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In this episode, Koyal and Kenar recap everything you need to know about IgAN for the board exam (or just to refresh yourself on the current state of knowledge) — from pathophysiology to treatment decisions. They also discover that nobody is really sure how to pronounce Peyer’s patches (hey, don’t blame us, they’re all the way over in the ileum) so make sure you read the show notes to settle that mystery and check out additional resources!
Board Review Bonus #1 - IgA Nephropathy
Online calculator to predict progression (International IgAN Prediction Tool at biopsy - Adults)
Inflammatory bowel disease and IgAN:
Rehnberg J, Symreng A, Ludvigsson JF, Emilsson L. Inflammatory Bowel Disease Is More Common in Patients with IgA Nephropathy and Predicts Progression of ESKD: A Swedish Population-Based Cohort Study. J Am Soc Nephrol. 2021 Feb;32(2):411-423. doi: 10.1681/ASN.2020060848. Epub 2020 Nov 11. PMID: 33177116; PMCID: PMC8054887.
MEST-C (Oxford classification):
Trimarchi H, Barratt J, Cattran DC, Cook HT, Coppo R, Haas M, Liu ZH, Roberts IS, Yuzawa Y, Zhang H, Feehally J; IgAN Classification Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Conference Participants. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017 May;91(5):1014-1021. doi: 10.1016/j.kint.2017.02.003. Epub 2017 Mar 22. PMID: 28341274.
DAPA-CKD:
Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjöström CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID: 32970396.
EMPA-Kidney:
The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, Brueckmann M, Landray MJ, Baigent C, Haynes R. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 Jan 12;388(2):117-127. doi: 10.1056/NEJMoa2204233. Epub 2022 Nov 4. PMID: 36331190; PMCID: PMC7614055.
STOP-IgAN trial:
Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, Panzer U, Peters H, Benck U, Mertens PR, Kuhlmann U, Witzke O, Gross O, Vielhauer V, Mann JF, Hilgers RD, Floege J; STOP-IgAN Investigators. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N Engl J Med. 2015 Dec 3;373(23):2225-36. doi: 10.1056/NEJMoa1415463. PMID: 26630142.
TESTING trial:
Lv J, Wong MG, Hladunewich MA, Jha V, Hooi LS, Monaghan H, Zhao M, Barbour S, Jardine MJ, Reich HN, Cattran D, Glassock R, Levin A, Wheeler DC, Woodward M, Billot L, Stepien S, Rogers K, Chan TM, Liu ZH, Johnson DW, Cass A, Feehally J, Floege J, Remuzzi G, Wu Y, Agarwal R, Zhang H, Perkovic V; TESTING Study Group. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2022 May 17;327(19):1888-1898. doi: 10.1001/jama.2022.5368. PMID: 35579642; PMCID: PMC9115617.
Phase 3 trial of targeted-release budesonide (NefIgArd):
Barratt J, Lafayette R, Kristensen J, Stone A, Cattran D, Floege J, Tesar V, Trimarchi H, Zhang H, Eren N, Paliege A, Rovin BH; NefIgArd Trial Investigators. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney Int. 2023 Feb;103(2):391-402. doi: 10.1016/j.kint.2022.09.017. Epub 2022 Oct 19. PMID: 36270561.
MAIN trial:
Hou FF, Xie D, Wang J, Xu X, Yang X, Ai J, Nie S, Liang M, Wang G, Jia N; MAIN Trial Investigators. Effectiveness of Mycophenolate Mofetil Among Patients With Progressive IgA Nephropathy: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e2254054. doi: 10.1001/jamanetworkopen.2022.54054. PMID: 36745456.
A note on pronunciation: We dug a little deeper after recording this, and following the people they’re named after, Jean Berger (a French speaker) and Johann Conrad Peyer (a German speaker), “Berger” should rhyme with “hooray” and “Peyer” should rhyme with “fire.” The more you know!
Disclosures:
ISGD receives general financial support from Boehringer Ingelheim, Travere Therapeutics, and Calliditas Therapeutics, among other companies, through corporate partnerships. None of these entities was involved in or had any influence on the content or editing of this episode.
Koyal Jain serves as principal site investigator for Kaneka’s FSGSALLAGE (NCT04065438) and FSGS Pediatric (NCT02235857) clinical trials.
