Welcome to KD GO Conversations in Nephrology. This episode titled Treatment Revolution in IGA Nephropathy is provided by KD Go and supported by Trevir. Here's your host, Doctor Donna Rizik. Hello and welcome to KD Go Conversations in Nephrology. I am Doctor Dana Raziq, I am a professor of medicine in the Division of Nephrology at the University of Alabama at Birmingham, where I also serve as the Associate Dean for Clinical Trials Research for the School of Medicine.
Joining me to discuss the latest updates in IJN treatment is Doctor Shika Wadhwani. Dr. Wadhwani is an associate professor of medicine at the University of Texas Medical Branch, and her clinical and research interests center around glomerular diseases. Dr. Wadhwani, welcome to the podcast. Thank you, so happy to be here.
It's a pleasure having you. So today we're going to discuss the treatment revolution that we're witnessing in IGA nephropathy and understanding how the IGA nephropathy pathophysiology contributed to this revolution. So let me start by asking you, how has the IGA and treatment paradigm changed since the KD GO 2021 guidelines were published? Yeah. So it's kind of incredible. You know, so much has changed in just four years. And I think prior to this, not much movement had happened in
this field. And now we're at a place where there's really been like a seismic shift in the treatment paradigm really based on our improved understanding of the disease, the risks associated with the disease, and as we're all excited about new available treatment options. So, you know, for decades the focus has really been on the effects of the disease, which we really collectively called
supportive care. And we would only resort to immunosuppressive therapies such as corticosteroids in those patients who did not have a proteinuric response to those supportive measures and remained at what we called high risk. In the past, we thought that threshold was greater than a gram per day of proteinuria, But as you know, the 2021 KD GO guidelines were an update to the 2012 guidelines.
And so much has changed in this field since 2021 that there has been a need for a major update, given the trial successes, which really led to the availability of therapies that now target not only the consequences of nephron laws, but also the drivers of the disease. Yeah, absolutely. Then it sounds like these updates may start coming more frequently, which is wonderful. So how did understanding the pathophysiology of IGA nephropathy contribute to this
therapeutic revolution? You know, I think that's a really important piece of this. And really I think better understanding the disease pathogenesis reframed how we think about our therapies and moved us from kind of a generic way of treating everyone the same to really being able to target specific hits in the four hit hypothesis of IGA nephropathy, which we're all becoming much more familiar
with. So when we think about a genetically susceptible individual, it's really felt that IGA nephropathy is initiated by increased production of pathogenic Galactus deficient IGA one in response to some sort of environmental or infectious
trigger. And we collectively named that hit one and then that antigenic GD IGA one is then recognized by anti GD IGA one auto antibodies and that piece of it is called HIT 2. And then the GD IG1 and the auto antibodies combined to form immune complexes, which we call HIT 3. And those immune complexes go and deposit specifically in the mesangium of the glomerulus,
which is that fourth hit. And that's when we get the glomerular inflammation complement activation and subsequent damage to our glomerular capillaries, which leads to the hematuria and proteinuria that we can detect in clinic and you know sets off our protocol for evaluating that patient, getting a kidney biopsy, et cetera.
So I think now that we are able to think about this disease from this sort of four hit hypothesis, we are able to then say, you know what, we we don't just need to address one part of this hypothesis. We can really look at targeting specific hits. We can look to maybe combining therapies and trying to target multiple hits so that we can hopefully have greater success. And I think that's what we're seeing with the recent clinical trials.
That sounds great. So if you're just tuning in, you're listening to the KD GO podcast on treatment revolution in IGA nephropathy. I am Doctor Danner Zuk, and I'm speaking with Doctor Shika Advani. So Shika, with the larger armamentarium of available therapies that you just alluded to, what are some of the factors to consider when selecting specific agents? Yeah, this is a great question and it's one that many of us in this space are really fielding regularly.
I think that just like with any other condition, we have to weigh risks versus benefits and actively engage our patients in these decisions. So I think that's the number one thing. So there's no one-size-fits-all therapy plan, especially when it comes to treating a disease with not only heterogeneity in terms of the presentation of the disease, but also in terms of disease course and prognosis.
So we now have the luxury of having observational registry data from multiple large international cohorts, which all point to the fact that again, patients have a very high lifetime risk of kidney failure even at proteinuria levels that were traditionally thought to be safe or low enough.
And we know from these studies as well as our recent randomized control clinical trials that patients who were treated with Ras inhibition alone actually have significant GFR decline even just in nine months, which is at the time of interim analysis for phase three trials currently.
So we've learned that in order to truly avoid kidney failure in the lifetime of our patients, our patients need to be able to reduce the rate of kidney function loss to around 1ML per minute per year GFR, which is essentially that of the normal population after the age of 40. So to me, anyone who presents with proteinuria over 0.5g per gram needs a kidney biopsy to first of all definitively diagnose hygiene nephropathy and
then initiate treatment. So I think the paradigm is really shifting to thinking about simultaneously addressing consequences of nephron loss and drivers of disease simultaneously. And so that means that we're sort of automatically considering a multi targeted therapy regimen. And just like with other autoimmune diseases we treat, I think we're really shifting our concept of what is standard of care.
