Welcome to KD GO Conversations in Nephrology. This episode titled How I Treat IGA Nephropathy Lessons from the Case Files is provided by KD Go and supported by Trevier. Here's your host, Doctor Donna Rizik. Hello and welcome to KD Co Conversations in Nephrology. I'm Doctor Donna Rizik. I'm Professor of Medicine in the Division of Nephrology at the University of Alabama at Birmingham, where I also serve as the Associate Dean for Clinical Trial Research in the School of Medicine.
Joining me today to discuss IG and nephropathy treatment are two distinguished guests, Doctor Andrew Lazar and Dr. Gaya Kopoc. Doctor Kopuk is an Assistant Professor at the University of Pennsylvania School of Medicine, where she runs the Glomerular Disease Clinical Trials Group, and her clinical and research interests include immunomodulation in glomerular
diseases. Dr. Lazdar is the Clinical Trial Director at the University Hospitals of Cleveland, and his clinical and research interests include glomerular diseases, genetics in kidney diseases, and the development of an implantable dialysis device. Doctor Kobuk and Doctor Lazar, welcome to the podcast. Thank you. It's so great to be here. I really appreciate you having me. Thank you. Pleasure. So we have a nice conversation ahead of us in light of the updated KD GO guidelines.
And as a reminder for perhaps our listeners, over the past two sessions, we reviewed some of the data behind the new KD GO guidelines that were recently published and the IGN nephropathy pathophysiology. So today we're hoping to illustrate how we would apply these new guidelines to cases that we see in our daily practices. So I'm going to just share with you a couple of cases and see how you would manage again in light of these new guidelines. So let's start with a newly diagnosed case.
This is a 19 year old Caucasian man with a history of depression, chronic Constipation complicated by hemorrhoids, but no history of inflammatory bowel diseases who presents with grossy materia around May of 2025 after having a sore throat.
At the time of resentation, his creatine was around 0.9 milligram per deciliter and his prior known baseline was about 0.7 and he was found to have quite a bit of hematuria with more than 100 red blood cells per high power field and quite a bit of proteinuria with about 2.3g per gram on a UPCR. So evidently, he was referred for kidney biopsy that confirmed the diagnosis of IGA nephropathy and his missed score that was provided by the pathologist was M1E 1S1, T0 and C1O Gaia.
Let me start with you. How would you approach the management of this patient? O you know, I think that this is a great example, maybe a classic example of why we need to address both immunologic and non immunologic aspects of disease in our patients with IGA nephropathy.
This one I think has a lot of features that would make us concerned for immune activation, including, you know, his young age is hematuria, the higher grade proteinuria and then of course the inflammatory changes on his mass C score, the M1, E 1 and C1. And so I think this is a very good example of somebody who I would quite early try to put on HIT one targeting drug as well as HIT for targeting agents. You know, in terms of what to choose for him for the HIT one
approach. You know, right now we're still we're choosing often times between systemic steroids and targeted release budesonide. This is a young person who has relatively well preserved kidney function and is a new diagnosis. And so just kind of to minimize toxicity and and hopefully achieve good outcomes for him, I think that targeted release budesonide would be a good choice. You know, with the systemic steroids, oftentimes it comes with the prophylaxis and other pills.
And so especially for a young person, I think that that can be a little bit more of an overwhelming choice. And then I like the data for targeted really speed us tonight efficacy. So that would probably be what I would choose for his hit one drugs. That sounds great. Yeah. And I guess if one doesn't have access to targeted release, the desonide and systemic steroids at the low dose based on the testing trial would be another option for sure.
So Andy, besides the immunologic management of this patient, would you consider any CKD management? And if So, what would you start with? I certainly would. I have a 19 year old, so I'm a little bit afraid that I'm going to bombard this young person with a lot of drugs. So I know that we have to be a little bit careful or will probably affect adherence, but I tell patients that I'm really as much their cardiologist as I am
just about anything else. Any CKD patient including NYGIA, nephropathy patients, they are at greater cardiovascular risk, certainly the worst their CKD is. We know that they really have a shorter lifespan. So very early on out of the gate for this patient while we're thinking about what can we do to lower the chance hit one, hit two, hit three at 4, we've got to think about we've got to get
blood pressure under control. We have data to show that these patients probably should be in the less than 130 range and they often do have high blood pressure. So certainly we want them on Ras inhibitors. But I think going to an endothelin antagonist early, you know, certainly if I can use a drug, maybe 1 drug to improve adherence, where I can do Ras inhibition and I can do endothelin antagonism should be something that we should think
about. We know when we add an endothelin antagonist, we usually drop by about another 5 systolic, you know, So that's something I want to think about in addition to that Ras inhibitor, Thinking about the SGLT 2 inhibitors, we have a lot of data now to show that we know they do lower proteinuria and that's something they want to do
as fast as possible. The less amount of time that we allow patients to be protein uric, we, we don't want that proximal tubule to have all that protein that it can take up, you know, and all the inflammation and the tubular interstitial fibrosis that may follow. So we know that SGLT twos are going to lower prognuria. We know it looks like they probably save us EGFR maybe on the order of about 1mm per
minute per year. And when you look at trials like DAPA CKD where they had 270 such patients, IGA patients, we know that adding the SGLT 2 for these pay that it did lower cardiovascular events. You know you looked at cardiovascular events last end stage and it lowered at about
70%. So I think pretty much out of the gate I've got to think about blood pressure, you know, so I'm going to think about Endofeon attacks them, the Ras inhibitors and I'm going to think about also LDL cholesterol that is probably going to be next, you know, and we have data also I gap patients LDL greater than 100 are also a greater cardiovascular risk and maybe even renal worsening. But I'll be careful adding too many drugs too fast.
