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In this episode, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain are joined by Dr. Matt Sparks (co-creator of NephMadness) and Dr. Aarushi Varshney to discuss the evolving landscape of C3 Glomerulopathy (C3G). The conversation highlights the shift from traditional electron microscopy-based classifications to modern immunofluorescence-based diagnosis, as well as the groundbreaking arrival of two new FDA-approved targeted therapies.
The NephMadness Matchup
This episode focuses on the C3G bracket pitting two critical aspects of C3G against each other:
- Team Diagnosis: Focusing on the challenges of distinguishing C3G from infection-related GN or monoclonal gammopathy.
- Team Treatment: Highlighting the new era of factor B and C3 inhibitors that are revolutionizing patient outcomes.
Key Takeaways
1. Challenges in Diagnosis
- The "Two Orders of Magnitude" Rule: Modern diagnosis is based on immunofluorescence (IF) showing C3 deposition that is at least two orders of magnitude greater than any other immunoglobulin.
- C3G vs. PIGN: It can be difficult to distinguish C3G from Post-Infectious Glomerulonephritis (PIGN). Clinical clues include patient age, the persistence of low C3 levels after infection resolution, and the presence (or absence) of sub-epithelial humps on pathology.
- The Role of Monoclonal Gammopathy: In older patients, it is critical to rule out monoclonal gammopathy (using SPEP and free light chain assays) as a driver of complement activation.
2. The New Therapeutic Era
The panel discussed two landmark drugs that have recently shifted the C3G treatment paradigm:
- Iptacopan: An oral factor B inhibitor that showed a 30% reduction in proteinuria at six months in the APPEAR trial.
- Pegcetacoplan: A subcutaneous infusion (twice weekly) C3 inhibitor that demonstrated a nearly 70% reduction in proteinuria and stabilization of eGFR in the VALIANT trial.
- A "Hammer" Approach: Pegcetacoplan is described as a "larger hammer" because it acts at the crux of all three complement pathways (Classical, Lectin, and Alternative).
3. Safety & Monitoring
- Vaccination: Because these drugs inhibit the complement cascade, patients MUST be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae at least two weeks before starting therapy.
- Prophylaxis: If urgent treatment is required, patients should start prophylactic antibiotics (such as Penicillin, Augmentin, or Ciprofloxacin).
Resources & Studies Mentioned
- NephMadness: The annual educational "tournament" in nephrology that inspired this discussion.
- The APPEAR Trial (Iptacopan): Investigated the efficacy of the oral factor B inhibitor in patients with C3G.
- The VALIANT Trial (Pegcetacoplan): Evaluated the C3 inhibitor in patients with C3G and primary immune complex MPGN, including post-transplant patients.
The hosts and guests of this GN in 10 episode do not have any disclosures to make relevant to the content of this episode.
Creators and Guests
Host
Host
Guest
Dr. Aarushi Varshney
Nephrology Fellow at Duke University
What is GN in Ten?
A bite-size podcast brought to you by the International Society of Glomerular Disease. Nephrologists and glomerular disease experts Dr. Kenar Jhaveri (Northwell Health/Hofstra University) and Dr. Koyal Jain (UNC Chapel Hill) take a lighthearted look at the latest research, discuss clinical practice, and interview leaders in glomerular medicine — all in a short enough time to listen on your coffee break.
Episode 11: Nephmadness C3G
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[00:00:00]
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 [00:00:15] Northwell Health and Hofstra University on Long Island, New York, and Dr. Koyal Jain from the University of North Carolina Chapel Hill.
Kenar Jhaveri: This is Kenar Jhaveri and Koyal Jain, and usually Koyal introduces but she [00:00:30] wanted me to introduce today because it's a NephMadness episode and we have a special today on C3G. So we welcome our two guests
Koyal Jain: we have Dr. Matt Sparkss and Dr. Aarushi Varshney, who joined us, and so really excited to have you here. Go ahead and tell [00:00:45] us a little bit about yourself.
