Episode 9 NephMadness 2025 Genetics

[00:00:05] 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.
[00:00:28] Koyal Jain: Hi everybody. Welcome to the new episode in GN in Ten. This is Kenar Jhaveri and Koyal Jain bringing in NephMadness for the region genetics in 2025. We have some amazing guests. We'll let Dr. Elena Cervantes introduce everybody.
[00:00:45] Elena Cervantes: Thank you very much. I'm going to introduce first Matt Gross, who is our second year nephrology fellow at Johns Hopkins, and he was the writer for the genetics region. And we have as well, Jordan Nestor, who is our content expert. She's a nephrologist at Columbia University, and she's also a specialist in genetics.
[00:01:04] Kenar Jhaveri: Can you tell us a little bit about NephMadness? Can you give our listeners what that is in a nutshell?
[00:01:08] Elena Cervantes: Absolutely. So the NephMadness is an educational initiative that was created in honor of March Madness, which is the basketball tournament. But here we really talk about nephrology. We have eight regions, two subtopics. And the goal is for us to discuss about all these topics so that we can identify a winner.
And the big question that we need to answer for ourselves is which of those will be the most practice changing over the next five years.
[00:01:36] Kenar Jhaveri: That's great. So one of the regions this year in NephMadness is genetics region and the two topics are genetics in FSGS versus genetic counseling. So I'm a big proponent of genetic counseling and I think it's something that everybody should be well versed with and a very important part of nephrology as we learn more about genetics and nephrology.
And I know Koyal doesn't really like that. She's a big proponent of genetics and FSGS. Is that correct, Koyal?
[00:02:06] Koyal Jain: I will say I 100 percent believe in genetic counseling. I don't think you can.
[00:02:11] Kenar Jhaveri: Ok, we have a winner!
[00:02:13] Koyal Jain: Wait no. We don't have a winner yet. I do think, however, for the next five years that maybe genetics and FSGS is going to be the one that is going to make a lot of difference.
So that's why I support that region. But I agree genetic counseling is so important. That's why we don't know the answers yet.
[00:02:30] Kenar Jhaveri: Let's just have our content experts decide that for us. So I have Matt on my side and you have Jordan on your side. So I'm going to ask Jordan a little bit about the genetics and FSGS. Can you tell us how many genetic causes do we know that are associated with FSGS?
[00:02:46] Jordan Gabriela Nestor: So as of now, at least 50 plus genes have been identified to be associated with these monogenic causes, these rare genetic causes with the histopathologic finding of FSGS pattern lesions. But that's, of course, We don't really know, it's all based on what we know so far. We need histopathologic correlation.
We also need an understanding of these other monogenic causes that might also have FSGS pattern lesions if we had ever biopsied them. And so really we talk about the phenotypic spectrum of diseases and we just think that FSGS pattern lesions are just one aspect of it, not a whole disease entity, which we have categorized FSGS as based on histologic findings.
Really, it's just a nonspecific lesion that we see histopathologically. And so we believe that there's probably a whole bunch of other disease entities that have that same finding.
[00:03:44] Kenar Jhaveri: One of the important things you quickly mentioned is pattern of injury. And I love when nephrologists say a pathology term, which is actually true. It's actually a pattern of injury and not a disease. And, just for our listeners, it's, you have primary FSGS, you have secondary, and then you have these genetic components, but they all have a pattern of injury, which is FSGS.
So, It's not a true disease, unless you don't know the cause.
What about Alport's? When do you connect those two together? That was something novel that we are learning about the connection of Alport's and FSGS. Any thoughts on that?
[00:04:17] Jordan Gabriela Nestor: Well, we see the FSGS pattern lesion in some individuals who have collagen 4A3 and 4 heterozygous variants, and the question is, do we also see it in some individuals had they been biopsied who have the classic Alport's, collagen 4A5 Alport's, male, hearing loss, ocular abnormalities. I'm really open to possibilities of finding that in individuals across all types of variants.
Causal variants that have a kidney phenotype that have kidney insufficiency and/or proteinuria and/or hematuria and/or histopathologic evidence of injuries, even that FSGS pattern lesion. It was novel to find that individuals who had proteinuria and didn't have ocular findings, didn't have hearing loss, weren't males, actually ended up having these collagen 4A, and now we consider this whole spectrum of Alport associated illnesses, it's very heterozygous phenotypically and genetically. And I'd say for now we think it's more in the collagen 4A3 and 4 variants that are causal of disease, but I'm open to the possibility that it's in all of the collagen 4A associated genes.
