Activity Transcript

Jonathan Barratt, FRCP, PhD: Hello, I'm Jonathan Barratt, professor of Renal Medicine at the Department of Cardiovascular Sciences in the University of Leicester and nephrologist at the John Walls's Renal Unit in the University Hospitals of Leicester NHS Trust in Leicester in the UK. Welcome to this program, Immunoglobulin A nephropathy, a call to action for personalized risk assessment and timely management. Joining me today, are Dr Rosanna Coppo, who directed for 25 years the Nephrology Dialysis and Transplantation Department at the Regina Margherita Children's University Hospital in Turin, Italy, and Dr Hong Zhang, who is a professor of internal medicine and deputy director of the Renal Division at the Peking University First Hospital and Peking University Institute of Nephrology in Beijing, China. Welcome Rosanna and Hong.

Hong Zhang, MD, PhD: Hi Jon.

Dr Barratt: So, what I'd like to do over the course of this session is really discuss with Hong and Rosanna how recent developments in IgA nephropathy can help us address some of the challenges that we face as nephrologists in managing patients with IgA nephropathy. And what I'd like to do is just kick off by talking through the recent high-level updates in the 2021 KDIGO guidelines for the management of IgA nephropathy.

And first, I am just going to talk to the algorithm for the initial assessment and management of the patient with IgA. So, we are given a biopsy. We see a biopsy, has an IgA-dominant glomerulonephritis. What are the things that we are thinking about when we are assessing that patient? So, the first thing is, have we thought about whether there are any obvious secondary causes for IgA nephropathy here? We are thinking about IgA vasculitis. We are thinking about IgA nephropathy related to other autoimmune diseases, such as inflammatory bowel disease, liver cirrhosis, or less commonly, but potentially in the right clinical setting, an IgA-dominant infection-related glomerular disease. Now if we are confident that we have excluded those potential secondary causes, then we can come to a diagnosis of idiopathic IgA nephropathy. And in that situation, the biopsy should be scored using the Oxford MEST-C classification, and then, in my practice and certainly KDIGO now recommends that we would risk-stratify that patient using the International IgA Nephropathy Risk Prediction Tool, and I will come onto that in a second. And the importance of doing that is that it allows us to have a personalized conversation with the patient about the likelihood of kidney decline over the next 5 years. And just to update you, we have a publication that is coming out that tells us that we can now use this tool up to 2 years after kidney biopsy, giving us outcome data 7 years in the future for patients with a recent diagnosis. The KDIGO guideline also suggests we should enroll our patients in a disease registry. And if we are fortunate to have one of those, that's important to help us to plan, research and understand disease progression, and of course then, the priorities to start treatment. And the best evidence we have is to start a program of goal-directed, supportive care, addressing lifestyle issues, risk, addressing cardiovascular risk, controlling blood pressure, and ensuring the patient is on the maximal tolerated dose of renin-angiotensin system inhibitor.

Now, if we think about the risk prediction tool, you can see here, the factors that go into that risk prediction tool. You can see the Oxford score, the MEST-C score is there. You can see that race is important in this tool, and I will touch on this with Rosanna and Hong in terms of the differences in the patterns of disease we see across the world in terms of the risk of developing IgA and the risk of progression. And you will also see there the proteinuria at the time of biopsy is a key factor in predicting outcome. And Rosanna is going to talk to us a little bit more about that in a few minutes. But you can see here the factors that go into allowing us to predict risk. And so, once we have instituted the basic maneuvers in terms of optimize goal-directed supportive care you can see here in this algorithm, we then need to reassess the patient's risk after being on stable, optimized supported care for a minimum of 90 days. If that patient has continued proteinuria above 1 gram in 24 hours, then they have identified themselves as being at high risk of progression. And here is where the challenge starts. How do we manage these patients?

