C3 glomerulopathy (C3G) is a very rare kidney disease caused by dysregulation of the alternative complement pathway. Its clinical presentation and manifestations can vary, and it may be mistaken for other conditions. At the recent National Kidney Foundation (NKF) 2025 Spring Clinical Meetings (SCM25), Purva Sharma, MD, provided updates on the evaluation and diagnosis of C3G during her presentation, “Pathophysiology and Evaluation of C3G: The Latest Science.”

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Following this presentation, featured expert Purva Sharma, MD, was interviewed by Conference Reporter Associate Editor-in-Chief Rick Davis, MS, RPh. Dr Sharma’s review of her presentation is presented here.

As discussed during my talk at SCM25, C3G is often triggered by infection, monoclonal gammopathy (which should always be ruled out in patients aged >50 years), and autoimmune conditions. However, it can also appear with no apparent triggers. The typical clinical manifestations of C3G are proteinuria, hematuria, high blood pressure, and reduced kidney function that can present either as a rapidly progressive kidney injury or as chronic kidney disease. There can also be other nonspecific signs and symptoms of kidney disease, such as fatigue, appetite loss, and sleep disturbances. Extrarenal manifestations of C3G can occur due to alternative complement pathway dysregulation in other parts of the body, such as with retinal drusen and acquired partial lipodystrophy. Finally, the incidence of post-transplant C3G recurrence is very high and leads to allograft loss in many patients. So, the disease burden of C3G is high.

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The most common differential diagnosis of C3G is postinfectious glomerulonephritis (PIGN). On a kidney biopsy, there is no way to reliably distinguish C3G from PIGN, as both present with C3-dominant glomerulonephritis. However, once PIGN resolves, symptoms improve and C3 levels normalize in approximately 3 months. In contrast, in patients with C3G, C3 levels will remain low even after 3 months. I cannot emphasize enough that, for patients with suspected C3G and a concurrent infection, you need to wait at least 12 weeks for any potential infection to resolve before making a diagnosis.

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Using light microscopy, different patterns of kidney injury can be seen in patients with C3G, including membranoproliferative, mesangioproliferative, and endocapillary proliferative with crescents. When making a diagnosis of C3G, the key point from the kidney biopsy is immunofluorescence showing C3 staining at least 2 orders of magnitude higher than any other immune reactant, including immunoglobulins such as IgM and IgG.

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C3G is further divided into C3 glomerulonephritis and dense deposit disease. That distinction is based on electron microscopy. In dense deposit disease, microscopy shows dense intramembranous deposits, and in C3 glomerulonephritis, the deposits are lighter, are amorphous, and can be mesangial, subendothelial, or subepithelial.

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C3G is considered an autoimmune disease that leads to dysregulation of the alternative complement pathway. After a diagnosis of C3G is made, we typically conduct testing for complement proteins and nephritic factors (that are autoantibodies stabilizing the C3 convertase), as well as genetic testing. These tests are generally performed as part of a panel at major academic institutions or private laboratories. As newer therapies become available, every patient with C3G should have complement and genetic testing done to identify those who will benefit most from these treatments.