Board Review Bonus #3: Lupus Nephritis
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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.
Kenar Jhaveri: Welcome to GN in Ten with Koyal Jain and myself, Kenar Jhaveri. And this is our Board review bonus. We've been doing these sessions with different glomerular diseases.
And today's special topic is lupus nephritis, which a lot of people need to know about. I'm sure both rheumatologists and nephrologists. We also have a very special guest. It's the first time we are doing this. We actually have a fellow in training here at Northwell Dr. Mahmoud Abdelaziz, since this is a board review, special, we felt a fellow's perspective or fellows asking us questions might be better.
Mahmoud Abdelaziz: I'm happy [00:01:00] to.
Koyal Jain: Welcome Mahmoud. You are our very first fellow on the. Series of podcasts.
Kenar Jhaveri: So lupus nephritis. Let's start with diagnosis.
Koyal Jain: What does Mahmoud wanna know? What do you wanna know as a fellow?
Mahmoud Abdelaziz: I guess the first thing I'd like to know is just some clues as to how we would suspect that there's kidney involvement in somebody with SLE.
Koyal Jain: I would say, this is how I teach the. So it's gonna get really basics, . I always think about three things, right? So yes, you have the extra renal manifestation, but it really boils down to three things.
One is what's your kidney function doing? What's your GFR doing? The other one is, what's your urine sediment looking like? And the third thing is, what's your urine protein? So if you boil down to these three things, that's how I'm really trying to figure out whether somebody's active or not. So somebody's, referred to me.
My question is, Hey, what's the UPC? How much proteinuria do they have? What does the urine sediment look like? Do they have acanthocytes? Do they have RBC casts? Often you can also see just w WBS casts or WBCs in the urine with a lot of inflammation and may not see a lot of RBC [00:02:00] casts. And then is the creatinine much higher, the GFR is much lower. And that's really helping me determine do I need to now biopsy this patient and determine if they have lupus nephritis?
Kenar Jhaveri: Of what degree of proteinuria do you usually consider biopsy?
Koyal Jain: So I would say that if somebody has above a gram, almost always they get a kidney biopsy, unless they've had like chronically some sort of like sclerosis and other things that we are thinking about. But typically above a gram for sure. And then about 500 milligrams. Usually they'll have some other symptoms, right?
Like they're 600, 700 milligrams, but they have a little bit of an active urine. I would still consider a biopsy at that time.
Kenar Jhaveri: I think that's fair. I think the recent KDIGO guidelines also say exactly 500 milligrams of the cutoff.
Mahmoud Abdelaziz: Yes. I guess the next thing that's confusing is how we classify lupus and why that really matters.
Kenar Jhaveri: Mahmoud and all the fellows, I think the role of the kidney biopsy here is gonna be critical, right? Because the kidney biopsy, as Koyal said, that leads us to diagnose the histologic classifications of lupus. And there have been a [00:03:00] lot of ways to define lupus in the kidney, but the classic one is the, the six classifications we have.
So that's the class one with minimal mesangial lupus nephritis. And it's very rare we see this because most of these patients don't get biopsied. They're normal urinalysis, minimal proteinuria, and normal serum creatinine. And it just, very minimal mesangial immune deposits. Maybe you'll see in. Basically in the immunofluorescence and EM. You might have normal light microscopy findings perhaps.
The second is class two, which is mesangial proliferative lupus nephritis also. And here you might have some microscopic hematuria, some proteinuria, hypertension, but really maybe even normal creatinine here. We rarely, again, biopsy these patients and you'll have, some mesangial hypercellularity in the light microscopy, and then you'll have some endothelial deposits.
Eventually you see in the EM Sometimes you can have a nephrotic syndrome with this, and then you'll have to think about lupus podocytopathy associated [00:04:00] with class two. And it's again, very good prognosis when you have class two. Class three to five is where we get the most worry.
So focal lupus nephritis, or the class three variant is where you have hematuria, proteinuria, and usually hypertension. Decreased GFR plus or minus nephrotic syndrome. And in here, this is where it's less than 50% of glomeruli that are affected by light microscopy. If there are more than 50% involved, then you actually define this as class four.
And there is active endo capillary or extra capillary glum nephritis, and you'll have some segmental component involved. And usually in the electron microscopy you have this, subendothelial deposits, immune deposits and that's your classic class three. The number, all lupus nephritis patients have a full house pattern, so everything lights up in immunofluorescence.