Kenar Jhaveri is the National Scientific Lead for Otsuka's VISIONARY trial for IgA Nephropathy, and serves as a consultant for Otsuka, Novartis, and Calliditas.
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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.
Board Review Bonus #1: IgA Nephropathy
[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 Northwell Health and Hofstra University on Long Island, New York, and Dr. Koyal Jain from the University of North Carolina Chapel Hill.
[00:00:29] Kenar Jhaveri: Hi, everybody. This is Kenar and I have my co-host Koyal Jain. This is a slightly different GN in Ten. We basically are going to do a board review made ridiculously simple on a special topic in GN. Today's topic is going to be IgA nephropathy, right Koyal?
[00:00:45] Koyal Jain: Yes, and I'm so excited about this. The idea behind this GN in Ten episode series, I should say, is that if you're going to take the boards, if you're a fellow and you're like, I just need to know what's commonly used. If you're in clinical practice and you're trying to figure out, wait, what should I be doing?
And not just the upcoming trials. How can I take care of the patients that I have in front of me right now? Or what questions to answer in boards? This is literally meant for you. Today we're going to discuss IgA nephropathy in detail, but at the end we're going to leave you with four important points that we really think you should take away from this podcast. I hope you enjoy it.
[00:01:21] Kenar Jhaveri: I'm going to present a case to Koyal and we'll quiz her. This is a 48 year old guy who is referred for hematuria and 2+ proteinuria discovered on urine dipstick.
He has hypertension, he's on Losartan 25, and really no other significant allergies or social history. Physical exam is consistent with hypertension of 130 over 80. His labs show an estimated GFR of 68 mls per minute. His urinalysis is 15 to 20 RBCs. For high power field, and 2+ protein, and a urine protein to creatinine ratio done by an astute internist is 1.5 grams per gram and all serological workup is negative. So Koyal, I guess this is your classic outpatient IgA nephropathy, right? This is the most common presentation we see in the office.
[00:02:11] Koyal Jain: You know, Kenar I'll be honest. In the forties, yes, I do see IgA. I sometimes see it a little bit earlier in their second, third decade of life, but. Absolutely, this is the classic presentation, hey, blood in the urine, protein in the urine, what do we do?
[00:02:28] Kenar Jhaveri: Yes. Sometimes just for our listeners, we do see the gross hematuria presentation with this, synpharyngitic with perhaps an infection, a nasal infection or upper respiratory infection. But, it is still the most common GN in the world and in the US. Its true prevalence really is unknown.
A male to female, I would say a ratio of three to one in the US. but in East Asia, it's one to one. And it's in, especially in the rest of the world, it's the most frequent cause of end stage renal disease. Would you say that's pretty reasonable, right? In terms of the epidemiology of the disease.
Now, some people might call this historically Berger's disease.
Pathologically, this is an IgA mesangial deposits right, that you would see in immunofluorescence and some mesangioproliferative light microscopy finding. And in EM, really, you see electron-dense deposits in the mesangium most likely.
And there's some C3, some IgG, sometimes IgM. For some reason the IgA is in love with lambda over kappa. If you just see a little bit of lambda, because it's IgA1, don't get, “oh, it's, my god, it's PGNMID.” It's not PGNMID. IgA nephropathy, the IgA molecule likes lambda.
[00:03:38] Koyal Jain: So then the question is, wait, why did this patient have IgA nephropathy? First of all, why does IgG nephropathy happen in any patient? Should we talk about the four-hit hypothesis here?
[00:03:51] Kenar Jhaveri: Totally.
[00:03:52] Koyal Jain: The idea is these IgA molecules are really created by our mucosal tissue, right? And we have production of this galactose deficient IgA1 molecule where there's reduced glycosylation of the IgA1 hinge region, which is foreign to the body.
[00:04:10] Kenar Jhaveri: The Hit 2 is really the production of these unique autoantibodies against that, right? And that's the immunopathogenesis. So the Hit 1 leads to the Hit 2, production of autoantibodies. And then the Hit 3 is the formation of pathogenic IgA containing circulating immune complexes.
So the Hit 1, 2, and 3 is really creating the immune pathogenesis of IgA nephropathy. And then Koyal will end with Hit 4, what happens in the glomerulus.
[00:04:35] Koyal Jain: Simple. It's trapped in the glomerulus, right? They're getting filtered. They get trapped in the mesangial region and then they can activate complement and other inflammatory cascades and result in injury.
