This transcript has been edited for clarity.
Matthew A. Sparks, MD: Hi. I'm Dr Matthew Sparks. Welcome to Medscape's InDiscussion series on chronic kidney disease (CKD). Today, we'll be discussing immunoglobulin A (IgA) nephropathy with my guest, Dr Dana Rizk. Dr Rizk is a professor of medicine and the director of the clinical trials research in the nephrology division at the University of Alabama at Birmingham (UAB). Welcome to InDiscussion.
Dana V. Rizk, MD: Thank you, Matt. It's a pleasure to be here.
Sparks: The first thing I want to know is how does someone become interested in studying IgA nephropathy?
Rizk: Somewhat by serendipity, I would say. Initially, my life in research started with polycystic kidney disease at Emory University. And when I moved to the UAB, I had the fortune of meeting Dr Bruce Julian, who was a colleague of mine and a world authority in IgA nephropathy. He opened my eyes to the disease, and I have, since then, had the pleasure of working with the IgA team on a lot of translational studies. I work with basic science colleagues, along with the clinical colleagues, all the way from general nephrology to post-transplant care. It's been a fun journey.
Sparks: That's one of the great things about medicine, and nephrology in particular. You never know when that opportunity is going to come, and sometimes you look at it and 5 or 10 years later, you don't even realize it was an opportunity. It's really amazing. Thanks for sharing this. IgA nephropathy to me is very fascinating, and I would like to know what is the pathogenesis? What's known about it? Why do people get IgA nephropathy?
Rizk: We have come a long way understanding how IgA nephropathy develops. We now think of it as an autoimmune disorder, and it is believed to happen in multiple steps or what we refer to as multiple hits. The first hit is an increase in the circulating levels of a specific kind of IgA that is lacking some sugars on its protein structure. This is referred to as galactose-deficient IgA, and it's essentially an IgA molecule that's lacking the right number of galactose sugar moieties. When those levels go up, that is recognized by the body as being an abnormal finding against which we start forming autoantibodies, the IgA or IgG subtype. The IgG autoantibodies seem to play the major role in the disease. They bind to this galactose-deficient IgA1, forming circulating immune complexes, that is referred to as hit number 3. Ultimately, these immune complexes deposit in the glomeruli, specifically in the mesangial area. Of course, they trigger a cascade of inflammatory events that ultimately lead to glomerular injury, but also tubular interstitial injury, fibrosis, glomerulosclerosis, and so forth. With that, kidney function starts to decline, and you develop CKD, ultimately leading to end-stage kidney disease in a subset of patients. It's worth mentioning that these events happen in the genetically susceptible host. Not everybody, of course, is going to develop IgA nephropathy. There's clear evidence that there are environmental triggers for the disease as well. I can't say that we fully understand why or when it develops, but we've come a long way in understanding the disease pathogenesis.
Sparks: When I learned about IgA in medical school, I learned that it was important for immunity at the mucosa. What does that have to do with the pathogenesis where IgA is typically acting?
Rizk: That's a great question. IgA is the predominant immunoglobulin that is produced at the mucosal surface. It is the immunoglobulin that's supposed to help us fight pathogens at the mucosal surface all the way from the nasopharynx down to the gut.
It stands to reason there is mucosal exposure that increases the production of IgA. This galactose-deficient IgA that I mentioned is supposed to stay at the mucosal surface and somehow gets translocated into the circulation in the susceptible host. We don't know how that exactly happens.
There are a couple of theories, including a theory wherein the B cells dislodge or move from the mucosal surface and mis-home to the bone marrow and start secreting galactose-deficient IgA into the circulation. There's also some evidence that there is what we call an overspill, where there is so much production of galactose-deficient IgA1 at the mucosa surface that it translocates back into the circulation.
Sparks: That's all very fascinating. Can you talk a little bit about the presentation? How do you diagnose it? Are there any biomarkers that might help in allowing us to diagnose this without a kidney biopsy?
