C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) are distinct subtypes of C3 glomerulopathy (C3G) that require intense laboratory evaluations for the diagnosis and evaluation of immune defects before treatment selection can occur. Presentations at the National Kidney Foundation (NKF) 2025 Spring Clinical Meetings (SCM25) provided insight into the contemporary diagnosis and treatment of C3GN and DDD.

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Following these presentations, featured expert Richard Lafayette, MD, FACP, was interviewed by Conference Reporter Associate Editor-in-Chief Rick Davis, MS, RPh. Dr Lafayette’s clinical perspectives on these findings are presented here.

There were several good case presentations at SCM25 looking at patients with DDD and C3GN. These included case reports of C3G in the setting of monoclonal gammopathy (poster G-159 by Kelly V. Liang, MD, MS, FASN, FACP, et al), C3GN that responded to a complement inhibitor or to regular immunosuppressive therapy (abstract G-483 by Christopher Shackleford, DO, and colleagues), and C3G overlapping with other glomerular diseases (poster G-217 by Ruchi Jalota Sahota, MD).

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Once we have a diagnosis of C3G, we need to look deeper to identify the pattern of disease. Historically, we have relied on our pathologists to differentiate patterns of DDD, which—as the name suggests—is based on an electron microscopic diagnosis where you see heavy dense deposits in the glomerular basement membrane area of the kidney filter. This is different from C3GN, where there are predominant mesangial deposits. There may well be some scattered subendothelial deposits or epimembranous deposits in C3GN. However, it is its pattern of very thick, membranous-style deposits that differentiates it from classic DDD, although there can be overlap between the 2. We may also look at C3 nephritic factor in these patients, more as supportive evidence that something may have stimulated the immune system to activate the alternative complement pathway.

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In addition, we used to feel very strongly that DDD was more resistant to immunosuppressive therapy and would lead to kidney failure more rapidly than C3GN, but this is not necessarily true. The overall treatment response may be similar, and the prognosis, when based on the patient’s urine protein levels and glomerular filtration rate, may also be fairly similar.

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The approach to therapy has been fairly consistent for both subtypes. For decades, we treated these patients with just corticosteroids until we learned that adding steroid-sparing agents and systemic immunosuppressive therapies could occasionally be helpful. Moreover, there was a time when we used cyclophosphamide and azathioprine for DDD and C3GN; however, more recently, reports of mycophenolate mofetil being a slightly better approach has led to this therapy becoming the more typical immunosuppressive for these patients.

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There have been individual cases of C3G being treated with anti-CD20 monoclonal antibody therapies such as rituximab, but there is still not clear evidence that these therapies work. In general, modern methods of more targeted complement inhibitor therapy, including the C5 inhibitors eculizumab or ravulizumab, can be effective. Additionally, both iptacopan and pegcetacoplan have been studied in C3GN and DDD. The overall numbers are small, but there appears to be efficacy in both disease patterns. The fact that iptacopan is newly US Food and Drug Administration (FDA) approved and the hope for the FDA approval of pegcetacoplan were also discussed at the NKF SCM25.