[00:04:47] Kenar Jhaveri: Something new that we're learning about IgA is that it's the gut microbiome and the mucosal immune system that leads to the galactose deficient IgA1 molecule. So it's something about the gut and the gut kidney connection. And then it leads to these formations eventually. And this might be happening, like you said, perhaps in the Peyer's patches, correct?
[00:05:08] Koyal Jain: Yes.
[00:05:08] Kenar Jhaveri: I remember reading a really fascinating JASN paper many years ago that inflammatory bowel disease was more common in IgA patients and vice versa.
So I always wondered, this was always like a GI disease and not really a renal disease.
[00:05:22] Koyal Jain: And now we know, right? There is an association there. And just so that we don't forget this nasal mucosa and tonsillar mucosa is also a site for IgA production. And that is why in certain parts of the world, there's a consideration for tonsillectomy, although we don't follow that here.
And then going back to the gut mucosa and the crosstalk there, this is why we're looking at drugs that are targeting that specific mucosa to help treat IgA nephropathy.
[00:05:49] Kenar Jhaveri: You think the complement plays a role in IgA? These complements are usually normal, the C3, C4, when we check them, it's a normal complement levels in IgA nephropathy, but yet, people think that there is a role of complement in IgA nephropathy.
[00:06:03] Koyal Jain: It is, and I don't want to sound like an ANCA person, but that's the same thing that happens in ANCA vasculitis, right? Complement gets activated, but your levels in the blood may be normal, and that really has to do with the amount of production versus how much is getting deposited.
In fact, if you look at pathology, you can see the deposition of some C3 pathologically in the kidneys.
[00:06:28] Kenar Jhaveri: There are three pathways, there's the alternative complement pathway, lectin, and classical. So in IgA, most likely lectin and alternative pathways getting activated and that's part of that Hit 4 that Koyal talked about, right? The whole injury in the glomerulus. So that's your pathogenesis of IgA nephropathy.
[00:06:48] Koyal Jain: Before we go into treatment and pathology, let's go back to your case, right? Let's tie it back to the case. You have this patient, you're now seeing them in clinic, right? Do you biopsy them? And why not?
[00:07:01] Kenar Jhaveri: That's a good question. I think it's opinion based, but anyone with a worsening kidney injury, more than a gram of proteinuria, should be biopsied because there are a couple of reasons. One, you want to make sure you're not missing a crescentic IgA. Two, you don't want to miss a chance of treatment options in clinical trials if they actually fit the criteria for that.
The other reason is to actually know the MEST score and to tell you exactly if there's proliferative and active IgA or there's just chronicity there that you're just treating with ACEs and ARBs and SGLT-2 inhibitors. So I think there's value personally in biopsying almost every patient with IgA, but I know there'll be people disagreeing on that.
[00:07:41] Koyal Jain: Yeah we, again, like you said, this is opinion based, we typically don't biopsy for just isolated hematuria, but yes, like you said, if there is worsening kidney function or there's increased proteinuria, we absolutely go ahead and biopsy because if there's a chance for recovery or treatment, we don't want to take away that chance from a patient.
And that brings me to the question of the MEST score, right? We keep saying MEST score, but should we just talk about what is MEST and what is MEST C score?
So it's basically telling you the histological variable. And that leads to eventually a scoring. M is mesangial hypercellularity, so there's M0 and M1. So if there are less than 50% glomeruli showing mesangial hypercellularity is M zero, M1 is over 50%.
[00:08:26] Kenar Jhaveri: Then there's endocapillary hypercellularity which is E. That's the one you really care about. E0 and E1. Segmental glomerulosclerosis is S. That tells you a little bit more about the scarring and adhesions and the sclerosis. It's either absent or present. So it's S0, S1. And tubular atrophy interstitial fibrosis is T.
That's the only one that has three scores. T0, T1, T2. So T2 is really over 50 percent atrophy. And then you have the other gradations of T0 and T1. And then the C was added later to tell you this presence of crescents. Cellular or fibrocellular. And that's important. So C2 is over 25% of glomeruli. So that's a crescentic form, or a pretty aggressive IgA. So again, MEST score is mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis. T is tubular atrophy and C is crescents. M and E tell me the activity of the disease and S and T tell me the chronicity of the disease.
