Subscribe
Share
Share
Embed
In this special bonus episode of the podcast, Koyal and Kenar provide a maximally useful review of minimal change disease, from diagnosis (including secondary causes to screen for) to treatment options, including how to decide which patients may do better with which therapies.
Can’t get enough minimal change? Check out Episode 6 (with Astrid Weins) and Episode 7 (with Felicitas Hengel and Nicola Tomas) for more on the potential role of anti-nephrin autoantibodies in MCD.
References
KDIGO guidelines: https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GD-Guideline-Key-Takeaways-for-Clinicians-Minimal-Change-Disease.pdf
Anti-nephrin autoantibodies:
Kronbichler A, Barnini C, Matyjek A, Gauckler P, Bruchfeld A, Caravaca-Fontan F, Floege J, Frangou E, Mirioglu S, Moran SM, Stevens KI, Teng YKO, Steiger S. Antibody-mediated podocytopathies: a disease entity that implies immunotherapy. Nephrol Dial Transplant. 2024 Jul 17:gfae166. doi: 10.1093/ndt/gfae166. Epub ahead of print. PMID: 39020250.
Hengel FE, Dehde S, Lassé M, Zahner G, Seifert L, Schnarre A, Kretz O, Demir F, Pinnschmidt HO, Grahammer F, Lucas R, Mehner LM, Zimmermann T, Billing AM, Oh J, Mitrotti A, Pontrelli P, Debiec H, Dossier C, Colucci M, Emma F, Smoyer WE, Weins A, Schaefer F, Alachkar N, Diemert A, Hogan J, Hoxha E, Wiech T, Rinschen MM, Ronco P, Vivarelli M, Gesualdo L, Tomas NM, Huber TB; International Society of Glomerular Disease. Autoantibodies Targeting Nephrin in Podocytopathies. N Engl J Med. 2024 May 25. doi: 10.1056/NEJMoa2314471. Epub ahead of print. PMID: 38804512.
Watts AJB, Keller KH, Lerner G, Rosales I, Collins AB, Sekulic M, Waikar SS, Chandraker A, Riella LV, Alexander MP, Troost JP, Chen J, Fermin D, Yee JL, Sampson MG, Beck LH Jr, Henderson JM, Greka A, Rennke HG, Weins A. Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology. J Am Soc Nephrol. 2022 Jan;33(1):238-252. doi: 10.1681/ASN.2021060794. Epub 2021 Nov 3. PMID: 34732507; PMCID: PMC8763186.
Creators & Guests
Host
Host
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.
[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, welcome everybody to GN in Ten. This is Kenar Jhaveri and my co host Koyal Jain joining us.
And today we were thinking of reviewing with our listeners minimal change disease, or some people call it diffuse podocytopathy.
What do you think, Koyal?
[00:00:47] Koyal Jain: I am so excited about this podcast because I feel like when I was a fellow, I would have loved to be driving and listening to these short board review podcasts to get my education in and something case based and just conversational. Really looking forward to this.
[00:01:02] Kenar Jhaveri: I always thought this was more of a pediatric disease. It turns out that we see so much of this now. And the terminology has been constantly changing. A lot of the glomerular experts might call this diffuse podocytopathy or diffuse foot process effacement, right?
But it's minimal change for people who are listening because that's what they're going to get on the boards, and that's what it's called, minimal change disease.
I had a case of a 22 year old female who actually had this minimal change disease as a child at age of 11 or so. She was treated with steroids and keeps having relapses perhaps every four or five years and always gets steroids and goes into complete remission.
So her question for this new adult relapse was, can you do anything but steroids? I'm 22 years old. I don't want to gain more weight. I feel like my bones are going to get hurt with all the steroids. I mean, she kind of listed all the side effects you can think of steroids. So that's where the world of nephrology, unfortunately, is in minimal change disease.
So let's backtrack a little bit, Koyal. You want to tell our listeners a little bit about minimal change disease and where it plays out?
[00:02:08] Koyal Jain: With minimal change disease, when I see a patient, there's a bias, right? We're seeing them as an adult patient. We're not seeing them as a child. And one thing that I always think about is, am I missing something else?