IgG IgM, C1Q, Light Kappa Lambda IgA. So it's the full house pattern. [00:05:00] Diffuse lupus nephritis or class four. This your diffuse proliferative class. This is the worst of the worst, where you have pretty much more than 50% of gloma involved in light microscopy. And it's again, the endo capillary, extra capillary glioma, nephritis.
And this is your classic one that most of the time on the boards and in clinical practice again, the EM is gonna show. The findings of subendothelial, maybe even mesangial deposits. You have the full house pattern. And in some cases that we have seen, you will have a crescentic variant.
So , remember, you know anything can become crescentic, any gn, and the one that does become here is usually class four. And then finally you have class five, which is a membranous variant of lupus where you have, the mebranous pattern of injury. So it's not proliferative pattern, it's not an MPGN pattern, it's a membranous pattern on light microscopy.
And the IF will be full house and the EM have sub epithelial deposits. And this is your classic, membranous [00:06:00] pattern. And then class six is really just end stage kidney. So you'll have a full house, but it's like a sclerosed kidney. And then you have these other patterns like lupus podocytopathy that is usually minimal change variant.
And there's FSGS variant, which is very rare. And sometimes you can see vascular lesions with. The kidney biopsy, which is thrombotic microangiopathy with lupus, and that's again, very rare as well. But this is very important for the board purposes as they will ask you questions of what class of lupus it is.
Koyal Jain: A couple of things that I wanted to add here is when you're making decisions about your patients, it's really important to also look at the activity index and the chronicity index, right? Typically. Most nephro pathologists will report, Hey, this is the amount of activity that's going on, or this is not really that active, even though it's class four, it's not really that active.
It's a lot more sclero. And those cases, you wanna be more careful about the amount of immunosuppression you use. You don't want to bombard somebody with a lot of immunosuppression if they have a lot of [00:07:00] chronicity and not as much activity. The other thing that I want to add
is whenever you see endo capillary proliferation, right? Think about you have these glomeruli, which are filters, and you have these capillaries, and if you have endo capillary proliferation, you'll have blockages of the filtering portion, the exact portion where the filtration is going to happen.
So you won't have as much filtration happening. That means the GFR is going to go down. So that's the reason why typically endocapillary proliferation is a little bit worse. And when we think about just mesangial, minimal mesangial, it's not really decreasing the GFR as much.
Mahmoud Abdelaziz: Okay. That clears things up.
Koyal Jain: What other things do you find that challenge you?
Mahmoud Abdelaziz: I guess that highlights the importance of biopsying because if there's different classes and different severities, I'm assuming that affects how we're treating the patients. And that's really the next thing that is pretty challenging to me, is how we approach treatment of different classes.
Koyal Jain: I feel like this is the area where most fellows struggle because there's so many options that exist out there. Typically the way I think of [00:08:00] treatment is I try to get the side classes out. So class six, you don't really wanna treat, it's all sclerosis, it's advanced stage sclerotic disease, and then class one and two.
Typically I would treat more conservatively if they have a little bit of proteinuria, maybe like a RAAS blockade. If somebody's not on hydroxychloroquine, I would put them on that. But unless they have lots of proteinuria, they often do not get immunosuppression for just class one and two.
I will say there's a caveat though, although for board purposes, you don't really treat class one and two. In clinical setting you'll often see that these patients will have some extra renal manifestations, right?
So sometimes these class one and two patients will also end up on immunosuppression, not for class one and two itself, but because of the extra renal manifestations.
Kenar Jhaveri: are not prescribing those? That's rheumatology, right?
Koyal Jain: Great question. Although that is true, we do have a combined clinic. And so we see them together and then there are patients who are not always able to afford copays and will end up seeing one or the other. So there [00:09:00] are some patients who say, Hey, I can't get in to see them, or I can just come and see you.
I've seen you for a while, and they just continue to follow me along. But that doesn't really apply to all nephrology practices.
Kenar Jhaveri: what you made is a very good point about class one and two. Lupus nephritis if there's low level of protein I wouldn't treat. But if they have nephrotic syndrome, then a lot of times they end up having foot process effacement. So you actually have a minimal change disease on top or podocytopathy on top of class one or two.
And then low dose steroids might just all they need or maybe, anti B cell agents. But that's only if you have superimposed minimal change on top of class one two.
I think the biggest challenge is class three and four,
Koyal Jain: Class three and four, and I think there's going to be controversy amongst the nephrologist, right?