[00:09:22] Koyal Jain: Absolutely, and just for our listeners, this Oxford classification, this modification with the MEST-C scoring, I'm taking it into account with their clinical presentation. It is a way for me to figure out: how severe is the disease? How much reversibility is really there, what can I treat and what can I not treat, and what is the prognosis really for this patient that we're seeing in clinic?
[00:09:46] Kenar Jhaveri: So that's an important point. The prognosis, what are these factors that give you worse prognosis in IgA, right?
[00:09:53] Koyal Jain: Yes, and so the MEST-C classification. Those are prognostic pathologically, but clinically there's at least three things that I think about. If I go back to just medicine and nephrology in general, what are the things that we care about? Protein in the urine, the creatinine, blood in the urine really doesn't matter as much.
Although there is some thought that asymptomatic hematuria forever, which doesn't go away, may have a role to play in worse prognosis. And really hypertension. So if you have a higher creatinine at presentation, or you have a blood pressure that's running high, or you have a UPC or a protein in excretion of greater than a gram, although people can argue half a gram versus one gram, you actually have worse prognosis with those clinical factors.
[00:10:37] Kenar Jhaveri: Yeah, in terms of histology, I just want to remind people also, like what Koyal said, the IFTA or the interstitial fibrosis tubular atrophy is so key, the presence of crescents, but even having thrombotic microangiopathy is actually a big risk factor for worsening prognosis on the biopsy. And what about, what do you think about having diabetes and obesity?
You think that might add to worsening risk of IgA progression?
[00:11:00] Koyal Jain: It really adds to progression for almost every disease out there.
Kenar, now you have this patient who was, what, 40 something years old, coming to you with proteinuria, has hematuria, you decided you're going to biopsy them, you get a MEST score back, you had the hypertension there, you had the proteinuria there, you're going to check the creatinine. Are you worried about any other diseases that this patient may have?
Could they have another association with another disease?
[00:11:23] Kenar Jhaveri: Sure. So like any other thing in medicine, you always want to rule out your secondary causes and IgA in the kidney biopsy doesn't mean It's the primary disease, right? It could be secondary GI disorders, Crohn's, ulcerative colitis, celiac. It could be from liver disease, cirrhosis, remnants of IgA that cause IgA nephropathy.
It could be secondary to a virus like CMV, HIV. H. pylori I've seen causing IgA nephropathy. It could be cancers. I've seen renal cell cause IgA nephropathy or some drug for cancer. Autoimmune diseases like lupus can present with IgA nephropathy, psoriasis is a big one, and rarely pulmonary disorders like cystic fibrosis.
Unfortunately it's a big basket. But we have to think about this sometimes, especially if they're refractory to your basic treatment.
[00:12:08] Koyal Jain: I heard somebody use this term of “latent IgA,” that a certain percent of the population may actually just have IgA, they just don't have other features of it, and they don't get biopsied, and we don't really find out about it, and it may be incidental in some of the biopsies, but it may just be present without any other reason.
[00:12:26] Kenar Jhaveri: For our listeners, there is actually a prediction tool available. It's an online calculator that was developed by Cattran's group a few years ago that predicts the five-year survival in IgA nephropathy. And it takes into account the GFR, biopsy, the blood pressure, the proteinuria the race, are they on ACE and ARB, the MEST score.
And then it gives you for example, if I put this patient in, the risk of 50 percent drop in GFR for this patient we just saw is 6.3 percent at five years. And that's all it can tell you.
It's not able to predict more than that, what I understand. So that's all you can really tell your patients if you want to give them some prognosis, but it tells you that it's not a benign disease. I think in the nephrology world it was really thought to be, “Oh, it's not that bad.
It's a little bit of hematuria, a little bit of proteinuria,” but people do progress even after years and years. So controlling the proteinuria, controlling the disease is probably very important.
[00:13:26] Koyal Jain: Exactly, So take a look at the show notes and you'll see actually the link to the calculator that Dr. Jhaveri was just talking about.
I will tell you that, often when I see patients in clinic you have these risk tool calculators, when you see the patient, they ask me, “Okay, am I this percent, am I within this six percent, for example, in your case?” and I don't know the answer to that. And I think it is hard to know what to say to patients. This is actually very hard to figure out what to do in these patients with IG nephropathy. Some of them can do well for years and decades. And then there are patients who rapidly progress. And when you have a patient right in front of you, you don't know which one they're going to be.
