The complement system is clearly overactive in C3G, and it is overactive in IgAN as well, so targeting complement is an appealing strategy in both diseases. Of course, we want to make advances along multiple fronts, and studies to find more effective B-cell therapies, for example, are also very attractive, since autoantibodies play an important role in IgAN and in some cases of C3G.

If complement is activated, oftentimes it is going to be the alternative pathway that really takes control, or amplifies the response. And, if you are able to control the alternative pathway—even if the classical or lectin pathway is the initiator of disease—you may end up with less disease intensity. I think that we will need to investigate complement as a potential target very methodically in clinical trials. It may be that there is a very broad involvement of complement in any tissue injury system, including kidney injury, so complement inhibition might result in long-term benefit across many different types of kidney disease.

In C3G, there has been recent excitement with regard to trying more specific anticomplement approaches. Multiple newer agents are under consideration, several of which focus on blocking the upstream alternative pathway more specifically. Years back, the anti-C5 agent eculizumab, which targets the terminal complement cascade, was tested. The observation was that only a minority of patients had a good response. Additionally, it was challenging to predict which patients would respond. Today, several inhibitors of the proximal alternative pathway are under investigation, with targets including C3 and complement factors D and B. 

There are multiple potential control points that regulate complement activation in the alternative pathway, and it is not yet clear if targeting one control point will be more effective than targeting another. This is the reason we have multiple ongoing trials targeting multiple aspects of the pathway. 

It will be interesting and exciting to see what happens in these trials. One hope is that, since we are not targeting the classical pathway, we might preserve a greater level of protection against infections. The ultimate hope is that these upstream approaches will be effective and will be less likely to lead to adverse events, but this still has to be evaluated in clinical trials. Thus far, the risk of infection seems to be small.