Activity Transcript

Jonathan Barratt, FRCP, PhD: Hello, I'm Jonathan Barratt. I'm a professor of renal medicine in the Department of Cardiovascular Sciences at the University of Leicester in the UK, and a nephrologist at the John Wall's Renal Unit at the University Hospitals of Leicester NHS Trust in Leicester, the United Kingdom. Joining me today are Sharon Adler, who is an investigator at the Lundquist Research Institute at Harbor UCLA Medical Center, and professor of medicine at the Geffen School of Medicine at UCLA, Torrance, California, and Ellie Kelepouris, professor of clinical medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Welcome to you both.

Ellie Kelepouris, MD, FACP, FAHA: Thank you, good to be here.

Sharon Adler, MD: Thanks Jonathan.

Dr Barratt: Today, we are going to have a discussion around giving expert perspectives on strategies for improving immunoglobulin A nephropathy, or IgAN, care. So first of all, I just want to give us a little bit of background to IgA nephropathy. So IgA nephropathy is a common inflammatory kidney disease that's characterized by the deposition of IgA in the glomerular mesangium. It is the commonest form of primary glomerular disease, but even though it is the commonest form, is still a rare form of kidney disease.

Up to 40% of those people affected with IgA nephropathy progress to kidney failure within 20 years of diagnosis. This is particularly important because this disease affects young adults predominantly.

Most of those affected are developing kidney failure in their 40s or 50s. So early in life, with a lot of life ahead of them to have to cope with the challenges of either dialysis or living with a kidney transplant.

Until now, the standard of care has been the use of supportive measures. But today, what we hope to do is share with you different perspectives on the overall management of IgA and think about how this is changing and how it's going to change over the next 5 to 10 years with some very exciting new developments and new treatment approaches for this disease.

Before we can discuss the treatment of IgA nephropathy and all these new, exciting therapies. I think there's much more we need to discuss around the background of the disease. So first of all, Sharon, I wonder if you'd talk us through our current understanding of the pathogenesis of IgA nephropathy.

Dr Adler: Thanks, Jonathan. IgA nephropathy is now appreciated to be an autoimmune disease, and we can think about phases in the development of that autoimmunity in a process called the 4-hit hypothesis. It is thought that an autoantigen induces an autoantibody in the mucosal immune system. The initial response is an IgA1 autoantibody in the mucosal immune system, directed at an antigen. This initial IgA1 autoantibody is found to be under-galactosylated in a specific part of the IgA1 molecule that's called the hinge region. For those of you who aren't familiar with galactose, galactose is just like glucose except that a few carbon spots, the hydrogens, and the hydroxyl ions are flipped. So we have this aberrant galactosylation of IgA1 that is insufficient in and of itself to produce IgA nephropathy but is directed at an inciting antigen in a genetically predisposed individual.

Antibodies then, usually thought to be either IgG autoantibodies or sometimes IgM autoantibodies, are developed to the abnormal, under-galactosylated IgA1. These then combine to form nephritogenic circulating immune complexes, which ultimately deposit in the glomerular mesangium where they induce glomerular inflammation. Some may argue that there's actually a fifth hit, because once those circulating immune complexes deposit in the mesangium, complement is activated. It is the glomerular inflammation induced by cytokines and other inflammatory processes, and upregulation of inflammation by the complement pathway, that ultimately induces glomerular injury and progression of renal disease in IgA nephropathy. Back to you, Jonathan.

Dr Barratt: Thanks Sharon. I think that's a really beautiful description of the pathogenesis and I think that that really helps us understand, I think, when we discuss in a few minutes time the new therapies, because new therapies are specifically targeting each of these hits, aren't they? We've got therapies targeting the mucosal immune system, therapies targeting B cells, generating this pathogenic IgA. And we've got a lot of interest in therapies that are targeting complement activation. Because as you say, complement activation is that major factor driving inflammation and ultimately scarring in the glomeruli. So, it's really nice to see how our understanding of the pathogenesis has evolved, and that has led very nicely onto new targeted approaches for our patients.

Dr Adler: That's really, really nice because in the past our therapies, to some extent, seemed somewhat divorced from our understanding of pathogenesis. We're starting to unite pathogenesis and treatment.