Kenar Jhaveri: That's the main movie. So can we go to the trailer before that? I always get worried about the prophylaxis
. They're already on immunosuppression. I think it's important for fellows to know that these patients need to be on statins. They're high inflamed state.[00:10:00]
Of course you need to control their blood pressure with RAAS blockade SGLT two inhibitors. And there's data now for SGLT two inhibitors in lupus patients. The one I always, and of course bone protection rheumatologists probably are on top of that, to make sure they are calcium, vitamin D and all that stuff.
And you just wanna monitor for cancer in terms of prophylaxis because a lot of these are net immunosuppressants, the one that is controversial. And I want to hear your thoughts on this is PCP prophylaxis or pneumocystis, prophylaxis for our lupus nephritis patients.
I know in transplant patients we do put these patients on Bactrim. But do we normally have to put these patients on Bactrim prophylaxis?
Koyal Jain: So I do, however, only do it if they're on like prednisone, some steroids 20 and above. So if somebody's on 10 of prednisone, they'll probably come off of prophylaxis at that time. And that's where the controversy rises for us, whether you wanna continue it or not. But if they are on higher doses of prednisone, [00:11:00] we typically will, especially because they're going to be on long-term prednisone therapy or steroid therapy.
Kenar Jhaveri: Just for the fellows to know, there is a controversy still about this. It's not written in books. The lupus literature from the rheumatologist side actually shows that actually there's a lot of drug reactions in lupus patients with Bactrim. So 41% actually have a reaction to it. So that's why rheumatologists don't really like.
Giving PCP prophylaxis, unless they're on triple immunosuppressive therapy it's actually by the ACR guidelines. I don't think it's recommended because also Bactrim causes lupus flares. So there is back and forth controversy right now. So you just want to know that because the rheumatologist you work with might have a different way of practicing.
Koyal Jain: Absolutely. And we oftentimes these patients have a low GFR to begin with, and so we actually end up not using Bactrim for that reason as well because of the low GFR. So we end up on something like atovaquone. Typically a lot of these patients might end up on like pentamidine, but then.
Trying to get outpatient in an isolation room that's a little bit harder [00:12:00] and then atovaquone or something, but patients don't like the taste of it,
Kenar Jhaveri: so let's go to the movie now.
How do you treat class three and four? What is your sort of algorithm or what is the recommended algorithm by the experts.
Koyal Jain: So let me tell you the recommended algorithm first one of the things that KDIGO recommends is nowadays triple therapy is a preferred form of treatment, right? So triple therapy means some sort of a steroid glucocorticoid, MMF or cyclophosphamide,
and the third agent, if it's MMF, could be a CNI. Or Belimumab. But if it is the second agent with cyclophosphamide, then the third agent can be belimumab. You can do a variety of combinations, but you don't do the combination of cyclophosphamide and CNI at this point, and it's not recommended for induction therapy is what I'm talking about.
They also recommend you can do triple therapy, which they prefer, but you could technically do dual therapy with MMF and steroid or steroid and cyclophosphamide and go from there. The cyclophosphamide that more and more people are preferring these days is the Euro lupus [00:13:00] protocol, which is the 500 milligrams every two weeks for six doses or three month long protocol.
But I do understand that there's some areas where that's not used and NIH protocols are actually being followed, which is the once a month Cytoxan dosing for six months.
Intravenous. And then the glucocorticoid regimen nowadays is the reduced dose of glucocorticoids, which is being preferred rather than the higher doses of glucocorticoid.
Kenar Jhaveri: So reduced dose, so you would still give up to 1.5 grams in three days of the solumedrol, and then you follow that by 40 milligrams of prednisone down to 2.5 milligrams by week 25. So very similar to the ANCA low dose protocol, correct?
Koyal Jain: correct. I will say that I've, now moved more and more towards less amount of Solumedrol upfront as well. So I might sometimes do two doses or two days of Solumedrol that reduces it, or two 50 milligrams for three days, so trying to cut it down based on the patient population to also [00:14:00] decrease the amount of side effects long term.
Kenar Jhaveri: Just for the fellows based on what the experts recommend actually is up to three days. But yes, people will have different, ways of doing that. And I think what Koyal said is I think it's very important to stress this. Because this would be the most common type of lupus is three and four, and probably the most asked questions on the boards.
So you have to induce them. So we're talking about induction therapy right now with steroids and IV and then followed by oral. That's one. Two, you have to either give them mycophenolate, up to three grams, but you can actually start off 500 up to go up to three grams, twice a day max to, three grams per day.
Or you give them IV cyclophosphamide, which you know, Koyal recommended, you can actually do combination therapies you've given CellCept with steroids. You're given cytoxin steroids.