Rizk: In children, the most common presentation is the onset of macroscopic hematuria or synpharyngitic hematuria, like I mentioned, visible blood in the urine, at the time of an upper respiratory or gastrointestinal (GI) infection. As you grow older, IgA presents like a typical CKD. People are picked up because they have an abnormal serum creatinine or they're picked up on the basis of urine abnormalities, be it microscopic hematuria or proteinuria or both. Very rarely do they develop nephrotic syndrome, and in those cases when we usually biopsy them, there's an overlap of IgA nephropathy with a podocytopathy that is reminiscent of minimal change disease. That's really a small subset of patients. Then you have the usual consequences of CKD. For example, people can have hypertension that, especially when seen at a young age, suggests to their physician that they need to be worked up for kidney diseases. Then there is swelling, if they're spilling enough proteinuria and so forth.
Sparks: There's a new term that I started seeing a few years ago called IgA vasculitis. It used to be termed Henoch-Schönlein purpura. It encompasses a little bit more than that term does. What exactly is IgA vasculitis?
Rizk: We think that IgA vasculitis is on the same spectrum as IgA nephropathy. It is a disease that presents, typically, again in children, young children. It peaks before the teenage years. We can see it all the way to adults and even elderly populations. Patients usually present with a vasculitis rash. It characteristically presents on the extensor surfaces of the lower extremities, but, of course, it can spread further up. The rash is purpuric, just like with any other vasculitis. Those patients can have other systemic manifestations like arthralgias, occasionally arthritis. They can have GI bleeding from vasculitis in the GI tract. A subset of those patients will then go on to develop renal manifestations, and the disease in the kidneys is indistinguishable from IgA nephropathy. A pathologist will report IgA nephropathy, and it's only based on your clinical history that you can really distinguish a patient as having IgA vasculitis with nephritis, what we used to call Henoch-Schönlein purpura, or IgA nephropathy without any systemic manifestations.
You asked me whether these are separate diseases and from a pathogenesis perspective, we have data to support the idea that these are on the same spectrum of the disease. They have the same galactose-deficient IgA1 elevation, the same immune complexes, and so forth. We do think that there is something in the size or structure of the immune complexes that puts people on the path of developing IgA nephropathy vs IgA vasculitis. These pathogenetic differences are not completely elucidated.
Sparks: Is there something we can use in the blood to diagnose this? I know not now, but do you think in the future there might be?
Rizk: Yes, there is a lot of interest and work on biomarkers, both in the blood and in the urine. At UAB, we have been working for many years on the galactose-deficient IgA1 levels in the blood, as well as the autoantibodies. We think in the foreseeable future, we will have assays on the clinical side where you can hopefully use these two tests in combination to either diagnose somebody or follow them prospectively and decide whether they're responding to therapy or not.
Sparks: It's been a renaissance for IgA nephropathy and that's a reason why we wanted to have this discussion. Over the past 5 or 6 years, every time you open the journals, there's a new paper coming out and it's very exciting. As a clinician, however, with excitement comes a lot of options. Not knowing exactly when and when not to use different agents can be an issue. Can you walk through what you consider when seeing patients before we advance to immunosuppressive medications?
Rizk: Absolutely. When you evaluate a new patient with IgA nephropathy, it's important to look for negative prognostic factors. Things that would tell you that this patient will progress and, with time, develop end-stage kidney disease or kidney failure. Remember, these are young patients, so the peak incidence of the disease is in your 20s and 30s. You're talking about prognosis 10, 20, 30 years down the line. We know that people with hypertension are more likely to progress. People who have an elevated creatinine at the time of diagnosis are likely to progress. People who have proteinuria, and certainly > 1 g/d, are likely to progress. But even milder elevations in proteinuria seem to carry a negative prognostic factor, so maybe > 0.5 g are at risk. There are things that you cannot change. Male gender is a negative prognostic factor. There are probably other genetic factors. It's important that we counsel people about excellent blood pressure control and that we give them angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for blood pressure control. You want to make sure if they have any cardiovascular risk factor, just like with any patient with CKD. You counsel them about a healthy lifestyle, including a low-sodium diet. Once you've titrated all this up and people continue to have negative prognostic factors, specifically proteinuria, then you're looking at adding or layering on more therapies beyond just ACE inhibitors and ARBs.
Sparks: What is the importance of smoking cessation in this disease? Is there any link between cigarette smoking and IgA nephropathy?
Rizk: I mentioned cardiovascular risk factor modification and smoking cessation is one of them. There are data supporting the fact that smoking increases your risk of progressing to end-stage kidney disease or reduction in kidney function. When you talk about kidney disease in general, these are vascular organs and anything that can damage the vasculature will ultimately cost you nephron function and glomerular filtration rate (GFR). It's important that we counsel about smoking cessation as well.