Dr Barratt: Before we jump the gun, because I'm so excited for all these new therapies, I think we need to take a step back. Ellie, could you put the living with IgA nephropathy and the challenges of managing that into perspective for us? In terms of how common is this disease, who does it affect, and how do patients typically present?

Dr Kelepouris: Well, Jonathan, when I was a fellow, IgA nephropathy was really not thought of to be very pathogenic. It did not lead to renal disease long term, we didn't really know much about it. We know much more now about this. It is the most common primary glomerular disease worldwide. 45% of all glomerular nephropathies (GNs) are related to IgA nephropathy. It's most common in East Asian patients, it's common in Whites, and relatively rare in Black patients. There is a 2 to 1 female predominance in North American and Western European patients, but both sexes are equally affected among populations in East Asia. So it is very common and can present in many ways. It can present at any age, although normally it's in the fourth or fifth decade of life.

It could range from asymptomatic microscopic hematuria just incidentally discovered on a physical examination, to a rapidly progressive glomerular process. In children, it presents with gross hematuria, called Berger's Disease, sort of synpharyngitic. It follows a throat infection or an upper respiratory infection (URI), and that's commonly seen in children. There's also subclinical disease or intermittent microscopic hematuria, patients that do not have proteinuria.

So we're going to discuss how proteinuria really defines the prognosis of this disease, and in the absence of proteinuria, there's a slow progressive nephritic syndrome that can lead to chronic kidney disease (CKD), but it occurs long term. Less commonly we see nephrotic syndrome and rapidly progressive glomerulonephritis picture.

But before we assume that someone has primary IgA nephropathy, we obviously have to allow secondary causes such as chronic liver disease, celiac disease, HIV-associated, and other GN diseases as well. So the manifestations are varied, the predominance is very high, and a racial distribution is equal. And the diagnosis, really the gold standard, is established by a kidney biopsy. The biopsy will give us a MEST scoring index to define chronicity of the disease, which in addition to proteinuria, really does impact the long-term prognosis of renal disease and how it affects GFR.

We have at our disposal some tools that can help determine the prognosis of IgA nephropathy. And the KDIGO guidelines have taught us that 2 important questions to ask, and using this international IgA prediction tool, are: what is the estimated GFR at biopsy? And, what is the proteinuria at biopsy? Because, we know that GFR and proteinuria are the only validated prognostic biomarkers for IgA nephropathy. This tool is really very important to accurately risk stratify patients at the time of biopsy, and also add 1 or 2 years post biopsy, and I use it when I discuss the prognosis with my patients.

Proteinuria, as I said, really prognosticates IgA nephropathy. So the lower the protein in the urine, below 500 mg/d. I think the threshold for risk progression, is at 1 gram per day. We know from clinical studies, the lower the amount of protein in the urine, the greater the survival from renal failure, the higher the progression is when it occurs greater than 1, to 2, to 3 grams of protein per day.

What we know from clinical trials is that patients who attain partial, at least even partial remission, less than 1 gram of protein per day, regardless of how high their proteinuria was when they started, had a similar favorable outcome. So, the goal of therapy is really to reduce proteinuria to at least below one gram per day. Maximal protection is 500 mg/per day.

Dr Barratt: That's some really good practical advice in terms of what the current state of play is, in terms of what you're thinking about when you're seeing a patient with IgA nephropathy.

So if we come now to the assessment of patients with IgA nephropathy, we need to exclude secondary causes, we look at the kidney biopsy, we look at a prognosticating in terms of helping us advise on what treatment decisions we might make. Then we provide comprehensive supportive care. So Sharon, in your practice what does that entail?

Dr Adler: So, patients with IgA nephropathy need the same supportive care that patients with other glomerular diseases do. We want to target blood pressure management, with a systolic blood pressure less than one 120 mmHg if we can get it. First-line therapy should be maximally tolerated renin-angiotensin-aldosterone system (RAAS) inhibition -- can use either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in all patients.

Then we can think about diet. It's reasonable to restrict dietary salt intake to less than 2 grams a day, and/or to use diuretics. Some have advocated reduced dietary protein intake.