[00:14:05] Kenar Jhaveri: So Koyal, how do you want to treat this individual? I guess we'll try basic conservative management first, right?
[00:14:11] Koyal Jain: Yes, I never really jump to immunosuppression, especially with IgA nephropathy, unless we start off with crescentic disease or really bad endocapillary proliferation that's happening with an AKI. Usually I start with conservative management, your regular RAS blockade, your blood pressure control, your sodium restriction, also smoking cessation becomes really important.
[00:14:35] Kenar Jhaveri: Yeah. But the patient's biopsy came back and it said M1E1S0T0 and C0. Would that change your treatment?
[00:14:44] Koyal Jain: What was the creatinine?
[00:14:46] Kenar Jhaveri: The GFR was 68.
[00:14:48] Koyal Jain: And if the creatinine has been stable and the proteinuria has been like one, one and a half grams, I believe you said, I might still start with conservative management.
[00:14:56] Kenar Jhaveri: Yeah. I think that's what KDIGO recommends in most of the cases. So KDIGO, the most updated guidelines, I believe are in 2022 and if the proteinuria is above a gram, despite three months of supportive care. So we haven't even done that yet, right? So your maximally tolerate ACEs and ARB, lifestyle modification, like how Koyal mentioned, and cardiovascular risk assessment.
And I'm assuming soon, SGLT2 inhibitors will be added to that. If that fails, then actually KDIGO recommends enrolling a patient in a trial. That's the first and foremost recommendation, which is actually good because when these guidelines were made two years ago, there were really no FDA approved medications for IgA nephropathy. Now the times have changed, but that actually makes sense to really try to get your patient in a clinical trial.
[00:15:46] Koyal Jain: I completely agree with trying to get patients enrolled in clinical trials. So important because I think we are not as far ahead as we would have liked to be, but at the same time, it's really promising that we've made so many changes and so many things have been upcoming in the past few years.
I will say that oftentimes I see patients coming from clinical nephrologists who may be in a setting where they don't have access to clinical trials or the patients may not be able to travel. So it's really becomes important to figure out what do you have in your armamentarium?
[00:16:18] Kenar Jhaveri: What are your thoughts on the SGLT2 inhibitors?
[00:16:21] Koyal Jain: I love them. I will also say that I have a very hard time getting it approved for my patients, especially because many of my patients have some sort of glomerular disease and may not have an existing diagnosis of diabetes, even though they've been used for CKD without diabetes.
So oftentimes financially, it becomes a problem for my patients, but regardless of that, if somebody has a GFR above 20, especially in a patient like this with IgA nephropathy, you've given them RAS blockade and they have proteinuria, I would certainly try to get them on SGLT2 inhibitors.
The DAPA-CKD trial did show us that compared to placebo, dapagliflozin did reduce the proteinuria and also the GFR decline was much less.
[00:17:03] Kenar Jhaveri: Yeah. I think this was probably one of the largest IgA components for any trial. And even EMPA, which came out last year, also had a large amount of IgA patients that also showed a similar story. So I think SGLT2 inhibitors are here to stay and that I'm assuming the next iteration of KDIGO will include ACE, ARB, SGLT2 inhibitors.
Now the other drug that is more of a stabilizer. So I guess we're talking about two types of treatments, right? One is more sort of conservative management. One is more aggressive, which is, we'll get to steroids. Do you think sparsentan falls in the aggressive category or more of a conservative, more scarring related treatment like ACE, ARB, SGLT2 inhibitors?
[00:17:46] Koyal Jain: I certainly think sparsentan is more conservative, right? It's not immunosuppressive in the same fashion, and it can actually reduce fibrosis. And for our listeners, sparsentan is a new drug which got approved by FDA for IgA nephropathy. It consists of a RAS blockade action by inhibiting angiotensin 2 receptor, but it also has an endothelin-1 blockade action, so it's an antagonist for both, and has shown to reduce proteinuria.
What are your thoughts on it?
[00:18:16] Kenar Jhaveri: So endothelin-1 plays a really big role in chronic kidney disease progression based on basic science studies. And it leads to a lot of vasoconstriction. So having endothelin receptor antagonists might be really helpful in terms of CKD.
When you have endothelin receptor antagonist, it relieves the vasoconstriction, it decreases endothelin damage, it decreases podocyte damage, decreases proteinuria, and decreases inflammation. As a result, to me, that sounds more of a conservative management arm: ACE, ARB, endothelin antagonist and SGLT2 inhibitors.
