Welcome to KD GO Conversations in Nephrology.
This episode titled Challenges of implementing evidence based
Guidance for IGA Nephropathy is provided by KD Go and supported
by Trevier. Here's your host, Doctor Donna
Ryzik. Hello and welcome to KD Go
Conversations in Nephrology. I am Doctor Donna Ryzik.
I'm 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 Trial Research in the
School of Medicine. Joining me today to discuss the
challenges of implementing evidence based guidance for IGA
nephropathy is our distinguished guest doctor, Sunil Udani.
Dr. Udani is a consulting physician at Nephrology
Associates of North Illinois, also known as Nanny and medical
director of Nanny Research. His clinical and research
interests include glomerular diseases and cardiorena
syndrome. Doctor Udani, welcome to the
podcast. Doctor Ryzik, thank you so much
for inviting me and having this conversation.
Great. So Sunil, I know of course you
are aware of the updated KD GO guidelines.
And so my first question to you today is what are the most
significant challenges to adopting these guidelines in
your practice? As you well know and has been
outlined, you know this is a rapidly evolving time in hygiene
nephropathy and the guidelines that have been just been updated
are quite recent and we know there's definitely always a lag
between them being published and then you know global awareness
especially in the community nephrology space.
So I think the first step is awareness and awareness of the
specific changes that have been highlighted.
The first being the partner threshold and that you really a
much lower partner threshold than we are previously used to
or previously had been targeting has been outlining the
guidelines to really getting down to as low as possible.
If you can get under 0.5g per gram ideal, but you know, really
as low as possible as opposed to simply being OK with the UPCR of
you know, 1g or is slightly below.
And the second thing I think is a key thing that'll be a new
change in the guidelines is the idea of simultaneous therapy of,
you know, multiple targets of they're treating renal
protection with our conventional agents such as Ras inhibitors,
SGL 2 inhibitors as well as endothelium receptor antagonists
while also treating the immune and inflammatory nature of IG
nephropathy. This is a very different concept
than that was previously outlined.
And I think, you know, disseminating this information
is going to be the first key. It's also a shift in the
paradigm and nephrologists are not used to, and I was
comfortable with implementing multiple therapies at once.
There are certain disease states where we've done this, you know,
lupus nephritis perhaps, and certainly in the transplant
arena we've done this, but not for IGAIGA.
It's been trying to find a single therapy that is an
effective or a single therapy that's been helpful.
We know that's you know, with the advent of multiple new
therapies available demonstrating reductions
pertinaria or preservation of renal function and knowing the
natural course of this disease being quite severe for young
people in terms of an expectation that they will
progress to NCH kidneys ease. We know that this sort of multi
targeted or simultaneous approach and treating the the
whole aspects of IG nephropathy become key.
So I think it's definitely a hill that nephrologists have to
sort of climb in terms of their understanding, their adoption,
integrating that into their not only their cognitive approach to
IG nephropathy, but their day-to-day therapeutic
interventions. Yeah, absolutely.
And you mentioned changing the therapeutic goal of proteinuria.
As you mentioned, the bar is much higher and we try to target
lower and lower levels of proteinuria.
And I think the guidelines also for the first time kind of
recommend performing a kidney biopsy to diagnose the disease
once you see a proteinuria of .5g per day, which was not
really spelled out in the previous guideline.
So again, increasing hopefully detection of the disease at an
earlier stage. I think we've been so complacent
with our approach because we thought there was nothing to do
or at least the things that were available, IE glucocorticoids or
conventional suppression like cyclophosphamide, they'll prove
the previous guidelines really highlighted that we should move
away from those because of the toxicity.
And so there was I think the people exactly to your point
that people would .8g per gram or you know, right around one
that had microscopic hematuria, they said yeah, we think
asidegian nephropathy, we're not going to do anything
differently. We're going to treat with RAST
inhibition etcetera. And so we didn't make a
definitive diagnosis, but I think, you know, I'm, I'm hoping
that it's not just IGA that changes with this, but really a
global direction of, you know, really defining kidney diagnosis
more precisely so that we really can then provide the specific
recommendations for patients that help them.