Aarushi Varshney: I'm Aarushi Varshney. I am one of the Duke Nephrology fellows second year, and my interests are glomerular diseases, so I'm very excited about this podcast and this NephMadness topic.
Matthew Sparks: Hi everyone, this is Matt Sparkss. I'm a [00:01:00] nephrologist at Duke and I'm also the co-creator of NephMadness. I'm very excited about a topic that really has seen just such a, a groundbreaking changes over the last year. So this is going to be a lot of fun.
Kenar Jhaveri: Thanks Matt. [00:01:15] Thanks Aarushi. And people who don't know what NephMadness is too bad because by this time you should know what that is and there are a lot of videos about it. It's basically a fun game that you, have topics that compete against each other. The two topics we have today for [00:01:30] C3G is the diagnosis of C3G versus the treatment of C3G.
Matthew Sparks: I wanted to tell the group why did we choose these two topics and the reason why is the executive committee for NephMadness, we wanted to highlight that the [00:01:45] diagnosis is pretty challenging and we don't really have good specific tools to do that. And the implementation of drugs really depends on a good diagnosis, and we felt that it was really important for us to do a great job educating the community [00:02:00] about the pitfalls and the challenges of diagnosing this disease.
So with that, I'll hand it over to Dr. Varshney, who really did a great job on doing the writeup for this region.
Aarushi Varshney: Thank you, Dr. Sparks. This is a ultra rare disease and it's a [00:02:15] entity that we are still learning to this date, and we have definitely learned good amount compared to last couple years. In regards to child diagnosis, I would say this is a diagnostic disease that needs to be diagnosed through a tissue biopsy, and it comes down to [00:02:30] immunofluorescence, staining dominance. Previously the nomenclature was MPGN and their subtypes. Type one, type two, type three. And now when we are learning a little bit more about immunofluorescent.
The way we diagnosis C3G itself [00:02:45] is by looking at the order of magnitude of C3 depositions on immunofluorescent. So if it's more than two order of magnitude compared to other immunoglobulins, then we could say this is definitely a C3 dominant disorder compared [00:03:00] to immune complex MPGN. However, this is a subjective test. We don't have lab findings that are more specific or sensitive to this date, so I'm hopeful in the next couple years we will learn a bit more about, and hopefully we will have [00:03:15] more specific assays. But right now this is what we have and we're trying our best to make most out of it.
Kenar Jhaveri: But I think for our listeners, if you had read one of the old textbooks of Robins or any nephrology textbook, the old classification was [00:03:30] EM based. And what Aarushi is proposing is the new classification that has been now been around for 10 years. It's immunofluorescence based for MPGN and that led to kind of birth of a disease entity of C3G [00:03:45] because.
There were diseases that were popping up. They were mostly three, three dominant and immunoglobulin negative. And that's where what you were talking about. But what about dense deposit disease? Koyal, where do you put that one?
Koyal Jain: So I will say that [00:04:00] dense deposit disease, which is traditionally MPGN type two is also part of C3G. I think people think of C3G as C3GN only. But in reality, when you have two or more magnitude higher staining with C3, with or without immunoglobulins, then you [00:04:15] can put them in this category of C3G.
And if you have, you know, sort of more like an MPGN glomerulonephritis pattern, you call it C3GN, but if you have those, ribbon like deposits within the basement membranes, then you can call this the dense deposit [00:04:30] disease. And both of these together come within the category of C3G. I will also say that this nomenclature had been proposed, close to a decade ago, because I'm pretty sure when I was a fellow it had just come out, but, I will say that even then I would [00:04:45] see some
path reports coming from other institutions, other places, which would mention MPGN as opposed to immune complex versus C3G. And I will say, personally, I found this new immunofluorescence, classification, a lot more helpful in [00:05:00] diagnosing and also treating, figuring out the right treatment for my patients.
And so I'm really glad that we're talking about this today,
Kenar Jhaveri: so if it's this easy, right, Matt, like it's C3 dominant, doesn't matter dense deposit disease or C3G. Why is diagnosis such a big issue? [00:05:15] I mean, it sounds like a slam dunk to me.