Now, Hong is going to talk in her session on the new therapies that are becoming available. And I think that's exciting for us in IgA nephropathy. And now, my strategy for these high-risk patients is to put up my patients into clinical trials. And we have a number that we are going to hear about from Hong. If there is not a clinical trial or the patient does not wish to be involved in a clinical trial, then the decision to be made is whether you wish to try systemic corticosteroids. And here it is a very personal discussion with the patient, looking at the pros and the cons, the toxicity associated with systemic [cortico]steroids and the likelihood of benefit. And this is something that KDIGO stressed very highly, is looking at that risk to benefit profile for that individual patient in front of you. And in some situations, it may be appropriate to prescribe systemic [cortico]steroids and in others, it may not. We also need to consider there are specific racial nuances to treatment. In Japan, there is a lot of cohort data supporting tonsillectomy, and in China, there's data supporting the use of mycophenolate and hydroxychloroquine as potential treatments that have a particular impact in patients of Chinese origin. So again, we need to be thinking not only about the treatments we have, but also the patient in front of us on what is right for them. And so, coming on now, really to a discussion, I think Rosanna, this is very much driven by what we do in adults. How does this reflect what you do in children?

Rosanna Coppo, MD, FERA: Well, in children, the KDIGO targets as well as the proteinuria, but the threshold is lower, it is 0.2 grams per day for body surface area. And blood pressure should be targeted to the lower fifties per sex and age. But what is of paramount important to note is that the KDIGO guideline address this to a typical patient with IgA nephropathy without any variant, that means patient with a steady, progressive decline in GFR over time.

However, the International IgA Nephropathy Network clearly showed there were more than 5000 patients, but this is true for adults and not for children because children have trajectories of GFR over time, which are completely different with an initial increase in GFR for their first 2 years, then a plateau and then, it declines like the adults after the age of 18, 20 years. So, the fear of the pediatric nephrologist is to waste time waiting for the benefit of renin-angiotensin system inhibition alone and not for a stronger treatment.

And this is why the KDIGO produced the same similar recommendations and practical points for treatment of children. For instance, when a child has a renal biopsy showing active signs of disease, like an important messenger proliferation together with proteinuria higher than 1 gram per day, most nephrologists, most pediatric nephrologists would start a short treatment with [cortico]steroids in addition to renin-angiotensin system inhibition, instead of waiting for 2 or 3 months the beneficial effect of renin-angiotensin system inhibition. And this is important because the threshold for proteinuria is to reduce proteinuria below 0.2 gram per day in children.

Dr Barratt: That is great. Thank you, Rosanna. And to Hong, I would be very interested because when I have been to China, Chinese patients with IgA nephropathy are very different to the types of patients I see in Leicester, in the UK. So how do these guidelines relate to your clinical experience in China and what are the nuances that perhaps come out when you are managing your Chinese patients?

Dr Zhang: So, thanks, Jon. I think since the KDIGO guideline was first released in 2012 and updated in the last year, it is already 10 years. So, most of Chinese nephrologists are aware of this clinical trial guideline and treated the patients according to the guideline. As Rosanna already said that in IgA nephropathy with the highly pathogenesis in clinical and the pathological features, and it may differ in different populations. In China, it shows more active patterns and more so with the high risk. So, I would like to show you the clinical and the pathological figures in IgA nephropathy in different readings.

Let just focus on the data from the 2 large multicenter IgA cohort that is the European validation cohort. Another is a Chinese Oxford validation cohort, both with the more than 1000 patients. And compare with the European patient, the Chinese patient's biopsy showed more active lesions. That is 43% with M1 lesions in Chinese patients, but only 28% with M1 lesions in European [patients]. And on the other hand, nearly half of the Chinese patients had a crescent forming, but the European only 11% of the patient have the crescent on the renal biopsy. This data show that active lesions are more commonly observed in Chinese patients. That is why maybe in Chinese patients we use the corticosteroids and the immunosuppressants more often. My point is that the approach of the management in IgA nephropathy may differ geographically.

Dr Barratt: Thank you. And now Rosanna, you are going to talk to us about proteinuria and why it is important.