Yeah, I couldn't agree more. So there have been a flurry of
new clinical trials and new therapies as we just mentioned.
What are the key learning points that we can take away from the
clinical trials in IGNF property, their design, the
outcomes? And you know, conversely, what
key knowledge gaps have been also highlighted in adopting the
new classes of therapy? Yeah.
It's such a great time in terms of the evolution of trials and
therapy. And I think naturally one of the
key steps and as you were, I'm sure involved with this idea of
looking at print nerve reduction as a surrogate outcome for
kidney protection. And the idea of the FDA adopting
that through the partnership between KHI and industry and and
ASN and the FDA that allowing for an accelerated pathway of
approval. And then of course then waiting
for the two year data to get confirmation.
And what we've seen really so far to date is that that is
translated over each time the protein air reduction that's
been achieved has also translated into preserved kidney
function. So it's reassuring to see that
surrogate outcome that has been sort of accepted is
demonstrating a better validity. I think the other sort of stark
reality that we've seen is what happens to folks in the control
arms, in particular the degree of GFR loss.
And I think it's again, easy to overlook in these young folks
with fairly well preserved kidney function, oftentimes at
diagnosis and even, you know, as we're seeing them, but they are
when we look and, and it you know, it's certainly in the
clinical trial set and we can see they're losing 5ML per
minute per year in the control arm variable.
Of course, it's been a harsh reminder of the Natural History
of the disease and why it's so important for us to act.
I think it's a couple other things have been notable.
I think it's been great that the more recent trials are allowed
for SGL 2 inhibition and in addition to Ras therapy.
So I think it's told us two things, you know, 1 is that the
use of SGL Geneva is more helpful does not providing our
treatment as their overall people still need specific
therapies for IGN nephropathy, but it hasn't attenuated the
benefits either. Also, it's been key that there's
been a wide variation in terms of where people are in the
disease state where I think that the idea of complacency and
saying oh, this person had a biopsy five years ago, they have
this much protein area. These are folks that are
enrolled the trials and then they're still eligible for these
new therapies that are becoming about.
There certainly are unanswered questions though, as you alluded
to. I think, you know, first is what
happens when patients, you know, are freshly diagnosed really,
you know, these are patients that have had an established
diagnosis. Usually the by the time they
have diagnosed, they've had to have established disease.
They've run through at least supportive care.
So what about patients that are newly diagnosed?
What's the role of these therapies upfront as opposed to
going through our conventional markers of RASA vision 1st and
sort of watchful waiting? We have not had at least to date
more information on which subtypes in terms of biopsy for
histological classifications, Oxford classifications may
respond to different therapies and you know really how long
those therapies need to be maintained.
The trials are all fairly similarly designed of two year
trials of open label extensions. And so we know at least that's
how long people were on the trial and how long to be on
therapy. But is there an endpoint?
And I think we don't know yet. And naturally patients want to
know. And I think that's unfortunately
we just have to be very honest and transparency.
We don't know yet. Certainly we hope to know, but
at least for now we'd say that if this is helpful now and
intolerable and safe that we should implement.
And with the flurry of therapies, the other sort of a
good problem to have is you know which therapy is best for each
patient. And I think with session with
multiple pathways being looked at, we know that the supportive
pathway of endotheam receptor antagonism and anterotensive
receptor antagonism. But in terms of targeting the
gut with an enteric budesonide or targeting April and bath or
targeting complement, which of these pathways is going to be
important for each patient? I think that's what's certainly
the next question. And for clinicians is the
hardest part is going to be saying, OK, well, how long do I
wait before potentially, you know, modifying therapy?
How do I know they're responding?
And you know, what's the sort of the the best response they're
going to get? And I think, again, these are
questions that we ultimately need to know.
Yeah, you mentioned great point, Sunil.
