Episode 9: Carla Nester on C3 Glomerulopathy and Complement-Mediated Diseases

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Laurel Damashek: Welcome to GN in Ten, a bite sized podcast brought to you by the International Society of Glomerular Disease. Our hosts are nephrologists and glomerular disease experts Dr. Kenar Jhaveri of Northwell Health and Hofstra University on Long Island, New York, and Dr. Koyal Jain from the University of North Carolina Chapel Hill.

Koyal Jain: Welcome everybody. GN in Ten. This is Koyal Jain from UNC and I have Kenar Jhaveri from Hofstra as well. And then we have a very special guest today.

Kenar Jhaveri: I was just gonna say that we have Dr. Carla Nester here. Carla would you like to introduce yourself?

Carla Nester: My name is Carla Nester and I'm currently at the University of Iowa in the Stead Family Children's Hospital.

Kenar Jhaveri: So tell us a little bit about what got you interested in complement mediated diseases.

Carla Nester: Yeah, so I'll go back a ways [00:01:00] and really talk about some of my training first because it's complement mediated glomerular disease that I'm really very passionate about. I was trained at the University of North Carolina first as an internal medicine and pediatric resident.

But then I stayed to do an adult and pediatric nephrology fellowship. Of course coming from North Carolina, I had excellent glomerular disease training and it worked out quite nicely for me when I moved to Iowa to continue my glomerular disease training and continue my glomerular disease work.

Plus probably pivotal in being able to really combine the two of those is the ability to work in the complement lab, which in fact, I'm the associate director for right now. It's a very large clinical and research complement lab.

Koyal Jain: Wow. That sounds super cool and fascinating, but Med Peds and then do you now focus on the pediatric side or the adult side or both?

Carla Nester: So it's really actually important because yes, I had the med peds practice training with an [00:02:00] appointment in both internal medicine and pediatrics at the University of Iowa.

But I'm also, so right now I'm housed in the pediatric hospital.

So I'm at the Stead Family Children's Hospital and I'm really very fortunate to actually hold an endowed professorship from the Stead family.

I also happen to be the division director for pediatric nephrology. So that of course, also puts me very soundly in pediatrics. But, it used to be very funny when my 83 year olds used to walk into the pediatric clinic, and in fact, one of my very first patients used to bring his great-granddaughter with him so he could fit in better.

But right now all of the people that I work with have just, they just take it in stride. They see. That 83-year-old the same time, I might have a newborn on the bed, evaluating. Everyone is completely comfortable with this concept of me having a med peds outpatient clinic.

And then of course I do consults in the adult hospital. I do inpatient service in the pediatric [00:03:00] hospital. Also tend to practice, med peds also in the hospital setting. I think that for me, the Med Peds training is even more valuable because I do rare disease and it just so happens that the rare disease that I work in doesn't only affect children, doesn't only affect adults, it happens to affect both of them.

So I can legitimately be their provider and understand their physiology, understand their other needs while I'm working on the glomerular disease aspect.

That's amazing.

Carla Nester: Yeah, and I think also the other piece of that is, is that and many of your pediatric nephrology listeners will know this, the data in pediatric glomerular disease, for instance, lags behind that.

That's in the adults. But if again, this is my bias, but if you're trained as an adult nephrologist, you know that data. I can bring that to children a little bit more and I can understand where we need to push the envelope in children a little bit more.[00:04:00]

And I think it also goes towards therapeutics. We are so slow about getting the therapeutics to children and because I do have a large clinical trial practice, I can see that we could do this. We can have children be in these therapeutic trials the same way as we can have the adults.

And so I think I can push that envelope a little bit more, having that Med Peds background.

Koyal Jain: I think you're uniquely positioned to do this and do it really well. Obviously everybody knows you. I see a lot of trainees who wanna do med-peds and then they don't know how to go about it and how to practice, and I think you have found that opportunity and you have obviously have done such a great job with that, that you're now doing both sides and you get to see both worlds and actually help each other out.

Carla Nester: I think that's true, and of course I have bias, but I think the value of Med Peds is I think your differentials are broader. You're a little bit more comfortable about thinking about heart failure in your 4-year-old or maybe membranous in your 10-year-old, which, that [00:05:00] doesn't happen in 10 year olds.

You're much more comfortable. I think that about that broader differential, and I think that Again, with the idea of therapeutics, if I'm comfortable using a complement inhibitor in an adult, I know exactly what my adverse events are gonna be, or I suspect I know what they're gonna be and I know when I can push people into thinking about doing that sort of thing in children's.