Matthew Sparks: The problem is the complement cascade is very important in many diseases. And this entity, which we're describing here, it's autonomous sort of activation of the [00:05:30] alternative complement cascade either through an autoantibody or through a genetic mutation. However, when you see pathology, often it's a reflection of what's happening in the body.
And for instance, infections need [00:05:45] complement in order to rid the body of infection. And there's really no way sometimes to distinguish the pathology report from C3G, which includes C3GN and dense deposit disease, and an infection related [00:06:00] glomerulonephritis.
Now, there are some subtle clues that can help push you in the direction of C3G versus infection, but sometimes it can be a challenge and a diagnostic dilemma. And so for instance, looking at the type of [00:06:15] deposits can be helpful, whereas in infection mediated glomerulonephritis or PIGN, you can have large sub epithelial humps.
However, there have been reports of that seen in C3G and dense deposit disease. Some [00:06:30] of the things you need to look at is the context of how this is occurring. For instance, a patients hospitalized for an infection, well, that's likely not going to be C3G. Sometimes the age of the individual is helpful.[00:06:45]
When we talk a little bit later about the randomized control trials, you'll note that the average age is in their twenties and thirties. You can also have the same pattern with someone with a monoclonal gammopathy. And so that needs to be looked at very carefully. And so when we talk about [00:07:00] the trials as well, we need to look at resolution of the disease.
For instance, having persistent low C3 level. After resolution of the disease should trigger in your mind that maybe this was an infection that just made their [00:07:15] underlying complement disorder be seen to the world. And so maybe they have like a mutation that wasn't causing overt disease that no one knew about, but now they had an infection and sort of triggered it.
And that's why this is a [00:07:30] challenging diagnosis because when we get the PATH report, we see C3G or C3 dominant staining. We get excited and want to use these new drugs, but these new drugs come with a lot of side effects, and we need to make sure that we're really giving these to the [00:07:45] right patients.
So that's why Dr. Varshney described, make sure they have no infection, make sure they have no occult infection that might not be apparent, and make sure they don't have a monoclonal gammopathy. That's very important.
Kenar Jhaveri: So I guess let's get to the ordering of labs, right? Would [00:08:00] you be satisfied Aarushi with just complement levels or would you want to do some send out tests?
Aarushi Varshney: Oftentimes they. Would say I think in a peer trial where they had patients with low C3, but it's not always seen. We [00:08:15] don't always have patients with low C3 or rarely even low C four. But I think that is an easy test, a test that is available at many centers that we can order.
So we can start with that. Like Dr. Sparks said, if someone is admitted and we're thinking [00:08:30] about infection we should do a very thorough workup to rule out any underlying infectious disease. Again, it comes down to the age. Also, if there is a young adult and they have pretty significant proteinuria, so I would say an infection has [00:08:45] been ruled out, then maybe we can take a next step and do more, send out tests like looking at nephrotic factors, looking at auto antibodies, looking at factors H B.
They are not available at many centers. So they are send outs and they do also have a [00:09:00] cost burden with them. Also if it's an elderly individual we need to rule out monoclonal gammopathy for which we can order s pap and free light chains and go from there.
Koyal Jain: I actually think that we've now talked about diagnosis, but I will say [00:09:15] practically in my experience having seen some of these patients and having seen post infectious GN a lot.
It is really hard and the reason it's really hard is because you can have same patient profile. You can have patients who present with an [00:09:30] infection, which triggered a post-infectious gn, but an infection also triggers C3G, right? And C3G is not like, once it's active, it's always active. It can also flare and go into remission.
So I think you really have to have that clinical acumen also to [00:09:45] pick up these diseases. Unless there's a genetic mutation. If there's not a genetic mutation, and it's something to do with functional assays, once things are in remission, they might be okay on your panels for C3G as well.
So again, that becomes really hard when you see these patients, not in a [00:10:00] flare situation, but subsequently trying to figure out what to do.
I wanna actually talk about treatment. I'm really excited to talk about treatment. So Matt, you know, there are a couple of studies that have come out in C3G world.
Do you wanna just describe that for our [00:10:15] listeners?