[00:05:29] Kenar Jhaveri: I mean, this is more likely that we pick up the FSGS first, and then in the EM, you pick up the Alport's, making diagnosis and management a little bit different, because now it's more of a genetic variant, as opposed to the FSGS might have been, you know, chucked along as, oh, this might be from obesity or something else.
[00:05:47] Jordan Gabriela Nestor: Yeah, I think ultimately if you identify someone, it's a non specific finding. So if you went forward with biopsy before genetic testing and you found the lesion, and then all of a sudden now you want to do the molecular testing to see if there's an underlying cause for that lesion, I think it's a stress that the glomerular basement membrane is under because of a faulty, protein structure because of these mutations, these causal mutations that cause the pattern of injury. Yeah, I think the management is completely different because now you have a genetic cause and I think the management is much more conservative. Of course you wouldn't go down the path of immunosuppression or anything.
It might be how you come across the diagnosis. First you did a biopsy and then that's how you identified it. And then you do molecular testing afterwards. Or, you had a suspicion, based on family history and or presentation, something in the history made you think let's avoid the biopsy and let's go forward with the molecular testing first. And then that actually maybe prevents you from having to get the biopsy downstream. And so however you come across the diagnosis is fine, but I think knowing that it's a molecular cause of this phenotype is very informative for management because the management is much more conservative, and you know that if the renal insufficiency is progressing, you're much more likely to refer them for transplant earlier because of these hereditary causes tend to progress, and the patients do quite well with the transplanted allograft.
[00:07:17] Kenar Jhaveri: And you probably refer them for genetic counseling too.
[00:07:20] Koyal Jain: I was going to say you're going to send them for genetic counseling, but she said it is key that we find out what genetics in FSGS are involved, because it would mean that you don't need to treat all the patients, right? So genetics and FSGS becomes really
[00:07:31] Kenar Jhaveri: That brings up a bigger question . The big elephant in the room is really APOL1 nephropathy and FSGS connection. I think with therapies on the horizon and where do you put in? How do you counsel your patients who have that mutation both heterozygous and homozygous?
Because we're picking up a lot of these mutations when we do genetic testing now for a lot of our FSGS patients. How do you counsel them? And how do you prepare them for potential future treatments?
[00:08:01] Jordan Gabriela Nestor: So it's very difficult with the APOL1. I think the APOL1 is ready to be used in clinical use the testing for the genotyping in the context of living donation, especially when you have an at risk family member who you're potentially the donor for. So if your family member has kidney failure, where you're deciding whether or not that person is maybe too high risk for being a donor and where the donor nephrectomy might put them, that second hit of having the high risk genotype and then undergoing a donor nephrectomy might be sufficient to then have a kidney phenotype downstream. I think that's very clear, the role of APOL1 testing clinically.
Whenever we get referrals in our genetics clinic for patients who have proteinuria, maybe they have FSGS, and then you want to identify the cause at a molecular level, we always differentiate in the pretest counseling component, the importance of knowing that we're looking for causal genes.
That includes the collagen 4A3, 4, and 5 genes, for example, along with tons of other genes associated with the FSGS pattern phenotype. But then we have these risk variants and the risk variants are not disease causal, but they're risk variants. But we don't really know what the modifying factors are except in the context of maybe a living donor who's at risk, undergoing a donor nephrectomy.
And because we don't really know what the modifying factors are, genetic or environmental, it's really difficult to counsel individuals. And so in the pretest counseling, we're setting expectations for the patient that we don't really know how this information is really informing the clinician, but then we have to do a lot of work with the clinician who made the referral, who's looking to see the patient's APOL1 status, genotype status. Because really the question is then, how is management going to change? If we don't know the modifying factors that can mitigate the likelihood of disease progression, how are we managing patients based on this genetic information?
So I think it's very important to then help them again understand that this is a risk variant and we're not identifying a causal entity.
[00:09:59] Koyal Jain: I will say that one thing that's very clear is, genetics in FSGS and genetics and other disease, but I think genetic counseling and all of this is really so intermeshed or intermingled, right?