Is this truly primary minimal change disease? Or am I missing a secondary cause of minimal change disease? And you really want to treat it. And I've had, for some reason, a lot of patients in their, seventies, Age group, coming over with minimal change disease and I worry am I missing some sort of lymphoma in these patients and is that what's causing it or some drug related minimal change disease.
So for me, my thought process for any minimal change disease patient and to be honest with any glomerular patient is I want to make sure before I give somebody immunosuppression or something else that I'm not lost a secondary cause.
[00:02:57] Kenar Jhaveri: I think the secondary cause is so key, right? So let's just go over those more in detail. So one of them is your classic NSAIDs, right? That's your most common thing we always think about. Lithium is another big medication, correct? Any other drugs that come to mind?
I think pamidronate, some antibiotics, and I know immunotherapy, some of the, the onconephrology world, we've seen minimal change disease with pembro, ipilimumab. I've also seen minimal change disease with the COVID vaccine. So vaccines are another secondary hit, right?
[00:03:26] Koyal Jain: That's true. And just for our listeners, remember, pamidronate is not just minimal change disease, but board review need to make sure that it's not also FSGS and which is,
[00:03:35] Kenar Jhaveri: Collapsing variant.
[00:03:36] Koyal Jain: Collapsing variant of FSGS. And absolutely right. And then in the malignancy world you really think about what, when I was younger, I used to call them liquid tumors.
[00:03:45] Kenar Jhaveri: Correct. Yeah.
[00:03:47] Koyal Jain: Although I just did air quotations and nobody can see those air quotations in a podcast but, really your Hodgkin's, your non Hodgkin's, your leukemias, solid tumors can be related, but usually less commonly with minimal change as opposed to membranous nephropathy.
[00:04:03] Kenar Jhaveri: The one I would remind our listeners is thymoma. And I have cases where I had relapse after relapse of minimal change and then I finally got a CT of the neck and I find a thymus enlargement or a thymoma and removal of that despite being cancer or enlarged thymus actually completely puts the patient in remission.
So look for thymomas if you have a relapsing or frequently hard to treat minimal change disease. And also that's associated with myasthenia gravis. All three of them go together. Myasthenia gravis, thymoma and minimal change disease.
[00:04:37] Koyal Jain: And we've seen that as well, although where I've seen it, we've had trouble getting patients in remission, but absolutely, that's such a key finding there. When you're trying to diagnose these patients, do you, Dr. Jhaveri, do a CT scan of the entire...
[00:04:54] Kenar Jhaveri: Yeah. Not the entire... if they have a risk factor for say lymphoma, I do look for that in a certain age group. Appropriate malignancy screening. Although a lot of that is not associated with minimal change, but I still do it in the right age group if I'm surprised why they have minimal change.
And like I said, refractory ones, I do look for thymomas more regularly and I've found that. Yeah, The other big one is infections, right? HIV, TB, syphilis. Think of infections. I know commonly these are more with FSGS than MPGN and so forth, but we have seen even COVID, right?
We saw various GNs. So it's good to think about podocytopathies with infections.
[00:05:36] Koyal Jain: And then again on the thought that you already mentioned about the myasthenia gravis autoimmune type other conditions, thyroiditis type stuff, Graves disease, things can be associated with minimal change disease.
[00:05:51] Kenar Jhaveri: And finally, I think another glomerular disease. So think about IgA with minimal change, or I've seen lupus with the lupus podocytopathy, right? Don't forget your combination diseases in the adulthood. That can be also seen with minimal change presentation. The rest of the stuff is rare.
And I think the most classic presentation that we all see is nephrotic syndrome, but I was surprised sometimes that, most of the time the creatinine is normal, but I have seen some AKI with these patients because of the large degree of proteinuria. But have you seen hematuria with a lot of minimal change?
[00:06:27] Koyal Jain: So I have read that you can see hematuria. Personally, I haven't seen as much hematuria as has been reported in literature.
