelial deposits. This histopathologic difference is critical for distinguishing between the two subtypes.

Learn more about C3 glomerulopathy.

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