Diagnosis and Treatment of Immune-Mediated Kidney Diseases - Episode 5
Carla M. Nester, MD, MSA, FASN, gives an overview of C3G.
Jonathan Barratt, PhD, FRCP: Thank you very much. And I want to move on now to C3G and to stay with you, Carla, and just run us through your experience of the disease itself, how it presents, and what our understanding is about what causes this very rare kidney disease.
Carla M. Nester, MD, MSA, FASN: Absolutely. And you brought up the first point. It is an ultra-rare kidney disease. And in fact, the prevalence is probably somewhere between 1 to 2 per million patients. You can see it's very uncommon but it's a very aggressive disease. We think of it in terms of - we don't have the best natural history data, but we think of it in terms of being a disease that will go to end-stage with everything that we're trying to do right now. We'll go to end-stage within 10 years of diagnosis. Unfortunately, that same group of patients already talked about the recurrence of IgA in the transplant, which very frequently recurs in the transplant. Unfortunately, we have a very aggressive glomerular disease in the first place, but then also one that is very frequently recurring. It's just a very difficult disease for the glomerular disease doctors to treat.
Jonathan Barratt, PhD, FRCP: And in terms of the typical presentation, and does the presentation change between children and adults, but how do patients present to you?
Carla M. Nester, MD, MSA, FASN: It is believed to be a disease of the young, I'll say. Teenagers and young adults. And that's the classic form of disease. We've now discovered over the last number of years that there are much older adults that will have a C3G presentation. But let's back up. For the most part, it is a disease of the young, and they present like a classic glomerular disease. They present with high blood pressure. They have high-grade proteinuria. These children very frequently can end up in the hospital with the need for diuresis or attempts to salvage an acute kidney injury. It can be a very aggressive disease. There are more indolent forms, forms that are in children, particularly that are found quite by accident, but that's not the most common presentation. The more common presentation is an aggressive renal disease or a fairly aggressive glomerular disease.
Jonathan Barratt, PhD, FRCP: And our understanding has evolved with our understanding of the complement system, hasn't it? In terms of what underpins C3G. And I wonder if you can give us a high-level view of what's happening in these patients.
Carla M. Nester, MD, MSA, FASN: It's probably the parent, if you will, of the complement-mediated kidney diseases. It's the one we perhaps know the most about. It's also a relative misconception that most of these patients, because they are young, young children or even young adults, might have a genetic abnormality, is the underpinning of their disease. But in fact, that probably only accounts for about a quarter of them. And in fact, three-quarters of them are more likely to have an autoimmune form of this disease. And that's the autoimmunity - it's an Ig, so immune globulin, it's called nephritic factor, and it's an immune globulin that binds one of the most important enzymes or the convertase of the alternative pathway, and it dysregulates it. It is dysregulation of the complement system that causes this disease, whether it's genetic or whether it's acquired or autoimmune, it is the cause of the disease and therefore it is innate to the patient to have this abnormality that makes it very hard to treat with current therapies.
Jonathan Barratt, PhD, FRCP: And I find C3 and C5 nephritic factors fascinating. But they're there all the time, but we only - we have flares of disease, don't we? So, in terms of C3G patients, what kinds of things might set a flare or make an exacerbation of the disease?
Carla M. Nester, MD, MSA, FASN: Well, that's a great question because it turns out that what we think happens because the alternative pathway is part of your innate immune system, then it turns out that one of the triggers could be simply that your immune system has been triggered. It's either infection or something like that. It turns out that you can have an infection that starts the process that you then can't regulate well, or it turns out that you could have a monoclonal protein, for instance, that limits the ability to regulate the alternative pathway. And in fact, it because of that risk or trigger for C3 glomerulopathy, it ends up being a confounding point for us when it comes to the pathology - and our pathologist will know this quite well. It becomes very difficult to tell the difference between a triggered disease that's just going to be transient and go away, versus now we have C3 glomerulopathy, which will not go away under current cares.
Transcript Edited for Clarity