Fluid intake should range between 1.5 to 2 liters per day. A healthy lifestyle is also highly important. Smoking cessation, if you're dealing with a patient who does smoke, weight loss for obesity, and regular exercise as tolerated are all approaches that can help patients to feel better and ultimately do better.

Dr Barratt: We've been doing this for the last 20 to 30 years, to greater and greater degrees, but without anything additional to layer on top of this supportive care. So Ellie, how confident are you that even if the patient were to take all of these measures on board, you would be able to get their proteinuria down to less than 0.5 g per 24 hours consistently for the rest of their life?

Dr Kelepouris: In some patients, the minority of my patients, they can achieve this over a period of perhaps a year, but it's not consistent. There's tremendous relapse and just optimizing supportive care alone although it's a great first start, really does not decrease the risk of progression.

If you, of course, have optimal supportive care in addition to RAAS blockade, you do a little better. But the residual risk is still very high, 30%/40% residual risk for progression. So that really begs the question, what can we do better for patients with IgA nephropathy in the future?

The next step is immunosuppressive therapy for the next 6 months or so. That's a prescription that we teach with glucocorticoids and different other immunosuppressive medications, that is cyclophosphamide, hydroxychloroquine, etc., MMF, that is also being used. But these patients really almost never achieve complete remission, and very few of them achieve partial remission with current therapeutic interventions that I mentioned.

I think the future is now, because this is a field that has really exploded with new therapeutic interventions that give patients a better opportunity for longer renal life, as well as cardiovascular mortality.

Dr Barratt: You touched on some really important points there. Supportive care is good, but it has its limits, and we know even in the best clinical trial setting such as the STOP IgA study, patients still progressed. They progress more slowly, which is what we want, but they still do progress. When we're talking about 30- and 40-year-olds, that means they will end up on dialysis in their lifetime. So we desperately need additional therapies.

Sharon, we talk about a 6-month steroid regime or these other medications. How do your patients tolerate those treatments?

Dr Adler: Thanks, Jonathan. I want to pull back just a little bit because I think it's important to recognize that not all patients with IG nephropathy are progressors. There are some IgA nephropathy patients who have just microscopic hematuria and little or no proteinuria, they're going to do well. We see some patients who remain with small amounts of abnormal proteinuria, 200 mg a day, 300 mg per day. We want to regress those with supportive care, but for the most part many of those will do well. But about 50% or 60% of patients with IgA nephropathy are higher risk and it is those patients who we do have to provide with more than just optimized supportive care.

So immunosuppressive therapy: in the original TESTING-1 study from China, while there was benefit in terms of an anti-proteinuric effect of steroids and an effect on GFR, the risk of serious infections, including death from infections, caused the stop of that trial.

Patients don't tolerate steroids well, they got cosmetic effects, moon faces, acne, they may have changes in sleep, and even frank psychosis. So, steroids are not tolerated well, and they have significant medical risk.

Dr Barratt: That's certainly my experience in the UK, in terms of what patients are telling me. I think this moves us nicely onto the 2021 KDIGO flow chart that really places at the center of evaluation and treatment of these high-risk patients, consideration of a clinical trial. Because I think, we know there is some evidence for efficacy for some of the therapies we have available, but none of these therapies come risk free or are well tolerated for our patients. So there is a significant unmet need for new therapies, and thankfully we are being inundated with new trials for new therapies.

Dr Kelepouris: I think one of the most important moments in nephrology, actually in medicine, was the understanding and the identification that clinical trials with hard outcomes such as mortality, morbidity, slope of GFR, very important. Besides hard outcomes, patients really want to feel better. I have my patients come to my office honestly and say, "I don't want to live another 20 years, I just want to live well, for the lifetime that I have left." It really does center you really, as a physician.

So, I think the NKF IgA, Nephropathy Foundation of America, the voice of the patient is just really crucial, and should be part of every clinical trial design. When (patients were) asked "what are the 3 most important symptoms which negatively impact your daily life?" they really pointed to fatigue, as you mentioned, Sharon. Being tired, being exhausted, fatigue, not having time or the desire to spend time with their family, anxiety or depression. We can't lose sight of what the patients want, to feel better, they want to look better, they want not to take a hundred pills a day to control their blood pressure. So that's a very, very important thing to keep in mind when designing clinical trials.