[00:06:36] Kenar Jhaveri: Yes, it's been 30 percent of what they say, but I, it's hit or miss. I have a feeling a lot of that could be the combined IgA- minimal change presentation patients, but maybe just minimal change can do it too. Hypertension is another big one I haven't seen too much, unless it's older patients who already have hypertension, but classically with this nephrotic syndromes, you don't get hypertension.
But it seems like they report 43 percent or so.
[00:07:03] Koyal Jain: I also think that the reporting could be biased, right? Because minimal change is mostly diagnosed in children. Treated without even a biopsy and may not get necessarily reported. Maybe that's a overrepresentation of what's actually seen practically.
Going back to your patient. Clinical features of nephrotic syndrome and how the patients present is so fascinating, right? So let's go back to your patient that you were talking about, the 22-year-old patient who has had recurrent flares of minimal change.
And yes, we'll come to the treatment in a second, but, and then has gotten steroids as opposed to the 80 year old or the 70 year old that I'm talking about, who first time presents with minimal change disease.
How do you see them? Do you diagnose one of them earlier, the other one a little bit later, one has more florid presentation?
[00:07:51] Kenar Jhaveri: I mean, most of the time I have seen a sudden onset, sudden onset presentation where they actually remember the day or the week that the edema came on, the foaming urine came on. That's how we clinically differentiate diffuse podocytopathy or minimal change disease from say FSGS or membranous because that's more of a slow onset disease as opposed to a sudden onset.
So it's like a light turned on and off. That's what I have seen 90 percent of the time. Yes, some of the secondary causes can be a little insidious onset, like NSAIDs, but most of the time it's sudden onset.
[00:08:26] Koyal Jain: It was like this was a challenge question. This was like, read my mind and answer the question. And what I was trying to have you read my mind was, like that older age group or the first time presentation, we often see, like you said, sudden onset nephrotic syndrome, but I feel like our pediatricians do such a great job when patients have had nephrotic syndrome as a child, they are often doing dipsticks, right?
So in the younger age group, I often see them because I'll get a message. Hey, my urine dipstick has been now positive greater than trace for a couple of days now. And I'm worried that I may be having an early
flare and can,
[00:09:02] Kenar Jhaveri: Totally.
[00:09:03] Koyal Jain: And so then they would get like a formal testing. And I actually catch them much earlier.
So I feel like pediatric nephrologists actually really set us up for success with those patients.
[00:09:13] Kenar Jhaveri: Yeah. No, that's totally true. I think that's why these patients, when they transition to adult, they actually know the whole deal. They tell me I need this dose of Rituxan. I need these dipsticks done. I'm like, Oh, wow. That's actually pretty impressive. So they actually, transition very well from pediatric world.
Let's just backtrack a little bit just so that everybody's on the same page. The pathology findings on minimal change on light microscopy is normal, right? Unless you're a little older, you might have some focal sclerosis from age, but it's usually normal. IF is usually normal. I'll get back to that.
But the electron microscopy is the key where you see this diffuse foot process effacement. And this is the classic finding, right? There is traction, widening, shortening of the foot processes, and there is no normal appearance. It's diffuse. It's not like your scattered foot process effacement, 2%, 3%, two thirds, no, it's diffuse, 100%.
[00:10:10] Koyal Jain: Absolutely, and do you buy into the idea that it's a separate disease or is it on the spectrum with FSGS? What are your thoughts there?
[00:10:20] Kenar Jhaveri: I think there are two diseases. One is diffuse podocytopathy, so it can present two different types of light microscopy. One is normal, and sometimes it's older patients with some FSGS, but it's still a diffuse podocytopathy, 100 percent effacement. And the other disease is where you actually have segmental foot process effacement, which is usually a secondary cause in majority of the time.
So I think that's the way to categorize podocytopathies better than FSGS and minimal change disease. I think it's all about the effacement of the foot process and nephrotic syndrome versus nephrotic range proteinuria presentation. I think that's the way to think about it rather than calling it by the EM finding.
[00:11:00] Koyal Jain: I 100 percent agree with you. And just to add to that, which is actually in the same line you're dividing this on the basis of the degree of effacement and the presentation that would happen. And I usually think of it in the terms of treatment, right? Are they responsive to treatment, or not responsive because technically the treatment is similar.