Thank you for all that. And just to remind the audience
that we are still writing this chapter, writing the story,
right? I mean, it's been tremendous
success so far and hopefully it will continue.
But some of these questions will be answered, hopefully with more
science coming out. To your point, and I think
that's what is also hard about adopting these in clinical
practice is this idea of the unknown for clinicians doing
things every day. You know, we sort of have all
these things we relied on these sort of things that we've been
using for the last 30 years. And with all these unanswered
questions, we have to be comfortable with that lack of
knowledge and still think, hey, I got to do as best for my
patient even though we don't have all the answers right now.
Again, as long as we're looking at safety and all those things.
Yeah, absolutely. And again, have the confidence
that these questions, you know, science is still trying to
answer. If you're just tuning in, you're
listening to the KD Go podcast on challenges of implementing
evidence based guidance for IG and nephropathy.
I'm Doctor Dana Risik and I have the pleasure of speaking today
to Doctor Sunil Udani. So Sunil, with all the, you
know, again, exciting news, but also challenges that we've been
talking about. What in your mind are strategies
to increase the implementation of these new guidelines?
I think we can learn from some of the experience that we've had
with evolution and renal therapeutics as of late,
including the SGLT 2 inhibitors in the sense of, you know,
seeing how did adoption come about with those therapies.
And I think that, you know, first, of course, the
distribution of knowledge. And I think that, you know, it's
no longer the case where people are always reading journals or
if they are reading journals, it's no longer the case that
everyone can go to scientific meetings.
So we have to be, you know, innovative.
And I think things like this where either, you know, podcasts
or webinars that are asynchronous so people can
listen in, you know, when they have the time, I think that's
key. I think that identifying the
local people that are helpful, right?
I mean, I think ultimately physicians want to do the right
thing, but they, you know, when it's a new therapy, there's
natural anxiety about it. And so who do they trust
locally? Because naturally there are, you
know, guidelines and, and there are, you know, national
speakers, but ultimately you want to have someone that it's
local you can be comfortable with.
And I think that's the key in terms of this idea of, you know,
hub and spoke model of expertise or identifying local centers of
excellence or local experts that you will feel comfortable with
approaching. And then for the people that are
experts, you know, being open to and, and accessible to people to
so that they can walk through cases and walk through concepts
so that these things become less intimidating.
The new therapies and things that and that can be, you know,
again, in a formal way, informal way.
I think it now we know that there's online forums, ASM
communities has one people have chat groups or their practice or
the local communities that are key that can be accessed as ways
to say, OK, yeah, I have this case, you know, how would your
approach this? What do you guys, can you
someone help me understand the new data on, you know, X
therapy, et cetera. So I think you all of the above,
we can't think of it, just saying like, put it out there
and expect people to do it. And we have to engage people
where they are and finding where they are is the key.
And then ultimately, I think as we evolve, I think, you know, at
some point we have to also have expectations to say, OK, this is
the standard of Care now that we approach this and give
clinicians feedback. And the last thing I'll say is,
you know, what is more motivating than anything else is
a motivated patient. And as we educate patients that
there are better therapies available when they go into the
nephrologist's office and say, hey, I've read about this or
I've heard about this, can you help me understand?
This would be helpful for me. I think that always spurs people
to learn and do more. Yeah, keeping the patient
central, absolutely. There are, you know, patient
advocacy group and we're certainly making a lot of effort
providing lay summaries of even scientific publications.
So I think all that disseminates information both to physicians
but also to patients. So what are in your mind
remaining research or evidence gaps that we need to fill in?
I think there's always been subgroups in each of the trials
that have not been included. YG vasculitis has been one that
has been excluded really from all the trials that I've
observed. And so, you know, in adults
particularly, they can be overlaps with, you know,
conventional hygiene nephropathy.
So obvious therapies would, you know, be implemented in their
cases, the pediatric population. I'm an adult nephrologist, so I
can't say see Pediatrics, but I know that my pediatric
colleagues, you know, they need trials and data for their
patients as well, or people that may have, you know, secondary
forms of IGA. And, and again, which of these
therapies that we see are, are safe and effective?