Dr Barratt: I couldn't agree more. I think it's really important to understand what symptoms are being driven by disease and what symptoms we are giving the patient by giving them a treatment that we think might be advantageous, that actually makes their life less tolerable.

Also, I think it's important to recognize that it's not just the doctor, the nephrologist, a patient should be managed by the broader multiprofessional team. In the UK we have clinical nurse specialists who help run our clinics.

Dr Kelepouris: One of the key positions that we have in our multidisciplinary team for glomerular disease patients is the nurses, the advanced healthcare, providers, APP's, they really serve as patient navigators. The patients trust them, and they really are very savvy in helping patients navigate through their disease and giving the patients the tools that they really need for this shared decision-making. Having really highly skilled, trained nurse navigators is really very important to the mission.

Dr Barratt: We are now moving very much towards targeted therapies based on our understanding of pathogenesis, as Sharon so nicely described earlier in our discussion. So, when we think about supportive care, we actually have some new kids on the block. I don't know Sharon whether you want to talk about where you see sodium-glucose cotransporter 2 (SGLT2) inhibitors fitting in, not just to IgA nephropathy but to general kidney disease?

Dr Adler: Through its underlying effects on tubular glomerular feedback, SGLT2 inhibitors appear to have similar results in patients with IgA nephropathy, as in the initial diabetic kidney disease population. SGLT2 inhibitors, therefore, have been accepted under the umbrella of CKD treatment for IgA nephropathy, as an agent with acceptable side effects that can reduce proteinuria and reduce the progression of estimated glomerular filtration rate (eGFR) loss.

Dr Kelepouris: I think that the SGLT2 inhibitors, as you said, Sharon, are really revolutionizing the treatment of proteinuric diseases, both diabetic and nondiabetic. But again, even with max use in addition to RAAS blockers the residual risk is still high. So, understanding the pathogenesis of IgA nephropathy, we are being much more sophisticated in the use of other agents.

I think one of the most exciting advances in the treatment field, is really the identification that the endothelin pathway. There are endothelin receptors, CT-1, and obviously, angiotensin II receptors in the kidney, in the structural elements of the kidney that are filtration barriers to protein in the podocytes, and the endothelin-1 and angiotensin-II receptors are both modulators and are modulated by inflammation. There's a sense that the kidney with glomerular disease is in a high state of inflammation. There's podocyte cytoskeleton alteration, the cytoskeleton is abnormal filtration barrier breaks down, the tight junctions open up, and protein escapes into the urine.

To have agents that really block this cascade, and dual-acting agents such as the agents that block both the endothelin-1 and the angiotensin II receptors, are really exciting advances in the management of IgA nephropathy and in clinical trials. Sparsentan is a combination drug that has irbesartan in it ... and obviously has not been studied long term, but the FDA has really recommended conditional approval since February 2023, as an indication to reduce proteinuria in IgA nephropathy.

Dr Barratt: This is all really exciting, but fundamentally none of these agents will stop the deposition of IgA complexes in the kidneys or trigger the complement activation that Sharon was talking about.

The B-cell directed therapies I think are really interesting. We can target the mucosal immune system to reduce a mucosal IgA. There's data out now showing a clear antiproteinuric effect of that approach, alongside the 2-year eGFR data, which shows a persistent, protective effect on eGFR. Then we have those drugs in earlier phases looking at targeting APRIL and BAFF signaling, which again are starting to give some really interesting information and in particular causing significant reductions of GD-IgA1, the pathogenic form of IgA that Sharon mentioned.

So, we are going to have potentially the opportunity to target the production of the pathogenic IgA at source. But of course, what we also want to be able to do I think is target that inflammation that results from IgA immune complex deposition, and we know how important complement activation is there. So we now not only have good foundational treatment, we have treatments able to reduce the production of the pathogenic IgA.

We now have the opportunity to have a very strong and directed anti-inflammatory approach by using complement therapies, which means we could potentially avoid those toxicities of systemic steroids but really target the fundamentals of what's driving inflammation. So Sharon, what's happening in terms of complement therapies in the IgA nephropathy space at the moment?