I club it as Minimal change versus FSGS are things that are responsive to treatment and do well, which is your category of diffuse effacement, do not have secondary scarring or some other secondary process. And then those that are resistant to treatment, and that's a different category. And well, FSGS is so many categories by itself, but we're not talking about FSGS today.
[00:11:39] Kenar Jhaveri: So if this is, I guess the problem with minimal change or diffuse podocytopathy is like, where is the pathophysiology, right? Is it a T cell dysfunction? And that's why maybe the thymus is getting involved in some of these patients? Or the whole association with allergies and younger people?
Or is it a permeability factor? A factor that's there, mostly maybe anti-nephrin that affects the slit diaphragm and that's why it's such a quick response to steroids because it just brings the slit diaphragm back as you give the steroids or is it B cell mediated, is it really a true B cell disease and you're attacking some sort of antibody production. And I think, I know this might not be in a lot of people's boards but I think it's an important study that was published a few years ago that discovered the auto antibodies that target nephrin in minimal change disease.
And in that one study that looked at the Neptune cohort, I believe 30 percent of those patients actually had anti nephrin antibodies in the serum and co stained in the IgG immunofluorescence on the kidney biopsy. And they actually went away when you gave steroids.
If you talk to an experienced pathologist who believes in this, and I'll say that with quotations, if you look at the immunofluorescence, the IF of IgG will show you technically a very slight coating and it's, they call it dusting. And that actually is the anti-nephrin. If you actually stain that with anti-nephrin, it'll co localize at that dusting area.
And that quickly goes away when you give steroids. So it's possible we're missing a lot of these. If you check for anti-nephrin antibodies, you might not find them if you already treated them with steroids. And a recent paper after that also showed that in post transplant FSGS, almost 99 percent of those patients, were anti-nephrin.
So maybe the permeability factor is anti-nephrin and we might have to just catch it very early. And that also brings two points together. Maybe it's not two separate diseases that this diffuse podocytopathy is anti-nephrin mediated in most cases. But again, that story is still unfolding.
[00:13:49] Koyal Jain: Correct. And then, obviously, we know about anti-nephrin and FSGS world already, so maybe that's the tying factor for minimal change and FSGS, like you said, for diffuse podocytopathies. And I do think that. I think there's a role for all, T cell, B cell, and the glomerular permeability factor. And we do give rituximab, which does help patients as well.
You can argue it's B cell mediated or it's the the permeability factor, which we found. So I do think that there's a component of all three in patients potentially. Which then means that now, going back to the case. Back to this 22 year old who has come in, you know why they have this disease, you know what the kidney biopsy showed, and again, before we get to the treatment, Would you re biopsy somebody?
When do you re biopsy somebody with minimal change disease is the next question I have. And personally, if somebody is responding well to treatment, has had minimal change disease that's been established in the past, I'm not inclined to biopsy these patients. Yes, a fresh new nephrotic syndrome for somebody who's an adult does get a biopsy from me, but otherwise if it's coming from a pediatric age group, I wouldn't re biopsy them unless they become resistant to therapy.
[00:15:09] Kenar Jhaveri: I agree. I won't argue on that one. Otherwise I would like to, but it's okay. We'll leave it at that.
[00:15:14] Koyal Jain: We have to agree on something. So I guess although I will say that we do agree on a lot of things. So this is
[00:15:19] Kenar Jhaveri: Because it's minimal change. I think there's a lot of agreement.
[00:15:22] Koyal Jain: I agree as well. No pun intended. Okay. So now you have this patient with you. How do you treat these patients? We said it's a childhood disease. In fact, pediatric nephrologists treat these patients with just steroids. When they present with nephrotic syndrome without a kidney biopsy because it's so prevalent and it's presumed to be minimal change disease, they get steroids, right?
It's only when they don't respond to steroids that they now head towards a kidney biopsy, right? Your 22 year old who asks you this question, I need something other than steroids because I've been getting it all my life. What would you do?
