Welcome to KD GO Conversations in Nephrology.
This episode titled Burden and Pathophysiology of a Pol One
Kidney Disease is provided by KD Go and supported by Vertex.
Here's your host, Doctor Kirk Campbell.
Hello and welcome to KD Go Conversations in Nephrology.
I'm Doctor Kirk Campbell, Chief of the Reno Division at the
University of Pennsylvania. Joining me to discuss the burden
on pathophysiology of April 1 kidney disease is Doctor Bessie
Young. Doctor Young is vice Dean and
medical director for the Office of Healthcare Equity at the
University of Washington, where she also serves as professor of
medicine in the Division of Nephrology.
Her clinical and research interests include genetic
testing and April one health outcomes in home dialysis and
health inequities in kidney disease.
Doctor Young, welcome to the podcast.
Thank you, Doctor Campbell. It's a pleasure to be here.
Thank you so much. So let's begin our discussion
around April one. Since it's a relatively new
genetic finding, can you discuss the history of the discovery of
April 1? Provide some background on how
quickly the findings have been translated into clinical
knowledge? Thank you for that question.
So the April 1 gene story is really one of discovery.
For years, researchers have been searching for a gene associated
with kidney disease and African American individuals or black
individuals or specifically people with recent African
ancestry. And we know that the rates of
end stage kidney disease are significantly higher and those
who are black compared to those who are white.
And black individuals usually develop kidney failure 10 years
earlier than white individuals. So there was a real search for
something that was related to, like a genetic finding that was
related to kidney disease. So there was a potential hit
that was found with MHY 9 in 2008, and people started to look
at that. But then in 2010, Doctor
Genovese and Martin Pollock discovered an association of
tripanalytic April 1 variants with kidney disease and African
American individuals, which was published in 2010 in Science.
And the same year Doctor Sewer and discovered the same April 1
genetic variants were associated with greater rates of kidney
disease than those with recent African ancestry.
So these variants are named G1 and G2, and that has to do with
their amino acid substitutions and deletions.
G1 has two amino acid substitutions and G2 has two
amino acid base pair deletions and these variants are
protective from African sleeping sickness from Trypanosoma.
Bruce I. I would say that this
information has been relatively rapidly translated into clinical
medicine. April 01 genetic testing is
currently available and there are recent clinical trials that
have been initiated with biologics that interfere with
April 01 and definitely long term studies that are still
recruiting for applicants with April 01.
Thank you so much for that very detailed, concise history.
Regarding April 1, can you tell us a little bit more about April
one kidney disease? What exactly is it then?
What's the prevalence, epidemiology, manifestations and
different phenotypes that one could see?
Sure. So we know from epidemiologic
data that there are approximately 30% of African
American individuals who have G1 or G2 or both G1 and G2.
And we also know that about 13% of those with recent African
ancestry in the US have both G1 and G2, which are termed high
risk April 1 variance. So this is roughly about 5
million people in the US who have the high risk April 1
variance. It is thought that these April 1
variants are passed down as autosomal recessive as a genetic
trait. And we also know from recent
data that the prevalence of April 1 high risk variance is
probably greatest in West Africa.
There was a recent paper in the New England Journal of Medicine
that showed that the individuals from West Africa have really
high rates of G1 and G2, and it varies by tribe and country.
We also know that those with high risk variants have the
greatest risk of developing end stage kidney disease are going
on to dialysis, while those who have either one of the variants
T1 or G2 have an increased risk of developing chronic kidney
disease or albuminuria. And we also know that there's
been a lot of progress in regards to April one kidney
disease. So now April one kidney disease
is termed April 1 mediated kidney disease or AMKD.
You'll see that in some of the literature, there's also an ICD
TEN approval and the 2025 ICD 10 update, so that there are now
diagnosis codes for April 1. But as you know, in a conference
in Ghana with patients, researchers and others, the term
April 01 kidney disease was also chosen to represent kidney
disease and those with April 01. So there are a lot of names out
there for April 01 mediated kidney disease.
And I think it just depends on, you know, where you're coming
from in terms of what name you use.