We have designed these trials based on previous KD GO
guidelines, which was, you know, at 1g per gram UPCR as the
threshold. But what about lower degrees of
protein area? If we get people down to .6 or
.4, but they still have hematuria, they still have IG
nephropathy, do they also benefit?
I think that you get, we don't know the answer to that question
yet, but I have to believe that that is a critical thing for us
to know so that we can really make sure that all patients have
good options. It's been great.
You know, there's been a lot of positivity in terms of the the
clinical trials and the evidence of protein neural reduction and
GFR preservation and many of them to date.
But what we don't always have with those trials at the end of
the granularity of understanding who doesn't respond.
And I think that's going to be a key thing to say, OK, well, why
does this person not respond to this therapy, but they respond
to the other one? And kind of when is the point of
saying there are there markers that we can look at that say,
OK, this person's having a response And this is helpful
beyond looking at simply proteinuria, beyond looking at
GFR even, you know, and without repeating a biopsy.
So non invasive ways that we can perhaps look at response rates
and then get a better idea of who doesn't respond.
Each of the trials have also included individuals with fairly
significant kidney disease. You know, thresholds have been
EGFRS of 30, but most of the exploratory cohorts of 20 to 30.
And so again, you know, is there truly a point no return?
I think the previous KD GO guidelines were very clear that
there's a point no return and then to not instituting no
suppression in those folks. But again, that was when we're
using therapies that had higher toxicity profiles.
So with therapies that are safer, is there truly a point no
return where they don't benefit at all?
Or what is that incremental benefit?
And is it worthwhile with ultimately those folks
progressing SH kidney disease is getting transplant then what
happens to the post transplant period?
We know IGA comes back in the allografts either at least
histologically it comes back. But what about those folks that
have more clinically relevant disease?
Are these therapies safe to use with back her immune suppression
already? Are they effective in the same
pathways? And then those are interesting
and naturally exciting questions as we learn more.
So what I heard you say, Sunil, is we're going to need more
clinical trials perhaps in some, you know, populations that we
left out. We're going to need the real
world data and we're going to need to just answer these
questions as you alluded to by a hodgepodge of sources to fill in
all these gaps as we start applying the guidelines.
So great points. Thank you for sharing that.
So before we close, are there any final messages you'd like to
leave with our listeners? There are knowledge gaps, there
are implementation challenges, but undoubtedly this is an
exciting time for IH and nephropathy, the patients and,
you know, the nephrology community and our clinicians.
And we need to embrace the knowledge that we've learned the
success of these new therapies that have demonstrated efficacy,
tolerability, safety, as well as a more sort of insightful
paradigm in terms of approach to therapy.
Simultaneously treating the kidney specific targets in terms
of things we've been doing supportively as well as novel
pathways to do that, but also treating the immune related
kidney disease. And as ultimately this is an
autoimmune glomerular nephritis and so much are other immune
glomerular nephritis, We need to find the effective ways to treat
that immune concept. You know, it's a remarkable to
be a Bevan part of some of these trials and to see the patients
that have been willing to be part of that.
None of these straws can be that big, right?
The IGN nephropathy is not a common disease.
So every patient counts so much. And it's incredible that this
many patients have stepped up to, you know, be part of this
process. And we are incredibly grateful
to them for doing this and helping us advance the science
as well as the whole research teams have been part of it.
The Pi is the coordinators, the sponsors that have made a
commitment to developing therapies that have been
otherwise forgotten. So I'm very excited that this
is, you know, really has changed the game in our way.
We evaluate and treat hygiene nephropathy and now the key step
is us doing the work to deliver these therapies to patients.
So need I want to really thank you for joining me today.
It was great having you on the podcast.
Doctor Rizik, thank you so much for inviting me and the
conversation. Always a pleasure to talk to
you. Absolutely.
I am Doctor Dana Rizik and to access this and other episodes
in our series, please visit kdgo.org podcast.
Thank you so much for listening.