So when I think about this and I think there's a lot more that we need to learn about the new therapies and real world evidence is of course going to be extremely helpful in addition to the trial data. But patients who have a very high degree of proteinuria have declining GFR, or some people may think about, you know, an inflammatory phenotype on a kidney biopsy. Those may be patients that are more likely to be prescribed immunomodulatory therapies.
But in many ways, this is really a reactive rather than a proactive approach. And some people would argue that all IGA nephropathy patients should be offered immunomodulatory therapy to really prevent disease progression and not just sort of cover up the problem that we've already discovered. So the choice between therapies that target the earlier hits and Igan pathogenesis is
challenging. And part of that is because the patients enrolled in the recent trials are pretty similar and also because the published analysis we have thus far has not shown that certain and subgroups seem to respond, while others do not. It's also important to note that patients in the recent trials were not enrolled at the time of biopsy. So it's really difficult to make any suggestions based on kidney biopsy findings in particular.
And that's something that comes down to conversations between the nephrologist and the patient.
But I really think that ultimately the decision of what therapies to start with will come down to what's accessible in that particular country, province, and whether the patient has any particular preferences regarding the mode of delivery, potential side effects, etc. Right. So it goes back to the conversation, the one-on-one that you have with your patient when you see him or her in clinic, no question about that.
So what are the roles of the traditional therapies, the non pharmaceutical lifestyle, non systemic steroids therapies in the context of these new agents? So we've relied so far on lifestyle modification, last inhibition as you mentioned and then systemic steroids when needed. What? What are the role of these traditional therapies in this new world? Yeah. So, you know, I think when we have better and we know better, we should do better.
So we of course always need to educate our patients on blood pressure control, you know, focusing on a healthy low sodium diet, weight loss as applicable. But I don't think we should be complacent and I think we need to instead be willing to gain experience with new therapies and someone who really focuses
their career on clinical trials. In my new role at my job, I also want to put a plug in for continuing to enroll patients in clinical trials so we can hopefully have even more treatments available for our patients in the future. So I'm not saying there's no role for traditional therapies, but I think that we owe it to the many, many participants in clinical trials who got us to where we are today to really utilize the new drugs we have so desperately been hoping we could
offer our patients. Finally. So as you know, there was not a head to head trial comparing TRF budesonide to systemic corticosteroids. But depending on, you know, where you are and whether the former is approved and accessible and affordable in that particular country or province, I do think that nephrologists may prefer the TRF budesonide due to perceived superior side effect profile and perhaps also beneficial local
inflammatory effects. So I think there's definitely a movement in that direction, especially because we know all the terrible side effects that come with systemic corticosteroids. On the other hand, we also now have a, you know, a dual endothelial angiotensin receptor blocker which is sparsentin and that was studied against an
active comparator urbisartan. And there was a clear benefit on proteinuran EGFR with this sparsentin, which probably makes it, you know, a better choice in patients who have access to and can tolerate this new drug given it was compared directly to maximum dose Ras inhibition. And then we of course we have
SGLT 2 inhibitors. We have two large scale trials that included a significant number of IGA nephropathy patients and they saw similar benefit over placebo in those patients with IGA nephropathy just like they did in the rest of the cohort. So in patients who have IGA nephropathy and decreased GFR at presentation, I do think that most of us would agree that there is definitely a role for SGLT 2 and inhibitor therapy. And then the story doesn't stop
there. So we now have complement inhibitors, anti April or April bath therapies and plasma cell therapies that are all in phase three clinical trials. So we will definitely be keeping our KD GO friends very busy updating the guidelines in the upcoming years because I think there's a lot more to come. Yeah, absolutely. And these are, you know, living, breathing documents that need to be updated as new data is generated.
So before we close Shika, are there any final messages you'd like to leave with our listeners? Yeah, thanks. So I think, you know, as many of us say these days, we're truly in the midst of a revolution in Igan. And this is really due to decades of global research by groups like your own and as well the landmark success in the Kidney Health Initiative, which established endpoints for clinical trials in IGA and
nephropathy. So there are, in my opinion, far too many people with this disease ending up needing dialysis or a kidney transplant. And we have to remember that these patients are typically diagnosed in their 20s and 40s, which is very, very young. So in my mind, you know, my message is let's seize the moment, let's shorten the time
to diagnosis. And then once we have a diagnosis, we really need to change our mindset to start with a multi targeted approach to this disease and eliminate any sort of therapeutic inertia we may have. And then above all, I think we need to continue to ensure we're engaging our patients in these discussions by educating them and really understanding their goals of care. Thank you so much, Doctor Shika Wadwani, thank you for joining me. It was great having you on the
podcast. Thank you so much, Donna. It was lovely to be here. I am Doctor Donna Rizuk and to access this and other episodes in our series, please visit kdgo.org/podcast. Thank you so much for listening and until we meet next time.