[00:16:00] Kenar Jhaveri: So let's go back to your steroids because what is the dose usually we give for these patients, right? Usually it's the one mg per kg, right? Oral. And that's been the standard. Have you used IV steroids at all for minimal change, or?
[00:16:14] Koyal Jain: I will tell you that this is something I learned from Dr. Falk just literally three years ago, maybe? And I've only given oral steroids up until that point, right? I have had patients in a couple of cases where they had Such severe nephrotic syndrome, and I, this is a presumption, this is not proven, that the oral steroids were not even working and the thought we had was that they weren't getting absorbed because they had gut edema.
And in those couple of cases where they had severe nephrotic syndrome and were having an AKI, actually did get a couple of doses of IV steroids and did beautifully well within a couple of days.
[00:16:55] Kenar Jhaveri: Is there any trials that compare oral to IV like that? ? don't think so, but I would think IV might work better in some really severe nephrotic patients, right?
[00:17:04] Koyal Jain: Yeah, and that's what we did. And then this patient, they beautifully responded within a couple of days, as opposed to not responding for so long.
[00:17:11] Kenar Jhaveri: But most patients who are steroid responsive will respond by 16 weeks or so, 16 to 18 weeks, right? And then you, how long do you continue steroids for? When do you taper them?
[00:17:21] Koyal Jain: I think we are getting into the areas of what's recommended versus what we actually do. And for board purposes you're giving it for 16 weeks and then you taper it off over a couple of months. Personally, we actually are a little bit more steroid sparing and we've seen patients go into remission, do get tapered a little bit faster and don't necessarily have an increased risk of relapse and that's what people worry about.
And I think we've headed into a steroid sparing era with so many diseases. I think minimal change disease would probably be one of those diseases eventually as well.
[00:17:58] Kenar Jhaveri: Okay. So for steroid sparing treatments, one of the drugs that I go to is tacrolimus. And I think we have a lot of experience of tacrolimus for other diseases like membranous and post transplant. So I feel very comfortable using it compared to cyclosporine, although the older literature is, a lot of it is cyclosporine.
So there has been trials that compared steroids with tacro, very small studies, and found equal remission rates. So I do use tacro. The problem with tacro is I just don't know when they will go into remission compared to steroids, and there's no optimal tacro level. I aim for five to seven, but I think that's personal choice.
It depends on the individual and their weight. So that's what I use, but lately I have been using a combination of tacro with Rituxan. Because I've learned, I feel minimal change disease, and this is not on the boards, that it is primarily anti-nephrin mediated. And I really feel giving them upfront rituximab... that's a bridge with tacro.
So instead of steroids , I use tacro as a bridge and give them rituximab two doses and most of them do go into remission with that combination. So tacro is used like a steroid rather than giving steroids. Alternatively, people have used oral Cytoxan. I don't know your thoughts on that.
[00:19:16] Koyal Jain: So we not only are steroid sparing, we're also a bit more cytoxan sparing just because of the side effects and profile long term. And personally also we've moved towards rituximab a lot more because with tacrolimus we've seen more flares, right? They're fine, fine for on tacrolimus and then you taper it off or you stop it.
People are more likely to flare and rituximab just has had less flares as opposed to tacrolimus. So we've also moved towards rituximab a lot more for our patients. It's not just for our frequently relapsing patients, but also for cases where we want to be steroid sparing . I've used the combination of tacrolimus and Rituximab, but I've used it a lot more for patients who are more resistant to treatment or maybe they just need higher doses of steroids to be dependent on those high dose of steroids. But typically I do end up using more rituximab these days and CNIs have become more a bridge for me to get to rituximab.
[00:20:16] Kenar Jhaveri: So, I just want to remind people there, like all these terms that are used in the literature, for example, relapse is when you have proteinuria for three consecutive early morning specimens after having been in remission previously. Frequent relapses is two or more relapses in the initial six month period or more than three relapses in 12 months.