Kenar Jhaveri: So let me ask a loaded question. Complement disorders, one of them is thrombotic microangiopathy. I have a problem with that name. Do you suggest a better name since you're the world expert and can we change the terminology?

Carla Nester: Yeah. It's excellent question and I would say there's a lot of us that are uncomfortable with that name and there is actually an effort ongoing.

It's really been bogged down. It's nobody's fault. It's really trying to get everybody in the mood to understand that saying all TMA equal complement mediated disease is just very hard to get people to agree on the proper approach. I think [00:06:00] what's gonna happen, or I think what I wish would happen is that we would make a decision about, we understand completely that if you have genetic abnormality or if you have autoantibody driven, complement mediated TMA, that's clear. But what we really need people to understand is that there's a lot of TMAs that are not strictly speaking, complement mediated. A lot of them. I mean, TTP is a perfect example, right? You can make a thrombosis, you can get schistocytes, or you can get LDH elevations or you can use up all your haptoglobin with a completely not complement mediated disease, right? So there are going to be others like that. So we need the research. You know what happened? As soon as we got terminal complement blockade, the research slowed down. Yes.

That's the worst thing that could happen because now we've got this whole group of diseases that we don't understand.

Kenar Jhaveri: Yeah. And why is this the kidney, why sometimes it's only in the kidney and it's so hard to convince the hematologist to treat [00:07:00] these patients because it's not their forte, it's in the kidney only.

Carla Nester: Yeah. It's hard really to know why it's only in the kidney except for to say the standard things that you know the kidney sees a lot of your blood supply.

The kidney's got a lot of endothelium that can be affected. But there have been discussions around the glycomatrix that the kidney is just it's the right zip code, if you will, to have confluent abnormalities at, that sort of thing. I don't think we completely understand why complement can be dysregulated so easily at the level of the kidney, but I think that's the kind of research that we need to really be thinking about.

But I agree with you 100%. Absolutely you can have clinical disease at the level of the kidney and not see it anywhere else.

Koyal Jain: And just to push that a little bit further, I feel like with complement mediated diseases in the kidney, there's a wide variety of complement mediated diseases itself, right?

I wish we could just target it. Okay. This is, you send this testing for complement disorders, [00:08:00] functional assay, and then this is what comes back and, hey, if this comes back, this is the treatment. If this comes back, this is the treatment. And what I often see people say is: any complement mediated disease, let's just start eculizumab.

Carla Nester: Yeah. Yeah. It's very frustrating and I'll, I think that for the TMAs that are complement mediated, that terminal complement blockade like eculizumab or ravulizimab excellent drugs, don't get me wrong, I think they're excellent drugs, but what you've said to me is really loaded with a lot of other issues because not all complement mediated TMA is terminal complement mediated, right?

Kenar Jhaveri: Correct.

Carla Nester: It's one size fits all for all of us right now in our complement thinking and that's not where we're gonna be five years from now. We're gonna understand that there are terminal problems, there are alternative pathway problems, and there are classical pathway problems, and that's really what you mean.

It's gonna mean to target something in the future you're gonna have a better sense that you need to target x, Y or Z, in the future. And that's, this is natural. This is exciting. I [00:09:00] remember Gerry Appel, who is a glomerular disease doctor at Columbia.

He once told me many years ago when I was still a fellow, he said, it's going to be really just amazing if the rarest glomerular disease of all. Strictly, he was talking about C3G, if it's the one that gets a therapy before any of these other things. And we were lamenting, the progress we've made in lupus at that time.

And again, this was, 10, 15 years ago. And he's exactly right. We're gonna have a targeted therapeutic for C3G . Whereas we're still struggling with exactly where are we with, whether it's IgA or whether it's Membranous or lupus, whatever it is.

And that's just because we got lucky. Frankly C3G is caused by complement dysregulation. These other diseases are probably not, complement may not be the absolute primary cause of the disease. No doubt it's gonna play a role in many of these diseases. But [00:10:00] again, when people can throw the eculizumab on or they can throw on terminal complement blockade, the research slows down into exactly what role complement might be playing in these diseases.

Kenar Jhaveri: That's, you bring up a very good point. With some diseases, it's a primary driver as opposed to end effect from another cause. So it could be antibody mediated or something that's triggering the complement. And then it's more of like a bandaid treatment rather than a primary treatment.