Dr Coppo: Yes, we know very well the typical answer to IgA nephropathy with gross hematuria following upper respiratory tract infection, or the persistent microscopic hematuria and minimal proteinuria. However, from the natural history and the progression of IgA nephropathy, we see a minor role of microscopic hematuria and a major role of proteinuria. This proteinuria in IgA nephropathy is due to the reaction of podocytes to inflammatory mediators, which are released by messenger cells or by infiltrating cells or can be due to hyperdynamic changes with glomerular hyperfiltration. However, whatever produces this proteinuria is a most relevant risk factor for progression in renal biopsy as reported more than 25 years ago by the similar study from the major clinic. However, more than proteinuria at renal biopsy, what is relevant as a risk factor for progression of IgA nephropathy is the persistence of proteinuria over time.

The so-called time average of proteinuria is demonstrated for the first time by the Toronto Glomerulonephritis Registry. And indeed, according to KDIGO 2012 or 2021, [patients with] IgA nephropathy deserving treatment are those with persistent proteinuria higher than 1 gram per day, despite renin-angiotensin system inhibition. And indeed, from our VALIGA cohort that gather more than 1000 patients from 13 European countries, we found that when proteinuria was reduced below 1 gram per day during the follow-up, there was a significant better outcome in comparison with patients with persistent proteinuria higher than 1 gram per day, despite the different treatments independently from a treatment with renin-angiotensin system inhibitors alone, or the addition of [cortico]steroids. And this was found in a propensity score matching population.

More recently, the International IgA Nephropathy Network focused on the duration of reduction of proteinuria that is remission. Indeed, about 4000 patients with IgA Nephropathy, 1800 had the proteinuria remission over the follow-up. That means that they had proteinuria higher than 1 gram in the renal biopsy. And then proteinuria was reduced by 25% and to values less than 1 gram per day. And this full remission often lasted 4 years. The study showed that patients affect ed (15%) who experience the unfavorable outcome, showed a steep reduction in the risk associated with longer duration of remission, particularly in the initial years. Indeed, each 3 months of sustained remission up to approximately 4 years, there was an association with an additional 9% reduction in the risk of disease progression.

And this study from Inker included the meta-analysis of different trials with different interventions in IgA nephropathy. And showed that greater reduction in proteinuria was consistently associated with lower progression of IgA nephropathy across all the interventions. And more recently from meta-analysis of individual data, 1037 patients from 12 randomized trials, they confirmed a relation between the treatment effect on urinary protein reduction and the treatment effect on GFR slope, at 3 years and chronic slope [for urine protein level at 6 months]. And they concluded that the treatment effect of approximately 30% reduction in the proteinuria would confer probabilities of benefit on the slope of GFR, and a reduction in proteinuria so early as after 9 or 12 months was significantly correlated with the results in GFR slope at 2 years. On this basis indeed, proteinuria reduction is considered a surrogated point for trial of IgA nephropathy. Thank you, Jon.

Dr Barratt: That was useful. Thank you, Rosanna. And again, I am going to touch back because a lot of this is based on adult data. Is proteinuria, as relevant in children? Do pediatric nephrologists look at this in the same way that we do?

Dr Coppo: Well, it is a good question because indeed in children, they have frequently such an acute disease, which is in part possible regression, that there is no significant correlation between baseline proteinuria and the subsequent outcome. The better results are on a persistent proteinuria in children as in adults. So, while in adults, the baseline initial value of proteinuria is a significant risk factor which can allow stratification of patients in it for treatment. In children, this point is different, at least when they have an acute onset.

Dr Barratt: And you showed very nicely in your study that reducing proteinuria with a renin-angiotensin system inhibitor in children is as effective at reducing proteinuria and long-term outcome, haven't you?

Dr Coppo: Sure. We must target too persistent proteinuria, and we must consider that in children, the threshold to consider that we have the effect is to reach proteinuria values below 0.2 gram/day/body surface area, so lower than in adults.