Can you add a third agent? And the third agent can be either belimumab, or Benlysta, which is a BAFF inhibitor, which is a novel drug. And or voclosporin, [00:15:00] which is calcineurin inhibitor or tacrolimus. Most of the US data comes from voclosporin. One of the Asian data comes from Tacrolimus. That's usually your induction treatment, which is for at least six months, correct?
Koyal Jain: At least six months unless you're doing Euro lupus, which is the three month cyclophosphamide. I will say that we made the biggest blunder of not seeing this upfront, which is really important, is the antimalarial agents. That is hydroxychloroquine has been shown to decrease relapses and, not just extra renally, but also renally. And so it is something that you definitely recommend alongside all of these treatments and is actually safe during pregnancy.
Kenar Jhaveri: And actually might even prevent lupus flares, right?
Koyal Jain: Exactly.
Kenar Jhaveri: So that's usually the induction treatment. What do you do for maintenance for class three and four?
Koyal Jain: Maintenance therapy oftentimes for me is basically MMF, right? Whatever formulation of MMF. However, there are patients who are not able to tolerate different formulations of MMF, and you end up on something like azathioprine or somebody is thinking [00:16:00] about pregnancy. Then you end up on azathioprine.
But typically, MMF is the maintenance therapy that I continue and then try to get them off steroids by that time later on.
Kenar Jhaveri: Just for the fellows, if you started dual therapy, so steroids and MMF, you continue the MMF, up to three years that's the max that people have studied. Some people do two years, some three years. If you are on Cytoxan. People do switch to MMF for maintenance or azathioprine.
What if you were on Benlysta and MMF or Voclosporin and MMF do you continue the dual therapy for two to three years or you just take them off the Belimumab and Voclosporin just to MMF for the remainder of maintenance?
Koyal Jain: I do continue both the agents. I believe the recommendation's different two and a half, three years for either one, belimumab versus Voclosporin.
Kenar Jhaveri: The other thing just for the fellows to keep in mind is that why are we continuing maintenance therapy was this long? I think studies have shown when you do repeat biopsies or when you try to take them off immunosuppression, [00:17:00] the disease does relapse.
And even with clinical maintenance, there's actually activity on the renal biopsy even after one year. So you want to continue these medications a little bit more longer in terms of maintenance. What about class five?
Koyal Jain: Class five, I think can be straightforward or not straightforward as much as what you wanna think about it. Although MMF is the recommended agent along with glucocorticoids this is the place where I would prefer A CNI based regimen over belimumab and or obinutuzumab, which is now the new approved agent.
Kenar Jhaveri: If you had low levels of proteinuria, you probably just do non immunosuppressive therapy, right? Although some people will treat for extra manifestations, but just plaquenil or hydroxychloroquine. If you had nephrotic range proteinuria, then you do this combination therapy similar to what we did in class three and four.
Now Koyal did bring up. Vitamin R or rituximab like drug. Rituximab unfortunately does not make it to any guidelines in the kidney world for lupus nephritis, [00:18:00] although a lot of fellows who are listening to this, they know people have given rituximab. The lunar trial was not a positive trial, although people might think it was non-inferior.
So people have used rituximab in refractory lupus patients, that some of these things failed. And as a result a new drug , which is vitamin R on steroids called obinutuzumab it's a humanized monoclonal antibody showed a really great response in proliferative lupus.
They didn't have that many Class five patients, but we know that from non lupus. Membranous said, B-cell therapy really works great with membranous nephropathy. Koyal is postulating from that, that not be the best agent down the road to treat Class five might be obinutuzumab, but right now you would just treat it like class three and four.
If you have nephrotic range protein area, right?
Koyal Jain: I will also say that a lot of these guidelines came out in 2024, so they didn't really have all the obinutuzumab information, when [00:19:00] probably they were working on this even a year prior to that.
Kenar Jhaveri: Just another thing, Mahmoud and fellows is that we keep talking about Voclosporin. Why Voclosporin? Because , it is the only calcium urine that does not require to check levels. And I think it's very easy to use. Whereas nephrologists, we are pretty used to using tacro and cyclosporine and it's cheaper.
So we do go to tacro a lot. When we think of using calcineurins in our patients.
Mahmoud Abdelaziz: I guess how do you monitor response to treatment and is there any role to rebiopsying them or is there any other clues that can suggest that they're actually responding to treatment
Koyal Jain: so we don't do protocolized biopsies and neither are they currently recommended as a requirement? I would say in terms of monitoring, obviously it again, boils down to the three things, the kidney function, the urine protein, and your urine sediment, right?