So that is one bucket of treatment. And then you have more targeted therapy that you want to attack, where it helps treat the pathogenesis of IgA. Would that be the way to think about it?
[00:19:04] Koyal Jain: I'm very simplistic. I always divide things into buckets like to memorize and not to forget things. I will say one other thing for sparsentan, though, it is in replacement for RAS blockade. You're not continuing RAS blockade with sparsentan because it has that action.
And you need to make sure that you do the REMS program to be able to provide sparsentan. You need to make sure that these patients have the LFTs and there's a pregnancy test associated with it as well.
[00:19:31] Kenar Jhaveri: So we went over all the conservative management. So either you have them on ARB or sparsentan, and SGLT2 inhibitors perhaps. And then if you're thinking of giving steroids, just regular prednisone, just keep in mind the toxicity of that.
So if someone has metabolic syndrome, obesity, some infection, advanced age, you might not want to consider giving corticosteroids. But steroids have been with IgA back and forth.
[00:19:57] Koyal Jain: We've gone back and forth so many times and I have mixed feelings about it. I'm being completely honest here, with the Stop IgA trial, the TESTING trial, we saw that there was more side effects. TESTING had to be stopped prematurely initially to reduce the dose of steroids.
So nowadays they recommend reduced corticosteroid dosing along with prophylaxis. But I will say there's this group of patients where you have really bad endocapillary proliferation. There's not much IFTA that is happening. It's not typical crescentic that you have to treat it like ANCA, but they're rapidly progressing.
Their creatinine keeps getting worse, and in those cases, there's a selection of patients that you might be using these steroids for. Maybe reduced dose, but there's room for them still.
[00:20:46] Kenar Jhaveri: I totally agree. The TESTING original dose was 0.6 to 0.8 milligrams per kilograms per day methylprednisolone. They cut down that to 0.4 in the reduced dose. And had less of the toxicities of infections and so forth. So I think that's reasonable, right, Koyal? For prednisone, I think we just get all scared and start putting patients on one mg per kg and IV steroids.
I don't think that's really necessary in IgA. I think reduced-dose steroids is good enough.
[00:21:14] Koyal Jain: 100 percent agreed. I think you can get the same bang for your buck with the lower dose and less side effects. Why not do that?
That brings me to the question, we kept talking about the gut and the relationship with Peyer's patches and IgA, and there's targeted therapy for that, right?
[00:21:31] Kenar Jhaveri: Yes, and that brings us to a targeted release formulation of budesonide, a form of steroid that goes directly in the distal ileum, targeting the Peyer's patches that Koyal can't pronounce. It's in the GALT or MALT. It's nine months of treatment with 16 milligrams, four capsules, and then a two week taper of eight milligrams, two capsules.
The recent phase three trial showed amazing results in terms of decrease in proteinuria and decline in GFR. So it's an FDA approved drug now. Again, it's not a new drug. We have seen our GI colleagues use it for a lot of IBD and other diseases, but in a generic format, right?
The generic version not targeted to the Peyer's patches. I don't know how it gets there and only targets the Peyer's patches. It's beyond me.
[00:22:14] Koyal Jain: It has to do with the pH changes, and it's got like multiple coatings and layers to it, and which coating comes off, and then it slowly gets released there and acts on the Peyer's patches.
[00:22:26] Kenar Jhaveri: According to the experts of the drug, they cannot be interchangeably used because the risk benefit ratio will likely change, but there's no clear data either way. If you can just use the generic version that apparently goes through the entire colon and not just the level of ileum.
[00:22:41] Koyal Jain: And that's what we did, right, before it was FDA approved and we needed some targeted therapy we technically used the one used for IBD.
[00:22:49] Kenar Jhaveri: So I guess you do have steroids and you have these more targeted steroids as a potential treatment for IgA nephropathy. And then what about MMF? What do you think about CellCept? Do you think that's still a potential?
[00:23:01] Koyal Jain: CellCept has been used frequently by me and my colleagues but I will say take it with a grain of salt because we've seen a lot of IgA vasculitis patients and it's not really IgA nephropathy only. Although the studies in MMF have been in a limited, I think, in the Chinese Asian population, and that's where the benefit has really been seen, and there's another trial that came out that did not show benefit in other populations.