Sparks: It's an additional incentive to stop.
Rizk: Yes.
Sparks: There are a couple other things that I wanted to touch on. We had a lot of discussion on the first series of talks on InDiscussion. It was on sodium-glucose transport protein 2 (SGLT2) inhibitors. At what point should you consider these?
Rizk: This becomes a little bit of the art of medicine. I do have colleagues that start SGLT2 inhibitors right off the bat. I would certainly consider SGLT2 inhibitors with somebody who has CKD, so any abnormal GFR, whether they're proteinuric or not. I will consider it if they have other comorbidities that also warrant the use of SGLT2 inhibitors. Remember, during screening, we're picking up people with IgA that may happen to have diabetes or may have congestive heart failure, or other indications.
Anybody who has persistent proteinuria despite being on ACE inhibitors or ARBs, all of these warrant the use of SGLT2 inhibitors. I do have colleagues who have almost all their patients with IgA on SGLT2 inhibitors right off the bat, and that certainly may prove to be the right thing to do. We have to balance this against not only the cost of the medication — to me, that's a minor consideration and if I can get them the drug, I will — but also importantly, young patients who have to take lifelong therapy. A lot of young patients, especially those in the high teens or low 20s, they're not eager to take medications every single day. In fact, there're probably more data in IgA specifically to your point from the DAPA-CKD and EMPA-KIDNEY trials, both of which enrolled a large cohort of IgA patients.
Sparks: One thing to always recognize is these weren't de novo diagnoses. These patients had a history of IgA nephropathy. That's correct?
Rizk: Yes, that is correct. Of course, they were not used in the context of immunosuppressive drugs either. There are other considerations as well. If you're going to start somebody on immunosuppression, for example, you may want to delay using SGLT2 inhibitors given the potential risk for infections, specifically the genitourinary infections.
Sparks: As someone who finished fellowship several years ago, we can't leave a discussion of IgA without discussing fish oil and tonsillectomy. Is that something you should or shouldn't do?
Rizk: There are two landmark trials for fish oil. One was the Mayo Clinic trial, the Donadio trial, published in 1994, that showed, certainly, benefit in the use of fish oil on slowing down kidney disease progression. It is worth mentioning that this trial was done in the pre-ACE inhibitor–ARB era. There was a different treatment, standard at that time. The 2009 Italian trial that looked at the benefit of fish oil, in fact, did show a reduction in proteinuria, but no benefit on GFR loss. A larger number of those patients were on ACE inhibitors and ARBs. We don't know if fish oil is beneficial nowadays.
To me, it's a fairly innocuous therapy. If people can manage to take it and it doesn't bother them and they want to take it, I tell them to go ahead and do that. They can stay on it lifelong. I have a discussion with my patients, and I leave it up to them. Tonsillectomy is an interesting concept. Again, the idea is that you're unloading or reducing this mucosal lymphoid tissue. As we talked about the mucosal kidney connection or interaction, it has mostly been shown to be beneficial in the Japanese population. It's almost invariably used on a background of steroids. It's a bit hard to tease out the effect of tonsillectomy alone, in the absence of concomitant steroid use. In the European population, a retrospective look at the very large VALIGA study, which is an observational study, did not suggest any benefit to tonsillectomy. We do not routinely recommend tonsillectomy unless somebody has recurrent tonsillitis and is in trouble all the time. In those cases, yes, we do refer them to ENT and have them evaluated.
Sparks: That was a fabulous discussion of supportive care. What a lot of the listeners are probably here for is some of these newer medications. As a segue to the immunosuppressive meds, we must give a little bit of time to discuss sparsentan, an endothelin receptor antagonist. Can you tell us about this?
Rizk: Sparsentan is a single molecule that has a dual action. It acts as an ARB and as an endothelin inhibitor. So, once you start somebody on sparsentan, you can take them off their ACE inhibitors or ARBs. Or you should take them off their ACE inhibitors or ARB. Endothelin inhibitors play a major role in perpetuating this kind of vicious cycle of inflammatory response to the immune complex deposition.
They also lead or promote fibrosis. It stands to reason that we would want to test them in not only IgA but potentially other kidney disorders as well. In the phase 3 trial, sparsentan was shown to reduce proteinuria quite significantly, which allowed the Food and Drug Administration (FDA) to give them a conditional approval or an accelerated approval.