Dr Adler: So complement therapy, or better said, anticomplement therapy, is really a very, very active area of investigation and there are 6 or 7 clinical trials that are currently recruiting to test whether complement inhibition will help patients with IgA nephropathy. Remember that the fundamental problem here is that we have circulating immune complexes in the mesangium causing inflammation, and that inflammation is driven, at least in part, by generation of the membrane attack complex in the mesangium which upregulates the inflammatory process.

Now, there are 3 complement pathways. The one that most of us of a certain age remember is the classical pathway, which was activated by circulating immune complexes. It used to be thought that IgA nephropathy did not activate the classical pathway because IgA doesn't bind C1Q, which is the initial binding factor that activates the classical pathway. Now it appears that there is actually IgG, anti-IgA1, in circulating immune complexes. And only some of that can be seen by our pathologist colleagues using usual immunofluorescence techniques.

So using nanoantibodies, IgG can be seen in a much larger number of patients with IgA nephropathy. So targeting the classical pathway, because IgG and sometimes IgM are involved in this process, makes sense. The lectin pathway is another pathway in which the abnormal carbohydrates are actually responsible for activating the pathway. So, mannan-binding lectin identifies these abnormal carbohydrates and activates the pathway. Notice that the classical pathway and the lectin pathway, once activated through independent processes downstream, uses both complement C4 and complement C2 in its ultimate activation of complement C3.

A third pathway also exists, that is the alternative complement pathway. As we sit around, our alternative complement pathways are usually kind of chugging along and active, and they are regulated by brakes called complement factor H and complement factor I. The alternative pathway can be super activated by endotoxin, otherwise known as lipopolysaccharide. The regulation of this pathway is importantly regulated by the complement factor H, complement factor I, and the factor H-related proteins. All of these pathways ultimately induce membrane attack complex that injures cells and tissues. So as I mentioned, there are 1, 2, 3, 4, 5, 6 active complement clinical trials. One that went through a phase 2 but isn't going to go through phase 3.

The active clinical trials are using medications that inhibit complement C3, that involves all the pathways, inhibits factor B, which involves the alternate complement pathway, inhibits MASS 2, that involves the lectin pathway, and inhibits complement C5A, which is an inflammatory molecule, which is a breakdown product of complement C5. Finally, a strategy to inhibit membrane attack complex (MAC) with a terminal MAC inhibitor. So, there are a number of strategies that attack activation of the classical pathway, the lectin pathway, and the alternative pathway. As a means of addressing that fifth hit, in the 4-hit hypothesis.

Dr Barratt: So, that's been a really great conversation today. I wonder, Sharon, if you could just give me some concluding thoughts about where you think IgA nephropathy might be, in the next decade.

Dr Adler: I think this is the most exciting time since Berger discovered IgA nephropathy. Because we are striving to develop drugs that relate to the pathogenesis that we understand causes progression of this disease and focusing on interventions with fewer side effects. So that the patients can control their disease and take over their lives in a positive way.

Dr Barratt: Ellie, what are you hoping for over the next decade for your patients with all the things we've just discussed?

Dr Kelepouris: Well, I'm hoping really that the trajectory of their disease improves and that their lives improve with these targeted therapies. I think it takes a village -- multidisciplinary care has never had a better platform, with the voice of the patient and new targeted therapies in place.

Dr Barratt: No, I couldn't agree more with both of you. It's not just about new therapies, it's about providing that holistic approach to patients who really, at a critical time in their life are given a diagnosis. At the moment, we really have very little to offer them and they're going to live with this diagnosis for the rest of their life. We want them to enjoy their life, we want them to achieve everything that they should be able to achieve in their life. We want them to put IgA nephropathy, hopefully, to the back of their minds and get on with their life, live with their families, with their careers, with their hobbies. So I hope the listeners agree with us, that we really are at the brink, I think, of something really special for these patients. Hopefully, we will be giving them a lot of hope for the future.

It's been a great discussion with both you, Sharon, and Ellie, and thank you for participating in this activity everyone who's listening to us. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.