Dr Barratt: Thanks. And Hong, I think it is very clear from Rosanna's presentation how important proteinuria is both in assessing response to treatment, but also stratifying your patients. And did you use proteinuria in that way in your population, in terms of how you manage your patients?

Dr Zhang: So, I already described the Chinese patients who are high risk. We are not talking about the special issues with IgA nephropathy with rapidly progressive glomerulonephritis (RPGN) or acute kidney injury (AKI) in the context of nephrotic syndrome (NS), but for most of the patients with the gradually progressive IgA nephropathy, these patients, so firstly, we, according the KDIGO guideline, treat them with supportive care with RAAS blockade. So, I just give an example for the testing study. When we are screening for the recruitment, half of them is screening failure, but in this half, half of them is because the RAAS blockade reveals protein less than 1 gram, so that is our ratio.

Dr Barratt: Thank you. And now Hong, you are going to take us through the emerging therapies that are targeted to our improving understand pathogenesis, aren't you? So, please go ahead.

Dr Zhang: Thank you. So, as we all know that IgA nephropathy showed highly variable clinical and the pathological presentation, as well as progression, but as you know, the mechanism responsible for the presentation and the development of IgA nephropathy are not completely understood. And that is and has limited us to treat the patients with highly targeted therapies. So, I will show the slide that highlights the well-adopted multi-hit pathogenesis model for IgA nephropathy, especially that hypothesis free approach of GWAS [Genome Wide Association Studies] from Wyatt to provide novel insight in understanding the disease pathogenesis. This slide, identified by GWAS, highlights several pathogenic pathways, including regulation of mucosal immunity and IgA production and antigen presentation, adaptative immunity and the complement activation and the new pathogenesis model for IgA nephropathy was proposed. So based on the proposed pathogenesis, some potential therapeutic targets are listed in this slide that includes the immunomodulation that targets release of budesonide in the gut mucosa. A trial in phase 2 already completed showed that it reduced proteinuria significantly. And the phase 3 trial is ongoing. And targets the BAFF/APRIL motivating B-cell activation, targets the proteosome inhibitors motivating the PB cells, and includes inhibitors of the immune complex formation and deposition such as the corticosteroids, spleen tyrosine kinase inhibitor and IgA1-specific proteases. So, another important pathway targets the complement modulation system, that is including the alternative pathway inhibitor and the lectin pathway inhibitor, as well as the C3b and the C5a inhibitors. More recently, the atresentan and the sparsentan, which are endothelin type A receptor antagonists with clinical trials also conducted in IgA nephropathy. These potential therapeutic targets shed a new light for effective and well tolerant therapy in IgA nephropathy and to prevent or slowing the progression to IgA nephropathy. But I think with our increasing understanding of the pathogenesis of IgA nephropathy, the treatment will be more targeted.

I also want to show you that some ongoing nonsteroidal-related clinical trials in IgA nephropathy and some trials in phase 2, some trials in phase 3 that will be completed soon. So, we expect these novel agents to achieve the efficacy and the safety results. On the other hand, regarding multi-hit pathogenesis, there is a theory. I think we may expect that the relative important of each hit may vary in different population, even in different individual. And this variation may underline the differences in the presentation and the progression of IgA nephropathy. So, for the personalized medicine in IgA nephropathy, we may base on 2 ways. That is, one is the therapeutic strategies based on the proposed pathogenesis and the potential targets of which we have discussed. On the other hand, the therapeutic strategy based on the stratification of progression risk by clinical and the pathological presentations. I think, novel paradigm of treatment likely to appear in the next few years.

Dr Barratt: Thank you, Hong, for a great overview. And I think it is exciting to look at all the potential therapies that are coming. And you know, we have very little to choose and in potentially in 5 years’ time, we may have lots of drugs to choose. So how are you going to decide if we have complement inhibitors, if we have steroids, if we have drugs targeting BAFF and APRIL, and we have other therapies, how are you going to make the decision about what treatment is right for which patient? What do you need to be able to do that?

