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.