Carla Nester: Yeah, it's more in the supportive region, if you will. And again I often in my head think about some of the glomerular diseases as very being very inflammatory. For instance, lots of cellular influx into the glomerulus, et cetera. It's entirely possible that the diseases that are more inflammatory in nature may respond very well to, yeah, to complement blockade, whether it's direct complement pathway blockade, or whether it's an aflatoxin blockade, they may, ANCA is the newest, right? Yeah. [00:11:00] Having responded quite well to a C5A receptor blocker, that sort of concept is going to sort out better for us in these coming years. I think once we get these complement inhibitors out there and once we reinvigorate people to study the complement system in their chosen disease, I think we're gonna have a few more of these answers.

Kenar Jhaveri: Which oral complement agent do you think will replace eculizimab? You don't have to answer that.

Carla Nester: Yeah, no, I because I don't actually, I'm gonna answer it because I don't know for sure, and I already mentioned that I think that for true complement mediated TMA, again, the genetic forms, the auto antibody driven forms, et cetera, I think the terminal pathway is going to be a great place.

People are certainly gonna be looking for oral agents. I don't know if it's gonna be okay to block the alternative pathway and still get good blockade, complete cessation of the TMA. I don't know yet, but we will also, I hope, know that within the next couple of years.

Koyal Jain: So this is the exciting [00:12:00] world of complement mediated diseases. With which I'm gonna ask you, what is your favorite glomerular disease? And it cannot be C3G or complement mediated.

Carla Nester: It has to be C3G. Of course. Yeah. I, I think gosh, let me think about this for a minute.

Kenar Jhaveri: I don't think you have that much time.

Carla Nester: Yeah, because of course, I was gonna say C3G.

Koyal Jain: It better be ANCA, you came from UNC.

Kenar Jhaveri: You want multiple choice?

Carla Nester: Yeah. In fact, I have to tell you the story of how I ended up in complement mediated disease from ANCA because of course I spent four years studying ANCA. And then in my fourth year you might remember this, or this might be an urban legend locally, I don't know. But Charles Jennette knocked out factor B in his MPO ANCA model, right? So this happened when I was a senior fellow, and so now all of a sudden I have to reckon in my head, now wait a minute, this is Pauci immune. How could it have such an important innate immune connection? Because when they knocked out complement [00:13:00] factor B in his usual MPO ANCA vasculitis model, the disease was completely ameliorated.

Not, maybe not completely, but it was much improved by knocking out complement factor B. So I had that background when I was a senior fellow, and then when I came to Iowa, I was on the internal medicine service. And I biopsied a young lady who had, really, RPGN essentially. And my pathologist called me.

He said, I don't know what this is. There's just a whole bunch of C3 deposited. It's not DDD. I can tell from the EM it's not DDD, but man is there C3 everywhere. I graduated in June. I had this patient in August, and then the French group published their report about isolated C3 deposits as being a new entity.

And so basically my career was born , with that sort of sequence of events I was suddenly in this world of, what is this, all this C3 deposition. And having already begun my [00:14:00] understanding of complement and then moved to Iowa to be in a complement lab.

It just all fell together right then. So I still have to say that C3G is probably my favorite glomerular disease, but I grew up as an ANCA trained glomerular disease person.

Koyal Jain: That makes me so happy that your journey included anca. I love all the ANCA vascular disease, but we'll stick with C3G for now.

Kenar Jhaveri: So you bring up a very good distinction of primary glomerular diseases that are probably C3 mediated or complement mediated like C3G and maybe some TMAs. But you can see now there are companies trying to get complement inhibitors in the IgA world, the membranous world, the lupus world.

Do you see that as a primary treatment for these disorders or maybe more of a secondary adding agents to already immunosuppressed patients?

Carla Nester: Yeah, my personal view of this, and again I don't spend time doing a lot of research in those other glomerular diseases, [00:15:00] practically all of my research is in the C3G world still.

I would say that none of them are gonna be like C3G is, or even like TMA is, the true complement mediated. TMA really is complement mediated and C3G really is complement mediated, but I think there's gonna be a spectrum. I think that you probably know that there's been lots of suggestion that the lectin pathway is playing a role for instance, in IgA. It's entirely possible that the classical pathway is playing a role for instance, in membranous. Again, to a degree it makes sense because during these glomerular diseases there's lots of immune activity and the complement system is incredibly integral to the immune system.

So it does make sense that there may in fact be complement playing a role in a lot of these, but I think you're gonna see it on a spectrum. You're gonna see from C3G maybe all the way down to minimal change disease, for instance. And then everywhere in between there is going to be some combination.

[00:16:00] So it's legitimate to think about these drugs in this setting. It is gonna take a really good understanding of what outcome you want first, but then also a ballpark idea of what your target is. Is your target inflammation or is your target blockade of the alternative pathway, et cetera.