Sparks: That's fascinating to see. We already have new drugs being approved. Let's talk about immunosuppressive drugs. Before we talk about the drugs, maybe you can tell the listeners a bit about when you should consider upping the ante and using either a steroid or another immunosuppressive medication.
Rizk: If you want to target just proteinuria, then you may go through the several drugs we already mentioned, like the SGLT2 inhibitors and the endothelin inhibitors.
On the other hand, there are patients who have immunologically very active disease and recurrent episodes of gross hematuria. Hopefully, we will have biomarkers that can distinguish these two phenotypes and will direct us to use immunosuppressants a little earlier in this subgroup of patients.
For the time being, I look at the patient holistically. For instance, if there is a young patient that has relatively new onset of disease where the biopsy shows a lot of inflammation, but not much fibrosis, I want to try to essentially hold the disease at its source, if you will, by using immunomodulating therapies or immunosuppressive therapy.
Sparks: Let's talk about prednisone first. Then we'll move on to some of the other agents. Prednisone is in a love-hate relationship with all of medicine, especially nephrology. We saw a series of publications, which are very confusing. You have STOP-IgAN and then you have, I called it TESTING high dose and TESTING low dose. How do you look at those clinical trials and put them into action for your patients?
Rizk: It's important to note that STOP-IgAN and the TESTING trials really recruited very different patient populations. In STOP-IgAN, patients had the disease for, many years before being recruited for the most part. The TESTING trial, on the other hand, recruited people who had an onset of disease closer to the time of enrollment.
So, potentially going back to this concept that they were immunologically more active with a lot of inflammation. They had a large subgroup of Asian population. In Asia, the disease tends to be more aggressive. Nonetheless, STOP-IgAN emphasized the fact that supportive therapy, everything we've discussed up until this point, is very important and may control the disease and obviate the need for steroids.
The second important point was that using steroids may be beneficial. However, we have to stop and ponder about the side effects and potentially fatal side effects of steroids that we tend to not think about when we're prescribing these medications. They had complications, of course, ones we expect, diabetes and fractures, and so forth. But they also had one death from sepsis, for example. The benefit does not seem to be sustained over the span of several years. This's a little discouraging. It seems like it gives you some short-lived benefit. Steroids are, as you mentioned, in a love-hate relationship with almost any disease.
Sparks: Thanks for that great summary. It is challenging to figure out whether we should use steroids. However, we have a new entry into this category, which is a different formulation of a medication that's been around for a while in the gastroenterology world called budesonide. There have been two clinical trials, NEFIGAN and NefIgArd, and it has achieved approval by the FDA. Can you tell us about this drug and how it could potentially have a lower side effect, but maybe not a completely nil side effect?
Rizk: As you mentioned, budesonide has been around for a long time. It's used in an inhaled form for asthma and things like that. It's certainly used in the GI world for inflammatory bowel diseases. Nefecon was actually encapsulated in a special capsule that allows the release of the drug at the level of the ileum. That's where you have the highest concentration of Peyer's patches, so presumably that's where you would have a lot of B cells that are producing this galactose-deficient IgA1. Hopefully, if you can modulate these B cells or suppress them at the mucosal surface, then you will have less circulatory galactose-deficient IgA1. You can see how you would change the face of this disease.
It's equivalent of taking a small dose of steroids. Below 10 mg is what the pharmacokinetic and dynamic studies suggest. The trial used the budesonide for 9 months and then tapered it off. It is not endless therapy. We don't know what happens if you use it over and over again, either — whether the cumulative steroid side effect would become more obvious.
Within those constraints, it did have a beneficial effect on proteinuria, which allowed the FDA to give it accelerated approval. More recently, the estimated GFR data seemed very promising. It did seem to protect against the decline in kidney function. The FDA is now reviewing these data to see if they should grant it full approval. The jury is still out on this part.
Sparks: That's exciting news to see, new studies and then a new drug that potentially could diminish the side effects. Some patients have a very aggressive form of IgA nephropathy that might have a lot of crescents and very fast presentation. What do you do in those patients? Is there any role for cyclophosphamide and mycophenolate mofetil (MMF) in treating them as if they have a full-blown vasculitis or crescentic glomerulonephritis?