Matthew Sparks: It's really unusual to see two drugs approved in the same year with high profile publications. So that really gives us great options for our patients. And the other thing that I really love about this is neither one of them requires them to go to an infusion [00:10:30] center. So there are two drugs currently available, which the community already has a little bit of experience with or heard about.
iptacopan a factor B inhibitor. And the trial name, is called APPEAR. And then Valiant is the other one.
This is a drug with [00:10:45] pegcetacoplan, which is an inhibitor of C3. Interestingly enough, these have been used for a long time with another complement disorder called paroxysmal nocturnal hemoglobinuria. And so an important thing is there's a lot of experience with these drugs. [00:11:00] Now, iptacopan is oral pegcetacoplan is subcutaneous infusion twice a week.
Now, as Aarushi alluded to early, these are ultra rare diseases and many nephrologists might see this once every five to 10 years. And so it's really [00:11:15] hard to have huge trials. So we're not going to see the numbers of the SGLT2 inhibitor trials. And so in the APPEAR trial, which is iptacopan, the number of patients was just 35 in each [00:11:30] group, 38 and 36 for placebo.
And pegcetacoplan was in the 60 range for both groups. They had a little bit of differences in who they enrolled. The iptacopan group enrolled individuals age [00:11:45] 18 to 60. They basically enrolled those individuals that had a diagnosis of C3G, whereas the pegcetacoplan had those with C3G, but they also included those with primary immune [00:12:00] complex MPGN, I think to cast a little bit wider net because if you look at the sensitivity and specificity.
If we're looking at C3 staining alone, you're going to miss some patients. 'Cause obviously it's ultra rare disease and these are not very [00:12:15] specific tests. Also, pegcetacoplan included those individuals with kidney transplants. However, it was just a handful in each group, five or so.
The primary outcome in both of these trials was proteinuria reduction, but [00:12:30] they also have secondary endpoints, which included, gFR and also they looked at kidney biopsies in patients that were on therapy.
We rarely get that in a lot of our trials. So both of these trials, just really quite [00:12:45] impressive. So we'll start with iptacopan first, and it had a reduction in proteinuria of about 30% at six months which was sustained.
And they had an open label extension period in which the patients that were on placebo got the Ipticopan, and it worked in them as well. Now the [00:13:00] pegcetacoplan was even more impressive, and it resulted in almost a 70% reduction in proteinuria. And if you look at the subgroup analysis, really it didn't matter what your age was, what your C3 level was, or really anything, it seemed to work [00:13:15] across the board, which I think this is just opening up a new avenue for our patients because prior to this, we didn't have a single randomized control trial.
iptacopan also resulted in stabilization of EGFR. However, the pegcetacoplan even had a more [00:13:30] impressive stabilization. And I think what really struck me is that the C3 staining almost disappeared in the patients that received biopsies during therapy in the pegcetacoplan group.
Now safety is another important consideration, and it actually [00:13:45] appeared quite safe. I will say though, this is not a long duration of therapy and a patient with a genetic mutation or an auto-antibody formation might need to be on this drug for the rest of their life. And so we need to know, what the long-term implications of [00:14:00] this is.
The need for immunizations and occasionally prophylactic antibiotics. When you give these drugs, you basically make it to where the complement cascade is not going to work. And it's really important for taking care of especially [00:14:15] encapsulated bacteria.
There was one death in the pegcetacoplan group versus the placebo group. But it looked like most of the other things were fairly well balanced. I think that patient ended up having COVID there was a few other infections that were [00:14:30] seen, but not a lot.
So it seems like they're very well tolerated. And now this has led to both of these drugs receiving FDA approval just within the last four to six months or so. So really we're in a whole new era now and it's going to be [00:14:45] great.
Koyal Jain: Can we pause here for just a second? Complement Cascade can seem really overwhelming so I'm gonna give you a quick two minute overview of how I think about it. I think of it as there are three systems.