[00:10:09] Kenar Jhaveri: You said it.
[00:10:10] Koyal Jain: I said it I, I mean it, right? Thankfully, I don't have any ties to one end or the other.
Yes, I'm supporting one region, but really they go hand in hand. There's nothing separated. And to Matt, I have a question. I have a patient in front of me. I see them in clinic and I say, you know what? I'm going to send you genetic testing and I send this genetic testing and then they run a slew of tests and I get this huge result back and they have all these variants that say variants of uncertain significance like VUS and I don't know what to tell the patients.
How are you counseling your patients?
[00:10:44] Matt Gross: So you're right. Typically, when you order these panels let's say if you're going through a commercial outfit, a lot of the time, they'll offer differing panels of different specificity and what genes you're testing. But you're right. Most of these companies will offer this big panel that essentially tests all the genes that they know are associated with kidney disease.
I do counsel patients that the variants of uncertain significance are relatively common. We're still pretty early in our knowledge of genetics in terms of kidney disease.
Two kind of important things. One is that variants of uncertain significance, I tell them, does not mean that you will develop kidney disease , but we will track these over time and as more data emerges, majority of the time, I'd say they tend to be reclassified as a benign variant. And if later research down the road shows that perhaps this is a pathologic variant typically the patient isn't informed of that.
[00:11:44] Koyal Jain: But that causes stress for patients, right? If I was told, you know what, you have a variant and we don't know what it does, and we will eventually find out, I will be stressed out for a while, which makes me think that any time you're sending a genetic test there should be some genetic counseling available.
So do we have regulations surrounding it? Are we required to have genetic counseling whenever we're sending a genetic test?
[00:12:04] Matt Gross: Typically no, there are no requirements prior to sending the tests. I will say if you're going through a commercial outfit, most of these companies nowadays do offer genetic counseling, both for the patient or for the physician. I can say anecdotally, I've even had a case where I've had a patient and we get a positive result. And before I necessarily want to talk to the patient about the result, because it had implications for children, I was able to get on the phone with a genetic counselor pretty quickly, even without having to schedule an appointment. They were able to see me within 10 minutes.
So you're right. It is a real consideration. I will say on the flip side to you also have to keep in mind that these patients, presumably if you're ordering genetic testing, they already have kidney disease and you already aren't quite certain exactly what is causing the kidney disease for the most part.
And so there's some uncertainty just with not testing as well. Those do have to be weighed back and forth. I think if it's a patient that you think is going to be really nervous about certain variants of uncertain significance. Maybe that's the type of patient where maybe you order a more targeted gene panel if you think that might really cause a lot of stress for them as well.
[00:13:17] Kenar Jhaveri: I have a question for Jordan because Matt brought up a very good point. So if I have a case and this happens all the time, especially now that we're ordering genetic testing for hypertension, we nephrologists see a lot of hypertensive patients too and The kidney function is pretty close to normal and you get a positive mutation for, say, complement factor H.
Would you biopsy that patient? What type of counseling would you give that patient? Because are they at risk? Is it underlying TMA in the kidney that's causing the hypertension? Do you biopsy that patient? Do you do further counseling? What do you do from there? When you have a normal kidney function, no hematuria, no proteinuria, but have a positive genetic test that is concerning and it's a red flag that this patient will get TMA in the future.
[00:14:01] Jordan Gabriela Nestor: I go back and I reassess everything like why was it ordered? What test was ordered? And those I personally am not a big fan of ordering those tests. Our glomerular center at Columbia, of course, refers us a lot. And I think a lot of it is the pretest counseling and also I'm speaking with our colleagues about what sort of, I think the functional assays that they offer for the complementopathies are quite useful. But I don't think again that the gene panel is very informative. Again, these aren't necessarily monogenic causes, oftentimes, those are very severe cases that we see in children, maybe young adults, but, usually the types we see are more complex forms that they're not monogenic.
They're more of these polygenic diseases when we see these TMAs. That I don't think that the genetic data that we're getting is necessarily that informative for the clinician. And so I'd go back and reassess everything. The most important thing I think is though there are no standards for offering genetic testing, it is the ordering provider's obligation to ensure informed consent. With genetic testing, unlike other tests, blood tests, urine tests, there are implications, not just for individuals, but for their families, potentially, and for their communities. And so I think that goes back to the need to counsel the individual, set expectations for what type of test and what type of results we're going to potentially get with whatever testing modality we go forward with. If we go forward with testing at all, and also going back to the clinician about what sort of answers are you seeking?