Yeah, I agree, especially with a 19 year old who was probably healthy a week earlier prior to his biopsy. So even though the guidelines do recommend potentially starting multiple agents at the same time, that doesn't mean we have to start them all on one single day. I totally agree with you. And you bring up and remind us again of the cardiovascular risk that's associated with kidney disease, even in these young individuals. So something to keep in mind and definitely look for
hyperlipidemia. Vaping is a big deal. I don't know about you guys, but we see a lot of vaping now. So you ask about smoking, they say no, I don't smoke. So you have to specifically ask about vaping, which is another risk factor. So, so guy, going back to you, this gentleman had the C1 lesion and you kind of alluded to the fact that this is part of, you know, kind of your treatment choice and you look at the inflammatory lesions.
Although of course, the guidelines could not have any stand on the use of the mesc score for treatment choice, simply because the data is not there. All the trials did not take into account, you know, athology findings, but I think in practice we do look at these lesions. So can you walk me a little bit through what are your thoughts and how do you distinguish that from a crescentic disease? Yeah.
I mean, I think crescents and IGA nephropathy are the very murky space because we see crescents and nephrology and it makes us quite alarmed. But of course, there is a distinction particularly in these patients between an RPGN and less than 25% of glomeruli with crescents, which is the C1
lesion. So with RPGN they fall outside the KD GO guidelines because they're not well they're addressed in the ego guidelines, but they fall outside sort of these new recommendations for management because people with RPGN were excluded from clinical trials. And so we do tend to and I tend to still treat them sort of with the classic steroids and cyclophosphamide based approach more like a traditional RPGN management.
However, this is this population, we see these people with Crescent sometimes even with like minimal other inflammatory changes in IGA nephropathy. And I think the mess group updated their scoring system in 2017 to try to address these patients specifically. But it's such a sort of sporadic finding that the data have been sort of a little bit hard to to classify. And so you know, as you said, the messy score is more about prognosis than it is about guiding management.
But I certainly with AC1 score would not put them into an RPGN category. But my personal preference is to treat those people with immunosuppression. Whereas in that higher grade, that RPGN category, more C2, I treat them more aggressively. Their prognosis tends to be core regardless of treatment because it's a more inflammatory subgroup. But we try very hard to do everything we can to mitigate their disease.
Yeah, great point. And again, RPGN just to remind the audience is a clinical diagnosis really. So you just have to look at this patient's trend in terms of fries and serum creatinine. So and did the critical guidelines mentioned the goal of reducing galactose deficient IGA, one that hit one that we've been talking about and the
circulating immune complexes. So how do you in your clinic when you're seeing patient, how do you operationally, how do you look at this at the time when we really don't have the biomarkers at our fingertips? That's really a great question. I think the three of us and I know a lot of the audience are very excited about precision nephrology that we're trying to head there. We don't want to put every single patient on all the agents that we have available to us.
So we are, you know, I hope that we're nearing that time that we'll have biomarkers, but looking at that table, you know, in the KD GO guidelines where they really prioritize thinking about galactose division, IGA 1 and circulating immune complex complexes made me really happy. Hopefully, you know, in the not so distant future, we'll be able to look at GDIG A1 and as probably a correlate to circulating immune complexes.
So, but the way that I prioritize it now or the way I really operationalize it is I want to think about prioritizing agents that I know do lower GDIG A1. They have legitimized it you know in the guideline. So we do know that TR budesonide does lower GDIG A1, you know maybe on the order of almost about 30%. And we know that some of the B cell modulators that we will
have soon are the other agents. We know that to lower GDIG A1 and some of those the anti April's you know as well as the anti bath slash April's I know have even looked. They have also measured circulating immune complexes GD IGA one in the accompanying IgG to it. And so looking at being able to employ those drugs first are what I'll be looking forward to doing. I personally am also very excited about other biomarkers
coming. Looking at some of the soluble CD163 data that you know is a marker of the M2 macrophage activation, which looks like that's going to correlate maybe with the inflammation of IGA nephropathy. This is where I hope things are going, that we'll be able to look at these biomarkers and choose drugs and then see what happens to those biomarkers as we treat. Yeah. I think people are working hard to get these biomarkers to clinical practice.
