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Melanie Cole (Host):  Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole, and I invite you to listen as we explore IgA glomerulonephritis, a review and update. Joining me is Dr. Wai Lang Lau. She's an Assistant Professor of Medicine in the Division of Hypertension and Nephrology at UF Health Shands Hospital. Dr. Lau, it's a pleasure to have you join us today. Tell us a little bit about IgA glomerulonephritis and IgA nephropathy. Tell us a little bit about what those are, the prevalence. Give us a little background.

Wai Lang Lau, MD (Guest): So, first of all, thank you so much for having me. IgA glomerulonephritis is really one of my favorite diseases. So, in terms of prevalence, globally, IgA glomerulaonephritis is probably the most common form of glomerulonephritis. By incidence, it has its highest incidence in the Asian countries, especially Southeastern Asia. And in fact in Japan, they screen for it in their elementary school children, how common that is. But as we go west on the globe in Europe, the incidence decreases. And then actually as you go further west into the African continent, that's where there's the lowest incidence of IGA glomerulonephritis. And I would say, the United States, I mean, obviously we're a melting pot. We have people from all over the place, but again, looking at the ethnicity, I would say in general, low incidence in African-Americans, highest incidence in Asians and sort of medium incidence in the people of European ancestry.

I IgA glomerulonephritis is really thought to be a deposition of an aberrant form of the IgA immunoglobulin that is galactose deficient, and predominantly this galactose deficient form is produced by the mucosal immune access. And it makes its way into the systemic circulation and it gets deposited in the kidney, predominantly of the glomeruli and that's where it causes inflammation. And that's how it causes this clinical phenotype that we know of as microscopic hematuria, sometimes macroscopic hematuria as well, proteinuria, and sometimes accompanied by renal dysfunction, meaning elevated creatinine.

Host: Dr. Lau, if IgA glomerulonephritis doesn't usually cause symptoms in early stages and can go unnoticed for years, what red flags would you like other providers to keep in mind if their patients present with some of these? You mentioned earlier, microscopic hematuria, will you please let other providers know what you'd like them to be on the lookout for?

Dr. Lang Lau: So, from a subjective standpoint, when you're just talking to the patient and getting the HPI, what you want to hear is whether or not they've ever experienced gross hematuria. Okay. So, that's frank blood that they see in the toilet. Okay. That's a big red flag that they may have this disorder, and I will say, especially around the times of infection, like if they can recall, oh yeah, you know, one time I had this bad strep throat or I had this bad ear infection and then a day or two later, I peed out blood, and it could be self-resolved, meaning it may just happen for a day.

And then the gross hematuria disappears. But nonetheless, that is a big red flag that they may have this condition. But really short of gross hematuria, I mean, there are some rare instances where patients can present with edema, meaning anasarca fluid retention, swelling in their feet and ankles, and they may tell you about that. Ask them about skin manifestations because IgA can be a systemic vasculitis. In addition to being a renal limited, disease, it can be a systemic disease. So, people can have these weird palpable purpura, these little red dots, especially in the lower extremities. But yeah, those are the main things that we ask subjectively in terms of what they tell you, what you might find objectively on exam.

And then of course, you know, in terms of diagnostics, the urine analysis is imperative, right? I mean, anybody can pee into a cup, and all you need to do is do a dipstick on it and that can tell you a lot, if it turns positive for hematuria or proteinuria, then for sure, you've got a big flag right there.

Host: So, Doctor as we're talking a little bit about the histology and the pathological scoring of IgA glomerulonephritis, tell us about the glomerular grading system and how it's useful to predict the natural course of the disease.

Dr. Lang Lau: So, they've come up with what they call the Oxford classification, to describe the histology of the disease. And this came out, I believe in 2000 and 16 and it contains a few elements. It's called the MEST-C score system. So, M in the word MEST-C stands for the Mesangial score, which gives us an idea of how many glomeruli exhibit the Mesangial proliferation that we so classically see in IgA. The E is the score for endocapillary hypercellularity. And this in general gives us an idea of how angry this process is, how proliferative this process is. The S is the segmental glomerulosclerosis score. And that tells us how many of the gloms or the filters have been scarred by this process. The T is for tubular atrophy. And that tells us what percentage of the space in between the glomeruli are scarred, because you know what starts out in the glomeruli, this inflammation, then extends out of the glomeruli into the tubular interstitium and that's where the T score takes into account of.

And then the latest addition to the MEST-C score system is the C, which is just letter C. So, in total, it's actually M-E-S-T-C. So the C stands for how many cellular or fibro cellular crescents are seen on the light microscopy. Now, crescents really are the most angry manifestation that you can see in terms of glomerular inflammation. Because crescents basically represent a blowout of the glomerular basement membrane, where the inflammation has basically blown through the GBM and then extends onto the urinary space in Bowman's capsule. So again, that it's really the most exuberant, inflammatory manifestation of glomerulonephritis of any kind of glomerulonephritis, whether you're talking about ANCA disease or lupus or any kind of GN when you see crescents, you'll have a really angry glomerulonephritis.

Host: So, let's talk about some of the latest treatment options. Tell us a little bit about what you're doing now. What's exciting. And what you feel other providers would like to know.

Dr. Lang Lau: So, the one thing that's sad about IgA is that we don't have good established treatment for it. I mean, it's a disease that we've known about for five decades. Now, I believe in the beginning, it used to be called Berger's disease, of course now we've, we have a better idea of the pathophysiology. But you know, here we are in 2021 and we still don't quite have a handle on how to treat these patients. Certainly most long standing most treatment option is steroids, right, with glucocorticoids, but you know, we all know that glucocorticoids have such severe side effects. And the fact that the epidemiology of this disease is such that a lot of young people get affected. Not too many, 20, 30 something year old people are interested in being on high dose steroids, where they end up having acne and weight gain and stretch marks and all the rest. So, we're really interested in exploring other treatment options. So, what we've recently been involved in, it's called the NEFIGARD study, N-E-F-I-G-A-R-D.