Dr Zhang: We already know the risk factors of the IgA nephropathy. So, we depend on the clinical and the pathological presentations. I think firstly, according to the guideline, we select the high-risk patient with the clinical trial, especially for these novel agents, but in my opinion, different targets may work on different populations. Well so far, the ongoing clinical trials cannot get conclusion yet. So, I think after we get some evidence from clinical trials, we may. So recently, the current clinical trial is a general way of screening the patient, just for the clinic high-risk patient, it is not mechanism based. So, I think that is another way for answering this question.

Dr Barratt: Thank you. Thanks very much. And Rosanna, one of the challenges I have is that I would really like to have a biomarker that could tell me what is going on in the kidneys rather than having one kidney biopsy. And 2 years down the line, still wondering what is happening in the kidneys now to help me choose. Do you think that we are going to make headway with biomarkers over the next few years?

Dr Coppo: That is a very good question. I think you are right. Indeed, there are some data from recent literature. For instance, the work published concerning the role of watching at macrophages population in the kidney biopsy and some new biomarker and then, NCD 206 and NCD 68 are correlated not only with the activity of the disease, but with the response, the clinical benefit of [cortico]steroids. So, I think that looking at this biomarker complement is another very relevant biomarker. We can look at not only at C4D but all the tool and other complement factors in renal biopsy, and the quantification of complement activation and the identification of different pathways of complement activation, together with signs of activity. For instance, the macrophage infiltration, so we can provide very useful data for stratified patient because I agree with Hong, what is of paramount important is to select the right patient for the right treatment. This is what is really the unmet goal now.

Dr Barratt: And taking that one step further, where do you think these drugs will fit with children? How are you going to select children? Do you think children are suitable for all these treatments or are there some treatments that are more appropriate for pediatric IgA?

Dr Coppo: In my opinion, it depends on the phases of the disease because in general, you can have 2 conditions, 2 clinical situations in children. One is an acute disease with a possibility of progression. And in this case, indeed having something in addition to [cortico]steroids may be useful because not all children had a good clinical response to [cortico]steroids. So anti-complement, for instance, may be of paramount importance. And the other condition is when there is microscopic hematuria and the persistent proteinuria, which is increasing over time. So, at that point, anti-proteinuric drugs may be relevant for instance, the targeting not only angiotensin system, but also endothelin. But in the meantime, having something modifying the mucosal immunity may be the clue for treatment in children in early disease, which can be strongly modified by a correct pathogenetic approach.

Dr Barratt: Thank you. So, we are coming to the end now, and I am just going to task each of us to produce a take home message for the audience. And my take-home message is that this is the golden age of IgA nephropathy. We have great advances in risk stratification. We have new therapies being evaluated. But the key for me, as we have just touched, is we need to get those biomarkers to help us make clinical decisions, to give the right drug to the right patient at the right time. And so, that is the area I really want to see growing over the next 5 to 10 years. So, Hong, your take-home message for the audience.

Dr Zhang: So, my concern is that IgA nephropathy is highly heterogeneous, so with our increasing understanding of the pathogenesis of IgA nephropathy, I think we will end up and already have some treatment strategy based on the target treatment, that personalized treatment is our goal, but we need evidence based on the well-designed clinical trial to prove the efficacy and the safety of these novel agents.

Dr Barratt: Thank you, Hong. And Rosanna?

Dr Coppo: My message is for children, please consider that IgA nephropathy in children is a progressive disease. It is a potentially progressive disease, which will take may be decades, but it is progressive. So, we must consider that children should be careful monitored when their proteinuria is higher than 0.2 grams per day for body surface area. Even though it is an older biomarker, it is still valued from the practical point of view to see if we are to take particular care of these children. New treatments will be for sure open to treatment of children, but we must consider them at risk. Even when from the clinical point of view, the disease seems too easy tolerated.

Dr Barratt: Thank you very much. So, Rosanna and Hong, thank you for this great discussion, and thank you for participating in this activity. Please continue to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.