Jonathan Barratt, PhD, FRCP: If we move to C3G you've mentioned that patients present in a typical way as glomeruli disease patients do, anything that you can think of that would be useful for people to understand about the tests you might be able to do that could give you an indication about a diagnosis of C3G when you're doing that work-up for someone presenting with hematuria, proteinuria?

Anuja Java, MD: If you're trying to come to a diagnosis of C3G you're talking about other than a biopsy right, some testing. As I think Dr Appel mentioned; we know that C3G is a disease of dis-regulation of the complement system. As Dr Nester mentioned, about 20% or 30% of these patients may have an underlying genetic etiology. A major component of these patients have an acquired factor. When we are worried about C3G, doing genetic testing to look for that genetic mutation would be one of them. The other thing would be checking for these autoantibodies, the C3 nephritic factor, the C5 nephritic factor would be critical. There are also labs that can sometimes help you do a panel of complement biomarkers that would involve the IC3B, the C3C, the C5B so a panel that if you don't identify a genetic test or if you don't identify an auto-antibody, sometimes you may be able to look at these complement biomarkers and understand that there is complement activation going on. Depending on what is elevated, you may be able to pinpoint that this is where the defect might be. Like I said, in older patients of course who present with C3G it's very important to look for serum protein electrophoresis, serum free light chains to look for those monoclonal proteins. These are some of the tests that you could do when you're worried about a C3G patient that'll kind of help you figure out where the defect is. Of course, that'll help guide therapy as well depending on if you identify what etiology is.

Jonathan Barratt, PhD, FRCP: In the UK we do something called a renal screen, immunology screen which is a high level approach which includes C3 and C4, no other complement. What's the value of a C3, C4 in a C3G patient?

Anuja Java, MD: As we talked about, since C3G is such a specific disease of the alternative pathway you will see a low C3 in these patients. In my experience, when you see both a low C3 and a C4 then I'm starting to think more about the other differentials. Are we dealing with more of an immune complex GN process, and this is not a C3G? Could this be a lupus and not really a C3G? Sometimes it's also important to remember that even if there was a classical pathway or an immune complex or something that initiated the process, if the patient has an underlying defect in the alternative pathway like an autoantibody or a genetic mutation then those patients can eventually develop C3 which is what we see with post-infectious GN. These patients who don't get better may have a low C3, C4 to begin with but they may progress to C3G because they have an underlying etiology. Sometimes the disease may start from a classical pathway initiation and may show both is low but eventually may progress to C3G. If you get an isolated low C3 you're thinking more the alternative pathway, if you're seeing both then it's more broader. You think it's more of a classical lectin pathway that may route to the alternative pathway defect.

Transcript Edited for Clarity