Steroid dependence means two consecutive relapses when on alternate day steroid therapy or within 14 days of stopping it. And steroid resistance is absence of remission despite therapy with daily prednisone at a dose of two mg per kg per day for four weeks. This is from the pediatric literature and also very steroid heavy literature so I don't know how useful some of that stuff is these days but KDIGO does recommend: frequently relapsing steroid dependent minimal change. The patient you were talking about, right? The one who's dependent on steroids or is just relapsing and we have to keep giving steroids. Then if they have no previous Cytoxan exposure to give Cytoxan, if they do have previous Cytoxan exposure or patient wishes to avoid cyclophosphamide, then rituximab or calcineurin or MMF is the preferred option. And that's based on limited data.
[00:21:30] Koyal Jain: And also don't forget the other things that we need to do apart from immunosuppression.
Immunosuppression is just one piece of treatment. We can't forget the supportive management that is required for these patients. If they're having a lot of nephrotic syndrome, the diuretics that go along with it, right? Low sodium diet making sure that they are comfortable. Sometimes, rarely, I have done anticoagulation and those have been patients with albumin of 1, and very high risk for thrombosis.
Even though we typically talk about anticoagulation with membranous.
[00:22:02] Kenar Jhaveri: No, totally. I think all those things. And now I don't know with the, renin angiotensin inhibitors and maybe even SGLT2 in the appropriate cases, right?
[00:22:10] Koyal Jain: Absolutely. And I don't think we have data for minimal change with SGLT2 and we don't have it for so many other glomerular diseases either, other than obviously IgA and CKD. But I still use a little bit more SGLT2 inhibitors.. Getting it approved and being able to actually use it is another issue .Obviously for these patients insurance doesn't always approve it.
[00:22:31] Kenar Jhaveri: Yeah, no, that's true. So again, I think to summarize, the initial therapy for minimal change disease is majority of the time, still with the highest grade of data, is glucocorticoid monotherapy, right? And you could see the remission 90 percent of the time. And ones that cannot tolerate, you think about cyclosporine, Cellcept, or rituximab. And the supportive measures that Koyal talked about. In relapsing disease, you might want to, give steroids again, but then consider Other options like cyclophosphamide, Rituxan or cyclosporine. And then finally you have the glucocorticoid resistant minimal change disease where you really have to go to one of those approaches.
We don't have any other drugs, unfortunately, in minimal change disease.
[00:23:13] Koyal Jain: And keep in mind that rituximab has really been effective in glucocorticoid sensitive patients as opposed to resistant patients, so CNIs sometimes become more important there.
I hope that you all have found this podcast to be helpful. We've really enjoyed it and I hope you've enjoyed it. So this is Kenar and Koyal signing off from GN in Ten. BRB or Board Review Bonus.
[00:23:37] 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.
[00:23:55] Kenar Jhaveri: I forget what we call this, Koyal, but it's some sort of board review.
[00:23:59] Koyal Jain: Or digest!
[00:24:00] Kenar Jhaveri: Oh, yes. Board digest.
[00:24:01] Laurel Damashek: Board review bonus.
[00:24:02] Kenar Jhaveri: Board- oh, yes, thank you, Laurel.
[00:24:04] Koyal Jain: I got it right. I got BRB right.
[00:24:06] Kenar Jhaveri: Oh my god.
Okay, we'll
[00:24:09] Koyal Jain: think it called a digest in the beginning. Oh no
[00:24:12] Kenar Jhaveri: Laurel, you want to send her a lollipop or something? I don't know if we're getting it right. Okay.
[00:24:16] Laurel Damashek: But isn't it board review bonus?
[00:24:18] Kenar Jhaveri: Oh god,
[00:24:20] Koyal Jain: I did not get it right. I did not get it right.
[00:24:23] Kenar Jhaveri: Scratch the lollipop.
[00:24:25] Koyal Jain: I am so sorry. I don't even know where I got it wrong. Okay. What was it? Okay.
[00:24:30] Kenar Jhaveri: We'll keep it funny. We'll keep that. We need to have those at the end.
[00:24:34] Koyal Jain: I hope you all have enjoyed this podcast and this is Koyal and Kenar signing off from GN in Ten, BRB, Board Review Basics.
[00:24:46] Kenar Jhaveri: Bonus! I'm sorry, you can't get it right every time.
I think we'll get it right by 2026. By that time, it won't be called minimal change disease.