There are a number of controversies related to the diagnosis and treatment of complement 3 glomerulopathy (C3G). This important topic was discussed at the American Society of Nephrology’s Kidney Week 2023.

Following these proceedings, featured expert Carla M. Nester, MD, MSA, FASN, was interviewed by Conference Reporter Medical Writer Rick Davis. Dr Nester’s clinical perspectives on this topic are presented here.

The controversies in C3G start with the diagnostic piece. The real problem is that the disease is diagnosed by biopsy, and, unfortunately, the biopsy can look like other things. Delays in diagnosis are also a problem, as discussed in abstract TH-PO647, which was presented at Kidney Week 2023. The biopsy for C3G can look exactly like that for post-infectious glomerulonephritis. So, it can sometimes be difficult to diagnose correctly. While we wish that making a diagnosis was as simple as measuring how much C3 is deposited on the biopsy, other diseases can also have C3 deposition too. Based on the local health care provider’s level of comfort with C3G, they may overread a biopsy, thinking that it is C3G, even though not all C3 deposition is related to C3G.

Ultimately, C3G-related controversies are primarily associated with making the diagnosis and the fact that C3G relies on an imperfect tool (ie, the biopsy). I think that this is physician related more than anything, but it is also because we do not have a perfect lab test, like we do for other diseases, such as paroxysmal nocturnal hemoglobinuria. In the C3G setting, we do not have a biomarker, and we do not have anything else that supports that a patient definitely has C3G. We just have the biopsy. So, it does lend to some confounders.

The next major point for physicians and patients is that, even though Kidney Disease: Improving Global Outcomes (KDIGO) guidelines provide guidance on treatment, only 38% of patients will respond to standard-of-care therapies, as reported by Bomback et al. This plagues physicians because they are trying their best by using what the guidelines recommend, and yet so many patients do not respond. And that increases patient anxiety. If there is suspicion that the drug will not work, and then eventually those suspicions turn out to be correct, that can be very difficult for the patient. We have a lot of hope for the targeted therapies for C3G. If the standard of care worked great, then we would not be as hopeful. But since the standard of care does not work well for many patients—probably the majority—we are hopeful about targeted therapeutics.

We believe that the underlying pathology of C3G is caused by dysregulation of the alternative complement pathway, and we are starting to see data in this area. Two complement inhibitors that are currently being evaluated in phase 3 trials are iptacopan and pegcetacoplan. These are the agents that will likely make it to the bedside the soonest. There have been other therapies that have had negative trials in C3G, including danicopan and avacopan.