What's in your decision tree? Are you on the fence about biopsying the patient or not? The patient is very mild phenotype and you don't know what to do. I think a lot of it is very individualized. You can't really make a blanket suggestion. You really need to see what is it that the clinician needs from your services that you might help, and more importantly, what will they not get? Right? Because a lot of time we're setting up I'm the one with the bad news. I'm the one telling you that whatever you're ordering isn't necessarily going to be the answer you're going to get, and also to the patients, I tell the same thing. The overwhelming majority of individuals, we're just going to get a lot of noise, the VUSs, but we're not going to get something diagnostic or causal.
But sometimes we do, and that's why we go through these procedures, and that's why we go through the testing, and that's why I think in your case, we should do it, right? Because of the percentage, 10 to 20 percent of individuals where we do find monogenic cause. But for these other diseases that are complex, that I think are much more polygenic in adults, there's some genetic tests you can do, but I don't necessarily know that it's going to guide the clinician very much.
[00:16:29] Koyal Jain: I go back to the clinician and say, what is it you need? What can I help you with? And more importantly, what are the limitations of the testing available now commercially that I can help you put into your framework so that you understand that if you want to go forward with a biopsy or maybe conservative management, serial observation, I'll be able to help you there because the test might actually cause more trouble for you and the patient than actually get you the information you need in your clinical decision making.
If you don't need the test and you get it and you get now a positive result, what do you do with it? Or what do you follow? Let's say you decide to biopsy them. Let's even treat it. What number are you following? They have a normal kidney function. They have no hematuria. There's no proteinuria.
[00:17:08] Koyal Jain: What are you going to, what's your marker?
[00:17:10] Jordan Gabriela Nestor: And a person with normal kidney function, biopsies are not risk free. Again, I'm a big proponent of conservative management, serial observation, blood pressure, blood urine check biannually.
So this may be just something that I'm the only person worried about but what are your thoughts about these commercial tests? Hundreds of thousands of people, I don't know what number, are getting the genetic testing done and it's just sitting there. What are the regulations surrounding it? Could it be misused? Is it safe? What do you think?
Depending on where you are in the country, I think your policies and your concern for patient privacy vary.
[00:17:46] Jordan Gabriela Nestor: We care about those things a lot. We care about patient privacy a lot. When individuals are in our genetic testing environment for a genetic consult, there's an option to maybe go through research based testing with a commercial clinical CLIA certified laboratory.
Because it's sponsored, or we can just go through your insurance. I'm a big proponent of let's just go through your insurance. But a lot of patients I find, unfortunately, are like, I don't care. Even though the insurance will likely cover it I don't care. I'll go with the sponsored testing.
And so I think at least my role is to inform individuals that if you're going with sponsored testing, and I think this is a big thing to be worried about, these individuals have your genetic data and how is it going to be used? If it's going to be used for research and development, fine, but Don't you think patients have a right to know, that this is your information that, you should fully know.
And this is, I think, part of the informed consent process and the pretest counseling requirements. But I do think it's something very important because, people are participating.
What are the obligations of these companies, these private companies, to protect your data? And what are they going to do with it? You should know what your data is going to be informing, and you have a right, I think, to the protection of your data.
And I think this is something we should stress very much in the pretest counseling portion of every session.
[00:19:00] Koyal Jain: I wonder there's some fine print when you know, when you sign off on these contracts is like such a long contract, who's reading the entire contract. I think that's what's happening with most people.
[00:19:08] Jordan Gabriela Nestor: In some institutions, they just have an opt in or opt out policy where people are just being biobanked in sequence. What's the downstream ramifications of this? What are patients rights to this? And also there's a lot of interplay between these academic institutions who are biobanking specimens and private industry and startups.
And what are the obligations to the institution? If a patient has a problem with that, right? And I think we have to be more considerate of the fact that patients might have a problem with this later on.
And I think it's important that patients have a right to know where their data is going to go.
[00:19:42] Kenar Jhaveri: She keeps mentioning the word counseling, counseling multiple times. So I think, we have a clear winner here, but that we just, to piggyback on her point, you can't stop community doctors, everybody from ordering commercially available genetic testing. We get patients coming in with these reports and they tell me to interpret this as a GN specialist.