So you have to take it with a grain of salt that it may or may not be beneficial. But I will say that most of the trials have excluded IgA vasculitis.
[00:23:33] Kenar Jhaveri: But there was this really nice randomized control trial recently and it's called the MAIN trial that was done in China, single center, but showed significant improvement with MMF compared to the standard of care in terms of decreasing CKD and proteinuria. But, I think if you have perhaps an Asian patient where they can tolerate MMF, I think it's a reasonable option compared to steroids. But that's the only thing I can take away from these trials as opposed to giving it to a Caucasian or a South Asian or a Black patient.
[00:24:00] Koyal Jain: So just one last thing that comes up is rituximab and people wanted it to be beneficial, right? Because antibody mediated disease, but we really didn't see any benefit of rituximab. So it is what it is at this point in time.
[00:24:15] Kenar Jhaveri: So B-cell activation although this, through T cell dependence, it might be a potential in IgA, but rituximab in a randomized fashion didn't really work in a small study. There are studies ongoing for B-cell activating cytokines like APRIL and BAFF that might be showing some promise. So maybe in the future we might see some targeted therapy in the B-cell realm and also the complement realm, right? There might be potential future therapies. But right now, what we really have is steroids, budesonide, and maybe MMF. Everything else, really, the data is really poor. So tonsillectomy, cyclosporine, tacrolimus, fish oil…
I would say the data is very slim. I would not suggest the patients go on that.
[00:25:00] Koyal Jain: Yeah, I don't stop people from going on fish oil though, good for your skin and your hair.
[00:25:04] Kenar Jhaveri: Yeah, that's fine. But it's not, there's no really long term benefit.
So before we end let's just summarize. These are the four points I came out of the discussion with.
My four points are: rule out secondary causes. I've seen IBD, liver disease with IgA, so rule out secondary causes. Treat the primary cause of the IgA. Don't just keep giving steroids. Use IgA nephropathy prediction tool. I think it's so useful to talk to your patients about that. Really intensify RAS and SGLT2 inhibitors.
I think there's enough data for both of those to be used in our patients. And then in adding immunosuppression like steroids and budesonide, we have to be very careful. And the prognosis and risk. And I personally think people should be aggressive about enrolling IgA patients in clinical trials.
[00:25:49] Koyal Jain: I 100 percent agree with you. And the only one other thing that I wanted to add is, although we have this cutoff for one gram for your proteinuria and treating patients, there's some discussion that the cutoff should be close to half a gram, and so consider treating for these patients, especially with conservative therapy, even if they have less than what used to be the traditional cutoff.
[00:26:08] Kenar Jhaveri: I agree.
[00:26:09] Koyal Jain: I've had so much fun, Kenar, discussing IgA nephropathy in this board bonus episode and I really hope that our listeners really enjoy this episode as well. We would love to get you such episodes throughout the year in a series format.
[00:26:23] 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.
[00:26:39] Kenar Jhaveri: Burger's disease. Berger's disease. I don't know how you say that. Maybe I'm mispronouncing that.
[00:26:46] Koyal Jain: If it makes you feel better, I had to look up the pronunciation for Peyer's patches or Peyer's patches because I could never get that right.
[00:26:53] Kenar Jhaveri: a form of steroid that goes directly in the distal ileum, targeting the Peyer's patches that Koyal can't pronounce.
[00:26:59] Koyal Jain: We hope, Kenar and I hope that you've had fun listening to the, this Boards Basics. What is, what did we call it, Laurel? I'm going to record this again. What did we call this digest?
Board Review Bonus. Okay. I'll do this again.
Sorry, I can't keep track of what is the name. I've still, I've forgotten again. I said board bonus. I forgot.
[00:27:17] Kenar Jhaveri: It's okay. We'll make fun of that. Do that after the thing ends. You know how you did that with the like the spoofs.
[00:27:24] Koyal Jain: Won't get this name right. I don't think I'm going to get this right. I'm sorry, but it's going to keep happening.
[00:27:30] Kenar Jhaveri: I think Laurel will get it right for us at some point. She'll be like, no, it's board review made, I don't know, simple?
[00:27:36] Koyal Jain: Bonus, bonus!
[00:27:37] Kenar Jhaveri: Bonus. Yeah! Board review, BRB, board review bonus. That's it! We finally got it. We can treat IgA, we can't get a name for this.
[00:27:44] Koyal Jain: This is how I remember BRB, be right back.