In thinking about whether a disease is complement driven, one could be a purist and say that to have a truly complement-driven disease you would need to have a mutation in a complement gene that then directly results in a very specific disease. In that case, you might be able to succeed by using a single, complement-targeted agent. IgAN and C3G are multifactorial and somewhat heterogeneous disorders, so you might not always be able to treat them solely by targeting complement. I would say that anticomplement therapy will be studied in a number of diseases over the next 10 years and might become an important part of a multimodal approach for some.

It seems reasonable to study anticomplement therapy even when complement dysregulation is not an obvious primary actor in the pathogenesis. Consider antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), a set of complex, "pauci-immune" diseases (ie, low Ig and complement in biopsies). Experimental and clinical studies suggested that the complement system was involved, and then, sure enough, we were able to treat patients with AAV with a C5a receptor blocker, and we achieved good outcomes (ie, avacopan was approved by the US Food and Drug Administration as an adjunctive treatment in severe, active granulomatosis with polyangiitis and microscopic polyangiitis). I think that we can all agree that C5a and the complement system are not central to the pathogenesis of AAV, but they may be central to the clinical manifestations of the disease. 

In C3G, we have some good data showing that complement-dysregulating events occur (whether they are genetic or autoimmune) that are primary to the pathology of the disease. In theory, if we were to eliminate these events, we would eliminate the disease, at least based on the current understanding from the animal studies. I believe that we can draw distinctions between AAV, C3G, and IgAN, but there is still much to learn in these and other glomerular diseases. If we could identify biomarkers at the tissue level in some of these diseases, you might find evidence of local complement activation rather than fluid phase activation. But I am curious to hear my colleagues’ thoughts on the role of complement in disorders such as IgAN and even FSGS.

We have a spectrum of glomerular diseases, with some being more “purely” driven by complement than others. I would consider C3G as a more purely complement-driven disorder, so that would be on one side of the spectrum. And then I would place FSGS on the opposite side because my feeling is that there is not much of a role for complement there. There is some work being done in animal models to determine whether podocytopathy in FSGS may be augmented by the activation of complement. However, based on what is currently known, I would not predict that complement is going to be a major target in FSGS. IgAN might go somewhere in the middle of the spectrum. There are many other diseases that are very much like IgAN in which complement may be a factor in the pathogenesis but is not the central factor. 

We are now trying to develop personalized medicine strategies for patients with glomerular diseases, and a key question is: In a given patient with complement-driven glomerular disease, can we look at some of the biomarkers that Dr Nester has been studying for more than 20 years and use them to predict who will respond to a very specific complement-targeted therapy?

This is a fascinating area, and I agree with my colleagues that we are really only starting to learn about complement and kidney disease. As Dr Nester alluded to, we learned a lesson from AAV, where there really is not any good pathologic evidence showing that complement drives the disease, and yet we find clinically that a C5a blocker can have significant benefits in the disease and the disease course. This really opened a lot of eyes. 

Historically, we have had the idea that there is very heavy complement deposition in the kidney on biopsy, so therefore, complement must be more primarily involved. C3G would be a prime example. And then we have diseases without complement on biopsy, where perhaps complement would be less of a target (eg, FSGS). We have to keep in mind that AAV is a disease that strongly impacts the kidney and does not show complement activation on biopsy, and yet complement inhibitors can help to completely control that disease in some patients. So, we need to reset our thoughts. 

Studies of complement-targeting strategies make sense for diseases that have pathologic evidence of complement activation, which we do see in C3G, IgAN, membranous glomerulonephritis, and lupus nephritis. Complement inhibition is being investigated in all of these diseases, which is very exciting. For other diseases such as diabetic nephropathy, FSGS, and AAV, I believe that there is still a rationale for further investigation. 

It may be that there is a very broad involvement of complement in any tissue injury system, including kidney injury, and that blocking complement will end up providing long-term benefit. We are going to have to plod through very methodologically with continued scientific investigation as we think about complement and the opportunity to control diseases.