And that uses a drug called Nefecon. It's actually repurposed form a budesonide. It is a glucocorticoid, but it is formulated to release in the part of the small bowel called the terminal ileum. And that's where we think that a lot of the abberant IgA is made. Remember how I said that, what's deposited in the Mesangium of the glomeruli, we think are IgA that is of mucosal immune axis origin. So, the Nefecon is a formulated, a special release glucocorticoid that really gets released in that part of the intestines where we think that this immunoglobulin is being produced. So, as such it's thought to have a lot less side effects than just giving the traditional prednisone, because of its targeted release, and also because of its extensive first pass hepatic metabolism. By the time it goes through the liver, only maybe about 10 to 15% of the drug then gets absorbed into the systemic circulation. So, it's thought to be a lot more tolerable than taking the conventional high dose steroid.

The other things that we're looking to be involved in is the role of complement inhibition. More and more we're understanding that many different forms of glomerulonephritis, perhaps a very basic common pathway, that precedes the glomerular inflammation and clinical disease, is the activation of compliment. And we know that an IgA that occurs in the Mesangium, because we see remnants or fingerprints of compliment degradation products as part of histology when we do the immunofluorescence. So, we are interested in exploring the use of compliment blockade in the treatment of IgA.

And there's a study that is using a lectin pathway inhibitor. It's sponsored by Omeros and I believe they're recruiting for phase three. There's interest with LNP, which it's a small oral molecule blocker of factor B for the alternative pathway that we're anxious to get phase two data on and they are recruiting for phase three.

And we might be a part of that, and then what we're also looking to become a part of is using sort of a non immunosuppressant way of reducing proteinuria, which I think is attractive. It's using endothelin receptor antagonist. It's not a total site targeted therapy, but it's kind of attacks at many different renal cells whether it be Mesangial cells, endothelial cells, Poto sites, tubular interstitial cells, but the end product is that it works to help decrease inflammation and to help decrease proteinuria. And so endothelian receptor antagonists, I think are an attractive arm of treatment that one might look for.

And what's nice about is that it's not an immunosuppressant drug and it can be used as an add-on perhaps to other immunosuppressant drugs. So, I think that's a very attractive arm to look at. Sparsentan is an endothelin receptor antagonist combined with a angiotensin receptor blocker. They will be closing their phase three enrollment. And so, we're all very anxious to see, what the sparsentan data will look like for the IgA group. Because I think that will be a good option. You know, of course, treatment always has to be individualized.

You have to look at the patient, you have to look at their comorbidities, you got to look at their BMI and, and then you also have to discuss the side effect profile of every agent that we have and then between the provider and the patient, you need to decide which agent has an acceptable profile, side effect profile that makes it a positive risk benefit ratio for that particular person. So, one other thing that I just want to mention that how we talk about IgA as being a disease of, deposition of aberrant IgA molecule in the glomeruli, so, you know, what seems a sensible possibility for treatment would be something that might affect the B cells that produce the IgA.

Well, oddly enough, there was a study done in 2017, by Lafayette et al, that looked at using rituximab to treat a group of patients with IgA and surprisingly enough to everybody, it was a negative result. In other words, it did not improve proteinuria or creatinine in these patients. Now, there's been a lot of discussion about what could be the cause of the result and some people claim that well the mean EGFR and the rituximab arm was 40 cc's per minute. So, maybe by that time, the horse is out of the barn already, and there might've been too much scarring. So, it may be just the stage in which we're catching these patients that the drug might have been ineffective. But there've been a few other theories that because again the aberrant IgA, we think that's the culprit, is of mucosal origin; maybe there's a difference between how we need to suppress these particular B cells compared to IgA B cells that are made in the bone marrow or other germinal centers.

So, maybe there's something special about the mucosal immunity. We know that there are genetic predispositions to who forms these aberrant IgA that somehow again, was able to escape the rituximab effect. There's concern that maybe it's more the plasma cells that are involved in producing the abberant IgA.

And of course, rituximab does not hit at the plasma cells. So, there's been a myriad of theories to explain, but for all intents and purposes, for now we do not believe that rituximab is effective for renal limited IgA glomerulonephritis.

Host: Wow. That was an excellent summary, Dr. Lau. So, any final thoughts you'd like to leave other providers with, when you feel it's important to refer, any clinical trials you'd like them to ask you about, just give us little bit of your final thoughts and best advice,

Dr. Lang Lau: Final thoughts and best advice, I would say certainly for all the primary care providers, the people who do physicals, please do urine analyses because a lot of these patients do come in asymptomatic. And if we can catch them early, get the referrals early, get the biopsies done and make the diagnosis and put them on appropriate therapy, then hopefully we can save a lot of these young to middle-aged people from going to ESRD. I would say to our nephrology colleagues, please refer for patients to go on to clinical studies because steroids really are very difficult for patients to tolerate. They are certainly not the answer for everybody. And I would really encourage them to look at the different centers and who's doing what study and make the referrals so that we can catch them because even for clinical studies, we generally like to see them when their EGFR is above 30. So, that unfortunately if you catch them too late, then they may not even be eligible for a study. So, I think those would be my two main ending remarks.

Host: What a fascinating topic we discussed here today. Dr. Lau, thank you so much for joining us and sharing your incredible expertise. Thank you again. And to refer your patient to Dr. Lau or to listen to more podcasts from our experts, you can always visit ufhealth.org/medmatters for more information. That concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. Please remember to download, subscribe, rate and review this podcast and all the other UF health Shands Hospital podcasts. I'm Melanie Cole.