And I think the education has to come at a fellowship level at this point to nephrologists and training that there has to be counseling. There has to be something that has to be done before you order these tests. So as new generation nephrologists get graduated, they're more informed about how to order these tests and what to do post and pre.
You can't stop the madness that's already opened up, no pun intended, but it's, I think counseling is the key to our fellows and to our patients.
[00:20:31] Koyal Jain: So my question to Matt, one last question is you're a fellow right now. Do you feel comfortable counseling patients?
[00:20:41] Matt Gross: That's a tricky word. I would say I certainly feel more comfortable now than, for example, I did last year as a first year fellow. When I listen to Jordan talk, I don't feel as comfortable. I would say, yes, I feel comfortable enough for some kind of more common reasons for genetic testing.
I think I feel comfortable enough. I'm using that word "enough" purposefully, because realistically, as you all have pointed out that, genetics is typically we see it in medical school and then that's usually the last time you see it until now this is becoming a big topic in nephrology and so I think there's a lot of discomfort.
Throughout all of nephrology with probably your average nephrologist now that this is becoming a bigger field. And so it's something we all have to learn, at least on a surface level.
[00:21:32] Koyal Jain: I think there's so much room for improvement. I'm a program director and I'm thinking about. How often am I teaching my fellows to actually do genetic counseling? We do teach them about the new genetic stuff that's coming out. They have these cool lectures. They see all these patients. But how much are they really learning about counseling?
So I really think that there's a lot of room for improvement, a long way to go. In genetic counseling, and so for the next five years, I still think the genetics in FSGS still plays a huge role, but I think genetic counseling is equally important, just not there yet, and it should be. It should be better than where we are.
So Laurel, you are going to be the judge for this region for us, and for our listeners, this is not the actual result of what the NephMadness topic is, Laurel's going to give our result. What do you think?
[00:22:22] Laurel Damashek: Yeah, I am not on the NF Madness panel. I have no insight into what the judges have actually chosen, but as the producer of this podcast, and more importantly, a patient with genetic FSGS, who has also had genetic counseling, I think you made a really great argument for the importance of genetic counseling, whether for FSGS or other conditions.
And certainly from my own experience, I think it's so important and so complex. I was fortunate to have my own nephrologist be a real expert and pioneer in genetics. And when I talked with him about my results, I brought up the genetic counseling and there's a shortage of trained genetic counselors who are familiar with all of the ramifications of genetics of kidney disease.
We need to do more to change practice on every level, really, in the way that patients are getting information and consent and the way that nephrologists are being trained and also supporting genetic counselors as a profession and their integration into nephrology practice.
[00:23:32] Kenar Jhaveri: I think to all the program directors out there, I think what Laurel said is so important. I hope the take home lesson from our podcast is that you think about incorporating some form of genetics training to our fellows in terms of counseling.
Not everybody can be a Dr. Nestor but at least we can be. Like, everybody should know how to treat minimal change. If it's complicated, you send to a GN center. The same way everybody should be able to graduate with basic genetics, knowledge of nephrology and counseling. And when it's a complicated case, you pick up the phone and call Dr.
Nestor. So I think that's what I'm trying to get at from the fellowship director standpoint. I think if we can all agree on that, then I think we have made a point with this podcast.
[00:24:15] Jordan Gabriela Nestor: And the option to call Jordan Nestor is absolutely on the table, please, I get calls I get texts, and I really enjoy seeing these cases hearing about these cases and I really am available to help you navigate these.
[00:24:28] Koyal Jain: We really appreciate that. And with that, thank you so much, everybody for listening to us on GN in 10. And this is our NephMadness episode on genetics in 2025.
[00:24:39] Kenar Jhaveri: Thank you.
[00:24:40] Koyal Jain: I cannot wait to find out who actually wins.
[00:24:42] 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. Thank you for joining us.
[00:24:58] Kenar Jhaveri: Okay, so Matt and Jordan , who is going to take on the FSGS response and who's going to take on the genetic counseling response?
[00:25:06] Jordan Gabriela Nestor: I was thinking Matt would take both and I'd provide moral support.
[00:25:10] Matt Gross: Oh, God, no