There's the classical system, which depends on antigen antibody binding, [00:15:00] but in reality, IgA is a little bit controversial there. It is really in more lectin and alternative pathway . Lectin pathway is something where triggering happens because these proteins bind to sugars on bacteria and viruses. And then you [00:15:15] have a third alternative complement pathway, which sort of has a takeover system where all of us have a little bit of auto activated C3.
Now all of these have different triggering mechanisms, but go through C3, C5, and then there's a terminal complex, which is [00:15:30] the soluble MAC complex that is then created. So if you are now thinking about the C3G, what essentially happens is the C3 breaks down to CA C3a, and C3b.
C3b then binds to factor B and makes C3 bB, which is called C3 Convert case. And [00:15:45] this is like a feedback loop system. It keeps breaking down C3 over and over again. And so C3bB C3b and bB are just bound together as a converters. So if you take away factor B, or if you take away C3 or C3b [00:16:00] with pegcetacoplan, then you're basically affecting one of these two components of C3 converters, and then eventually through this amplification loop you affect
C5, C5 convertase, which eventually leads to this terminal complex cascade. Now I [00:16:15] don't really have time to go through all the details, but just to understand both of these drugs that we'll talk about today, iptacopan and pegcetacoplan are affecting factor B for iptacopan and C3b and C3 for pegcetacoplan.
Kenar Jhaveri: Alright. I know some of [00:16:30] us have used both the agents and I personally have had much more luck with the PEG than iptacopan. What are your experiences?
Matthew Sparks: Well, first off, we're not gonna let you get away with not saying the whole word.
Kenar Jhaveri: Oh, peg [00:16:45] Ceto. I can't
Matthew Sparks: if you look at the clinical trial data, it mirrors that my experience is that pegcetacoplan is a bit more of a larger hammer, if you will, and that, it's right in the crux of all three pathways.
And so you're likely going to [00:17:00] affect more patients with the disease. And I think the one thing to recognize is that a patient can have a disorder affecting multiple different areas. The autoantibody to C3 nephritic factor C4, C5 nephritic factor mutations in many different genes that [00:17:15] regulate this system.
We don't yet know. If we can profile a patient to say, you would be better for this drug, but it seems that the pegcetacoplan might be better for most patients. But also we have a backup to say, all right, well maybe a patient can't tolerate the subcutaneous [00:17:30] infusions and maybe they have a reaction to the drug.
Or maybe they don't respond to pegcetacoplan. We have an alternative agent to try as well.
Kenar Jhaveri: The device is actually pretty interesting. It's not like a straightforward, like a EpiPen or you know [00:17:45] Ozempic. It's like a device you put on your body and then give it like an hour to infuse it. And it does look like a parasite, but the pills could be appealing to some patients too.
So again, patient preference may play a role as well. Some patients like injections and less [00:18:00] pills, some like pills. You still get proteinuria reduction either way.
Matthew Sparks: Maybe it's important to talk about the vaccines. Aarushi do you wanna talk about what to do in that situation?
Aarushi Varshney: So before we start this drug, we definitely [00:18:15] have to ensure the patients are vaccinated against neisseria meningitis and then streptococcus pneumonia. Oftentimes it needs to be done within two weeks. If they're not, and this is something where we urgently do need to start on the medication, then we can start prophylaxis [00:18:30] antibiotics.
We have options the antibiotics are penicillin, Augmentin, and if they're allergic, then we can think about ciprofloxacin.
Matthew Sparks: A lot of these drugs are used in many other settings and often our pediatric colleagues like to vaccinate and use prophylactic [00:18:45] antibiotics as well. Because really these patients are at risk, need to be monitored very carefully and given antibiotics if they have signs or symptoms of infection.
Given this is NephMadness. It's a tournament, we gotta have a winner. And for anyone who's [00:19:00] interested in participating, this is just a way to have a debate, a discussion about different topics that are emerging in nephrology. And so I'd love to hear from this esteemed panel, which one of these teams is going to not only win the game [00:19:15] against each other, but win the whole tournament.
So we can start with Dr. Jhaveri.
Koyal Jain: The most
Matthew Sparks: go to Koyal. We'll, Dr. Jain is next. Don't worry. I wanna start with, and if you use the drugs, you have to pronounce them both.
