There are a number of controversies and challenges in complement 3 glomerulopathy (C3G) that are related to the underlying pathogenesis, biomarkers, and clinical presentation. These important topics were covered at the American Society of Nephrology’s Kidney Week 2023 meeting.

Following these proceedings, featured expert Andrew S. Bomback, MD, MPH, was interviewed by Conference Reporter Medical Writer Rick Davis. Dr Bomback’s clinical perspectives are presented here.

At Kidney Week 2023, there was an entire session dedicated to controversies in C3G, for which I gave a presentation titled “What Is C3 Glomerulopathy and What Is It Not?” As a field, we are still struggling with how best to work up the complement pathway in our patients. Currently, we principally rely on relatively old diagnostic testing for complement. There are newer techniques for evaluating the complement pathways; however, they are not the standard of care, and they are not available at commercial laboratories. These assays are only part of research studies. We are still searching for the best biomarkers of overactive complement or biomarkers that truly implicate complement in the pathogenesis of disease. In addition to using the complement testing that is currently commercially available, we put a lot of stock in biopsies, which can give us a readout of how active complement is.

One reason biomarkers are so crucially needed is because patients can be initially classified as having 1 lesion that is eventually reclassified as C3G. For example, it can be almost impossible to distinguish infectious-related glomerulonephritis from C3G at the time of the biopsy because they have very similar features and can overlap almost perfectly. You need time to detect a difference between infectious-related glomerulonephritis and C3G. Hematuria, proteinuria, and complement levels in infectious-related glomerulonephritis should typically resolve in 3 to 6 months, whereas these abnormalities persist in C3G. It would be great if we had the ability at the time of diagnosis to say something like, “No, this is a disease that’s clearly marked by overactive alternative complement pathway, and there doesn’t appear to be any generation of infection-mediated complement activation. What we’re seeing here is truly the result of an intrinsic alternative pathway overactivity.” We are not at this point yet.

There has been some work from the Mayo Clinic looking at biopsies and doing laser dissection and mass spectrometry to try to get a proteomic readout of the biopsies to determine which complement proteins are involved. Perhaps each glomerular disease will have a signature profile, but this is a technique that is not widely used at the present time. It is still considered more research than standard of care. I think that those of us in the field would agree that one of the biggest missing gaps in C3G is an easy-to-access, reliable biomarker of complement activity to help us manage some of these interesting, confusing cases.

The reason this has become an issue is we now have promising therapies for C3G, which was the topic of discussion in abstract SA-PO916 from Kidney Week 2023. In the past, there were no therapies that were considered disease targeting for immune complex–mediated membranoproliferative glomerulonephritis, C3G, or even immunoglobulin A nephropathy. However, now that we do have therapies, it puts a big onus on the treating physician to be able to say, with a fair amount of certainty, what they think the root cause of the disease is and use that information to choose a therapy that specifically targets the root cause.

We talk about precision medicine as the goal for how we should be treating patients. You need to have the confidence that you are precisely identifying the lesion and the pathogenesis of that lesion when you have available therapies that are as targeted as some of these newer therapies are.