And I would say to the audience to keep an eye out on some of the exploratory studies that come out of the large clinical trials because they will all be looking at different biomarkers to hopefully guide treatment choice in the future. So if you're just tuning in, you're listening to the KD Go podcast on how I treat IGA nephropathy, lessons from the
case files. I'm Doctor Dana Rizik and it is my pleasure today to be speaking with Doctor Andrew Lazar and Dr. Gaya Kopak. So let's move on to our second case. This is a little bit different in that this is a prevalent case that comes to your office. A 34 year old Korean woman who has a history of obesity and uveitis. She has had episodes of synpharyngetic hematuria after strep infections as a child and ultimately underwent tonsillectomy.
Since that time, she has not had any more recurrences of her grocery Victoria. She reports having had the biopsy as a child but does not have access to the biopsy report she presents to your office. Refers from her primary care physician with microscopic hematuria and proteinuria as well as mild CKD with a creatinine of 1.4 milligram per
deciliter. Her UPCR was 2G per gram and her urine analysis was remarkable for not only proteinuria but also hematuria with five to 10 red blood cells per high power field. She's already on the Ras blockade for treatment of hypertension. So you send her to have a repeat kidney biopsy and again you confirm the diagnosis of IGN nephropathy. This time in this case, the mesc score is M0E0S1T0 and C0. So Andy, let me start with you in clinic.
Do you calculate the patient risk using the IGN prediction tool at the time of a biopsy? And if you do, what do you do with that information? I like to use the IGAN prediction tool and I try to get my fellows to use it also. I do it because I can start to better communicate with the patient regarding just how bad IGAN is and I do it. This may sound funny, but I like to do it also to remind myself
of how sick these people are. Because, you know, I trained during those years where we didn't think. Again, patients did that poorly, but we didn't realize that they're so young when we meet them. And you know what? 20 years may seem like a long time, but it's not when you're 30 years old and suddenly you're on dialysis or requiring transplant when you're only 50 years old. So I think that I'd like to do
that. You know, I'd like to be able to take clinical and look at that biopsy to use a validated tool that I could sit with the patient to say you fall into this low, medium or high risk. But what's funny is that a low risk of 15%, let's say of a 50% drop in GFR or end stage kidney disease at 5:00 or seven years, you know, it's still pretty darn high, you know, So I think it really instructs the patient. It reminds me that wait a second, these patients really
are ill. What I like to do is do it at the time of biopsy with the first two that have been published and then consider about two years later, I'll use the updated tool that was published maybe in 2022 that I can do the math when a biopsy was done up to one to two years prior. And I'll like to do the math upfront, do the interventions we do, and then do the math using that updated tool two years out and see if we've moved that needle. Yeah, hopefully the risk, you
know, is reduced by then. So you make a great point. The tool can predict up to 5, up to seven years maybe, which in somebody's lifespan is not a long period of time, but it does really put in perspective sometimes how bad the prognosis is. I totally agree with you. So and then the older you get, the, you know, the more you feel like, oh, you know, 40 years old, 50 years old is nothing. They still have a long time ahead of them.
So Gaia, in this case, does the patient's racial background, so the fact that she is Korean, change your approach to management and if so, how? Yeah. So, you know, the East Asian population, they tend to have had a little bit more success with different immunosuppression options looking back historically at data. And I think that has led to KD go including some alternative therapies for these populations, specifically cellcept or mycophenolate moffatile we can use in East Asian patients.
Primarily it's indicating K digo. They referenced the Chinese population tonsillectomy, which this patient did have as a child is also in the K digo guidelines for Japanese populations. And so although I mean that comes from the evidence, but sometimes I think in East Asian populations in general, I will sometimes try an alternative agent even if they don't fit into the exact basket.
Just with the knowledge that those studies and in these various ethnic groups have shown some more efficacy than we've seen, like in some European studies, for example, in terms of the newer agents, the targeted targeted release budesonide recruited very few Asians in their study, which is something to maybe consider when you're trying to think about how it may apply to our own patient populations. Systemic steroid trials actually tended to recruit larger numbers
of of Asian populations. And so I think that has been not necessarily a criticism, but it's always something that's looked at in clinical trials because we know this in our field that with patients with IJ nephropathy, when you see a response to immunosuppression as a reader, we always try to see, is this skewed by a population that tends to respond better to immunosuppression or does it have more of a global effect
across different ethnic groups? And I think because this question comes up a lot, there's a big focus in the newer clinical trials that are being published to have a good representation across diverse population so that they can try to answer more of these questions about like applicability and which of our patients might have a better
chance of response. Yeah. And I think emerging data from these large clinical trials, at least the baseline characteristics that they're sharing publicly, does look like they've achieved that goal of having this global representation, which is wonderful. So with that, I want to thank my guests, Doctor Andrew Lazar and Dr. Gaia Kopak for joining me today. It was absolutely a great pleasure having you on the podcast. Thank you so much. It's great.
Really appreciate you having me. Thank you. Thank you both. I am Doctor Dana Rizuk and to access this and other episodes in our series, please visit kdgo.org/podcast and thank you so much for listening.