Rizk: I'm going to leave the vasculitis aside because it was really excluded from all these trials. There're even less data to know or figure out what to do about the vasculitis component of the Henoch-Schönlein disease. For crescentic disease, if you have clinical evidence of rapidly progressive glomerulonephritis (RPGN), for example, you're rapidly losing GFR, those have been excluded from all these clinical trials. And so, you revert back to the data we have, which was published by Dr Tumlin, a colleague of mine. There is a case series of patients with RPGN from IgA nephropathy from crescentic IgA nephropathy. These patients are treated with steroids and Cytoxan. The subset of patients have IgA and overlap with minimal change disease or podocytopathy. These also warrant steroid use right off the bat. If you have nephrotic syndrome with IgA, you also go straight to steroids. These were excluded from all these clinical trials that we're talking about today. That's important to keep in mind.
Sparks: Tell us about MMF and IgA nephropathy. Is this something that is a potential drug to use?
Rizk: I would say “maybe.” There are data for MMF mostly in the Asian population, specifically the Chinese population, that show some benefit. In a randomized control study that looked at patients of European descent, it did not show any benefit to MMF. The jury is still out there for MMF. In the Chinese population, it showed reduction in proteinuria. But again, those were limited studies in a single center. There were a lot of limitations to it. I would say, “maybe” in a patient of Chinese descent, but again, with the word of caution based on the limitations of the data available.
Sparks: Speaking of limited data, the last real drug that I want to talk about is hydroxychloroquine.
Rizk: That's a very interesting concept. It's the same kind of idea. It blocks the toll-like receptor-9, which is involved in mucosal immunity. The study was very encouraging. Again, it came out of China and had limited data from a single center. The jury is still out, and it's too early to tell, but the preliminary results were supportive. We have to wait for more formal testing for the hydroxychloroquine.
Sparks: We talked about some exciting biomarkers that you're interested in and what you're excited about coming to the future. How about any randomized clinical trials that are currently ongoing?
Rizk: There are still lots and lots of clinical trials, which is great. I hope we continue to enroll our patients in these trials so that we have all these options available. Chances are you're going to need different treatments for different patients. If we put them in big buckets, some are looking at immunomodulating or immunosuppressing B cells, whether you do that by things like monoclonal antibodies against CD8, CD38, or whether you are using drugs that inhibit cytokines like BAFF and APRIL, which are important for B-cell maturation and proliferation. Another big bucket is complement inhibitors. As best we can tell, the alternative and lectin pathway are both involved in IgA and nephropathy.
The classical pathway is not. People are testing different drugs that inhibit either the alternative pathway alone, like a factor B inhibitor, for example, the lectin pathway alone, or the terminal complement cascade. We should keep an eye on those trials; they are very exciting. And then, there are more endothelin inhibitors, in isolation.
Sparks: We picked a great person to talk about IgA with, and it looks like a bright future. It's very exciting to have all these different opportunities to treat patients with IgA nephropathy. It's been a great discussion about IgA nephropathy with Dr Dana Rizk from the UAB. Thank you so much for joining us. It's been a pleasure.
Rizk: It's been an absolute pleasure. I hope to see you again to give more updates on upcoming clinical trials. Thank you for having me.
Sparks: This is Dr Matthew Sparks for Medscape's InDiscussion series on CKD.
Listen to additional seasons of this podcast.
Resources
Biomarkers for IgA Nephropathy on the Basis of Multi-Hit Pathogenesis
Galactose-Deficient IgA1 as a Candidate Urinary Marker of IgA Nephropathy
Immunological Drivers of IgA Nephropathy: Exploring the Mucosa-Kidney Link
IgA Vasculitis (Henoch-Schönlein Purpura)
Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors
Dapagliflozin in Patients With Chronic Kidney Disease
Empagliflozin in Patients With Chronic Kidney Disease
A Controlled Trial of Fish Oil in IgA Nephropathy. Mayo Nephrology Collaborative Group
Tonsillectomy in a European Cohort of 1,147 Patients With IgA Nephropathy
Intensive Supportive Care Plus Immunosuppression in IgA Nephropathy
Crescents and IgA Nephropathy: A Delicate Marriage
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Cite this: Does Your Patient Have IgA Nephropathy? - Medscape - Aug 24, 2023.
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