Jonathan Barratt, PhD, FRCP: So how many diagnoses of C3 would you make in a typical month would you say, just to give it into the context of IgA nephropathy?

Sanjeev Sethi, MD: Again, in terms of IgA, I would say I would see one IgA every- one or two IgAs every month. I will say I see one C3 every day, IgA- one or two IgAs every day. I see one C3 a month. Although, I still feel that C3 glomerulonephritis is sort of under-recognized. It is under-diagnosed to a certain extent. Now that we recognize it better, we are making the diagnosis more often. Many of these were previously post-infectious GNs, even now many of these are C3 GNs and they're not post-infectious disease, post-infectious glomerulonephritis. Some of these are mislabeled because of poor understanding of the disease entity.

Jonathan Barratt, PhD, FRCP: Jerry mentioned, congregating these patients under nephrologists who know what they're doing but reviewing the biopsy by a pathologist. If you see one a month at the clinic, then general renal pathologists are not seeing very many at all. It does make sense to have these patients have a central pathology review by an experienced pathologist, be looked after by an experienced nephrologist. I'm going to come to you now Jerry, because we have the Oxford score which has prognostic implications. I know Columbia has developed a way of interpreting the biopsy that helps understand prognosis and potentially treatment response.

Gerald B. Appel, MD: We can see what Sanjeev says about that, but it was very important initially to be able to be talking about the same thing, because if different centers talked about different things when they said this was C3 glomerulopathy, you could never do a study. That's where the pathologists came in and said we're going to say you must have- C3 must be this much greater than any immunoglobulin deposited there to call it C3 glomerulopathy. I think that was a good step forward. It may not always be the case but again it means we're talking about the same things. That was a big advance there. I do think that a good pathologist can tell you it's C3 whether there's trapping or not. This caused a lot of problems for nephrologists when they said the C3 and the IgM are trapped, and whether you get deposits for that or not. But I still think the value of having a defined system is very important. I can tell you that in about a decade of following patients at Columbia, we had 113 patients, and a lot of those were referred in with C3 glomerulopathy. Now, Carla may have more experience because they've been involved in this in terms of the genetics of it, the complement system for even longer. I'm not sure what the total is at University of Iowa now, but that was what it was three or four years ago. We're seeing more and more because as you publish papers, you get a referral center. People start saying, OK, the center deals with this, we can refer to them.

Jonathan Barratt, PhD, FRCP: And it is a challenge because for the Oxford classification when we developed it, we shared hundreds of biopsies globally. You're talking about a hundred cases with a decade's worth of experience at a center of excellence. How many patients would you have, Carla?

Carla M. Nester, MD, MSA, FASN: Well, right now, like he said because we were primarily a biomarker and a genetics lab, we have a little over 280 of those. Not as wonderful pathology experience though for our group, because we didn't have a resident renal heavy-duty glomerular pathologist reviewing all of these. But I agree completely because the problem with the biopsy is that I think a good pathologist can tell the difference, but still there are some clinical- for instance, you all will remember we originally said it had to be isolated C3. Then we move to know it can have other things present, but this still has to be two orders of magnitude. Now we are to the point of understanding that you must pay attention to where the C3 is being deposited and what the patient's clinical scenario is at the time that you're actually getting a chance to see the biopsy. So now it's becoming much- our information going into the diagnosis is much more robust but there's still lots of questions.

Gerald B. Appel, MD: In our hands, initially a lot of the studies came out with major differences between dense deposit disease and C3 glomerulonephritis. In our hands, when we followed them out, they were about the same. Now again, each center may see something different. I know at the Mayo Clinic; they're going to see many more patients with monoclonal diseases associated with this than we would see at Columbia. They are a major referral place for the entire country for this. So given that, you'd have to look at this and say, OK, if they get 30% of their patients having a monoclonal immunoglobulin, we're going to get much less at Columbia. The other thing I will say is that even finding this, we've had people who have had monoclonal disease, clear-cut findings and yet we couldn't figure out how that interacted with a complement system. It wasn't like they had an antibody against factor H or factor I, these inhibitory proteins. We did everything we could, and we just could not find out in terms of which it was. That's added to the fact that some people have more than one defect. They'll have a C3 and nephritic factor, but they'll also have an antibody against factor H or they'll have another defect along the pathway. It's a very complex area, but again, it's so important because it lights up the whole area of complement for all glomerular diseases.

Transcript Edited for Clarity