And those three things, if they're all improving , think about the partial response or complete response, which is very similar. They slight differences between different gns, complete response would be something below 300 or 500 milligrams, right of proteinuria with a [00:20:00] GFR that's maintained within 25%, 20 to 25%, and partial response is non nephrotic, but decreased by half from whatever the protein area was.
And the GFR being maintained. So very similar definitions, slight differences between different gns. Are they getting into partial response? Are they getting into complete response? Are they not responding? How much chronicity did they have? If they did not have a lot of chronicity and they're not going into complete response, then I would wonder, Hey, is this partial response?
And then I'm just not getting the bang for my buck, and I need to either increase immunosuppression or do a repeat biopsy. Or if I'm thinking, Hey, this is actually more chronic. I don't wanna increase and add a third agent or a fourth agent on top of this, should I biopsy them and see, hey, now they just have some secondary FSGS that has settled in and they're going to stay around one to two gram protein range.
So you're trying to figure out how much is active and how much is now just chronic and you should just not worry as much.
Next, what do you have next?
Mahmoud Abdelaziz: I guess what are the most common mistakes that you see fellows [00:21:00] make when managing lupus nephritis?
Kenar Jhaveri: I think the most common mistake is probably just not understanding the pathology component. I think there's a lot of confusion, probably class 3, 4, 5, because they're still learning what renal path looks like and lupus brings in so much pathology, variants, in terms of which is secondary, primary and things like that. I think it's probably one, two is, you know when to add a third agent or can just continue two agents when to repeat the biopsy. Probably those are the places where they probably are, confused at least. I think a lot of places the rheumatologists are running the show and not nephrologists the fellows also have this assumption of what am I really doing here in the care of this patient? And I think that's one mistake. They give up very early in the care of the patient because they think the rheumatologist will take care of everything
Koyal Jain: can I leave you with a piece of advice, and this is for anybody who's listening to this podcast, it really doesn't matter if you're a fellow or not. I [00:22:00] believe that all of us have more to learn and none of us is a true expert, right? We are not the end all, be all. And so I genuinely believe that there are complicated cases and you need to talk to each other.
There's a lot of cases that I say, you know what? This is really complex. Can we just talk it out? And within our GN team, we will do that and it's okay to ask for help, right? To me, the patient is primary and it's not about my ego or somebody else's ego, and you should know it all. It should all be what can we do?
Mahmoud Abdelaziz: Very good advice for a fellow who's about to graduate
Koyal Jain: absolutely. And there's still a lot of fellows that I keep in touch with. Like I get texts from them and say, Hey, when you have a minute, can you call me? And I call them. And then we talk about a patient and come up with some ways to go forward. Because again, in the end it's all about the patients.
Kenar Jhaveri: No, I was just, basically thinking maybe we might have exhausted all the questions Mahmoud wants to ask, but I just wanted to just, because I like TMA I just wanted to throw in that, you can actually have lupus with the TMA and that actually is a whole different mode of treatment.
Then you're going into the whole [00:23:00] plasma exchange route. Make sure you don't have antiphospholipid syndrome and if you need to give eculizumab or not. So it's very rare. It's probably not something on a board review purposes, but it's like special situations, right? When you have that or you have a pregnant patient with lupus, what can you use?
What are the drugs that are not allowed? The only drugs I know that are allowed Azathioprine, steroids and calcineurin, but that also only Tacro Cyclosporine because we have no data on Voclosporin and we have no data on obinutuzumab. MMF is dangerous in pregnancy and we have actually have no data on Voclosporin with pregnancy and benlysta either.
Koyal Jain: And don't forget, hydroxychloroquine.
Kenar Jhaveri: Thank you for joining us for our GN in Ten podcast. I know it's not really 10 minutes, but we really wanted this special for the fellows and hope our listeners learned
Mahmoud Abdelaziz: thank you everyone for having me. I really learned a lot and I was happy to be here and ask all my questions
Koyal Jain: thank you so much for being here and [00:24:00] from all of us at GN in Ten, thank you for joining us and listening to us. Have a great day
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.
Kenar Jhaveri: BB, B, or I don't know what Koyal calls
Koyal Jain: BRBB
Kenar Jhaveri: What is that? Board review.
Koyal Jain: basics.
Kenar Jhaveri: Oh God. There you go again
by the way. It is board review bonus by
Koyal Jain: Oh my goodness, I have never gotten it right in the entire
Kenar Jhaveri: welcome to our world the listeners. This is the problem I deal with.