You're gonna have to think about all those pieces before you can design a really good trial or a really good understanding of whether it works or not. I will throw one thing out there that has made me more comfortable. We've been in the clinical trials in complement for, we did our first testing in 2007, but I would say we've soundly been in the complement trial world since 2018 or 19.

And we've discovered that the safety is much better than we thought it was. We used to worry about overwhelming infection, people turning green, whatever it was, whatever our suspicion was, we thought about lots of things could potentially happen if you block the alternative pathway because it is so [00:17:00] important.

But generally in a well vaccinated monitored patient these agents are gonna be safer than we ever thought they were going to be back in 2018, 2019. I think that gives you some leeway to test it in diseases where you may not know exactly where the target is. I think it gives you some leeway knowing that it's perhaps a little bit safer than what we originally thought that they would be.

Koyal Jain: Okay. I have a controversial question and we can decide what to do with it, and I might give you a few seconds to think about it, but I often send the genetic panel, the functional assay. We send it for complement testing, and it is not cheap. It is expensive and you can't send it from the hospital. 'Cause the hospital says that it has to be covered by the insurance, which it doesn't get covered oftentimes. And so it has to be sent by the clinic. Lots of complicated process, but oftentimes patients can't afford it. What do we do?

Kenar Jhaveri: And it takes a year to come [00:18:00] back.

Carla Nester: Yeah. Yeah. It's a great question and of course what would help you more than anything is for me to be able to say to you, you have to have this test because it's going to change what you're going to do for the patient. And I will admit completely that some of that data is missing yet. We don't know completely what the connection is between the biomarkers and the patient's outcome, or the genetics and the patient's outcome.

I think it's clear for me in pre-transplant patients that if you've got a patient with what you thought was complement mediated TMA going into transplant, you have to understand what you're dealing with. You need to know what the risk for recurrence are. I think if you've got a patient who is not nephritic factor positive, you've got to understand whether they've got some genetic, I'm talking about the C3G patient here, you've got to understand whether they have a genetic abnormality, because again, [00:19:00] the risk for losing your kidney in those two settings is huge. So you have to have a better understanding of it. That doesn't answer your question about cost. And frankly, there are even states that won't allow you.

So what I really encourage people to do is, and I can say this presumably somewhere there will be a list of my disclosures. I am the associate director of this clinical lab, so I'm obligated by a lot of regulatory, CLIA, et cetera, et cetera.

But I will say that we have a very large research arm, and if your patient legitimately, for instance, has C3G, enroll them in research, and then they get their genetics and their complement biomarkers free.

Now my director might not be too happy about me advertising that too widely, but the truth is that, we have about 250 C3G patients that we monitor.

We do their genetics of course. You don't have to keep doing them. We monitor their biomarkers every six months if the provider wants them. So there are options right now. And that serves two purposes. First of all, it [00:20:00] gets you what you need to treat the patient. 'cause I firmly do believe you need to know what the nephritic factor status is on your patient.

You need to know how deranged the biomarkers are because the more deranged they are, the more active your complement system is, the more likely the patient's going to be losing their kidney, that sort of thing. So it serves two purposes. It gives you the answers you might need to actually help understand what's going on with your patient.

But frankly, by advancing our population, we'll have a better sense of what the biomarkers are. How the biomarkers, you'll, you should expect publications from us to tell you exactly what the connection between the biomarkers and the clinical outcomes are.

Koyal Jain: You've done a phenomenal job with that.

Dr. Nester, that was wonderful. We've had so much fun learning from you. Dr. Nester is so phenomenal.

Kenar Jhaveri: I know.

Koyal Jain: I think I could just sit with her and talk to her for the next hour or two or more.

Kenar Jhaveri: That's amazing.

Yes, totally. See you guys. Signing off on GN in Ten.

Koyal Jain: Bye-bye.

Laurel Damashek: This has been GN in 10 from the International Society [00:21:00] of Glomerular Disease. You can listen and subscribe wherever podcasts are found and tweet at us at ISGDtweets. Thank you for joining us.

Koyal Jain: Kenar, I did remember you this time.

Carla Nester: Hold on just a moment, please.

Koyal Jain: I love that this is uh, not recorded. Uh, This is just recorded. This is not,

Carla Nester: I apologize about that because there's a huge sign on my door saying that I'm in a session. Doesn't make any difference. People just walk in.

Koyal Jain: No, this is all good. And just

Laurel Damashek: You need one of those on air lights. Yeah.

Carla Nester: I and again, that's the whole purpose of the sign. Anyway, I anyway, back to the question.