Kenar Jhaveri: So I [00:19:30] would say I would go with the iptacopan and pegcetacoplan. I think it's not just C3 where these drugs are gonna take over. Even if the C3 is activated by an infection a month later, I think we could probably end up giving these drugs, even if you have MGUS, triggering the [00:19:45] complement cascade.
You might still have to use these drugs down the road. I think these drugs might be very good for TMA and other complement disorders. So I think forget the diagnosis, the drugs wins hands down. So it's not just C3 I think it's gonna [00:20:00] change the rest of nephrology
Matthew Sparks: That's pretty passionate. Let's go on Dr. Jain.
Koyal Jain: So I will say that this one I actually genuinely feel it's the medications. I feel like with nephrology we haven't had for so long innovation, and now the past few [00:20:15] years we've had so many new drugs and it's become so exciting. As a fellowship program director, there's nothing more exciting to tell other incoming fellows look at the world of nephrology.
We are really changing and we're really at the forefront of all these changes and medications that are coming up. And I agree with Kenar. [00:20:30] We have another NephMadness episode on IgA right that our listeners will be listening to, and we talk about one of these medications again, and who's to say the other one won't be used there either in the future, right?
So there's just a lot of overlap between all these diseases which have had no [00:20:45] treatment for the longest time and now all these upcoming treatments. The one thing that we didn't really mention in the midst of our discussion is iptacopan and pegcetacoplan, both of them allowed MMF to be used.
We now have some data on MMF plus [00:21:00] iptacopan and MMF plus pegcetacoplan. So if you're thinking about IgA and other diseases. But regardless, my preference is the medications for sure. Should we go with Dr. Varshney?
Aarushi Varshney: Yeah, I am. I would say team management for sure. It's so much is happening you both said it so beautifully, [00:21:15] it's going to reshape the world of C3G and just glomerular diseases. And it has such positive findings that we have seen so far. Obviously we need to see what it's going to be like in terms of adverse effects in the next couple years, how patients are going to behave.
And also we [00:21:30] need to know the duration of the treatment. So there's a lot of things that we still are learning about it, but definitely have seen a lot of promising findings for the treatment. So definitely team management.
Matthew Sparks: I don't have a lot more to say that I think this is gonna be a front runner to [00:21:45] win all of NephMadness. That's team treatment. So yeah, like it's looking back, like right now in time, you can draw a line in the sand and look at all the papers that were done on this disease prior. And then we're gonna see everything in the future,
you're not [00:22:00] even going to see someone even get a transplant with this disease. And to me that's just an amazing thought because, if you look back at the case series from Columbia that looked at this recurrence post-transplant prior to the initiation of these drugs and it's [00:22:15] very, very high
even in their thirties on their second transplant. And so this is gonna revolutionize that and to me, like the patients really have a shot now and that is just amazing. So I'm a hundred percent behind the therapeutics here.
Koyal Jain: For our [00:22:30] listeners, they heard it first here. So if this wins
Kenar Jhaveri: Yes.
Matthew Sparks: I have no inside connection.
Koyal Jain: I dunno. Dr. Sparks is saying, this is winning, this is winning.
Matthew Sparks: I have never won NephMadness, just to be clear. So I'm not the [00:22:45] best person to look at.
Koyal Jain: He's never won it, but he's always been second, you know? Well, with that, thank you so much everybody for listening to our NephMadness episode on C3G. We'll see you next time. This is Kenar and Koyal signing off. Thank you, Dr. Sparks and Dr. Varshney for joining us.
Kenar Jhaveri: Thank [00:23:00] you.
Laurel Damashek: This has been GN in 10 from the International Society of Glomerular Disease. You can listen and subscribe wherever podcasts are found and tweet at us at ISGDtweets. [00:23:15] Thank you for joining us.
Kenar Jhaveri: Whoa. That was a handful.
Koyal Jain: I need a break now.
Kenar Jhaveri: you need a break? You said that without a breath and like you had all these tongue twists just be beep packed or beep. I was just, what the heck?