But AMKD is showing up in the literature more and more.
April one kidney disease was initially associated with FSGS
or focal segmental glomerulosclerosis.
It was also shown to be increased in those with HIV
nephropathy and hypertensive kidney disease.
So originally there were case control studies that showed that
there is a 7 to 10 fold greater risk of FSGS, end stage kidney
disease and those with A41 positivity.
It was also shown in those early case studies that HIV
nephropathy had like a odds ratio of 28% to 29% increased
risk of HIV nephropathy and end stage kidney disease.
So with larger population based cohort studies, that risk
decreased to about twofold. But there's still an increased
risk of Apollo 1 kidney disease with end stage kidney disease
and kidney disease progression. And then pathologically, I'd say
the spectrum of kidney disease associated with 01 is probably
bad of the collapsing variant of FSGS and it's known to affect
podocytes. It can cause tubular injury and
interstitial fibrosis and global sclerosis if it's diagnosed
later on. If you're just tuning in, you're
listening to the K Diego podcast on the burden and
pathophysiology of April 1 kidney disease.
I'm Doctor Kirk Campbell and I'm speaking with Doctor Bessie
Young. Doctor Young, thank you for that
description of April 1 kidney disease.
Can you describe what we know about the disease mechanisms
based on the current pathophysiology?
Are there any protected variants, for example we should
be aware of? Yeah.
Thanks, Kurt for that question. So the disease mechanism of the
April 1 genes are complex and I think people are still trying to
figure out the exact mechanism. But what the research data has
shown and points towards is there is injury of the POTUCite.
So April 1 can basically form a pore or an ion channel in the
podocyte which leads to an increase in chloride or other
ion flux and causes osmolysis of the podocyte.
And this is a similar mechanism to that found in the
tripanosomes, which basically leads to their death and those
who have April 1 variance. So this osmolysis leads to put
aside effacement and detachment, which can then result in
increased inflammation and probably leads to what we see
when people actually have biopsies and we see inflammation
or we see FSGS. April One has also been shown to
cause misfolding of the endoplasmic reticulums and it
could compromise mitochondrial function.
So it has a wide variety of functions and I don't think we
know all the mechanisms of disease of April 1.
April 1's also found in lung, it's found, I think in liver,
it's found in vessels. So there may be some additional
function that we're not aware of.
It's also thought that environmental stressors such as
inflammation or high interferon states may really exacerbate
April one disease and lead to progression.
And some of the drivers that have been found include things
like viral infection. So the research really points
towards HIV sort of being a driver of April 1 kidney
disease. We know from the COVID pandemic
that COVID and those who had COVID and developed kidney
disease, they had faster progression and they had acute
kidney injury that was associated with April 1.
There's ischemia reperfusion as a driver and there's an
increased risk of progression in individuals who have sickle cell
disease. We know that there's kidney
allograft rejection that might be a driver associated with
April One disease. And then in lupus, we know that
autoimmune diseases can lead to worse disease with April 1.
And then you asked about a protectant variant in April 1.
So there is a study from Doctor Adriana Hung at Vanderbilt who
used data from the Million Veteran Program, the Vanderbilt
Biobank and the NIH, All of us study to look to see if there
were any protective variants and they found one called PN264K.
And I'll assume that they'll probably change the name of
that. But this variant was shown to
basically block the poor forming function of APOL one and the ion
channel conduction and reduce the toxicity of APOL one.
It kind of plugs the hole of the poor, if you will, and decreases
the pathology associated with the ponocyte.
So there are people who have this variant, but the one study
that I think led to the discovery of this variant showed
that if a person has this variant, they actually are
susceptible to African sleeping sickness.
Story certainly is getting more complex and interesting.
Can you describe what studies are out there that might provide
additional information to our listeners regarding April One
kidney disease? Sure.
There are additional studies that will provide information
about April 1 gene and the development of that first kidney
outcomes. And 1 of this is called Apollo
or the April 1 Long Term Kidney Transplantation Outcomes Network
study. And this is a study that will
look at the long term effects of April one on kidney donors
prospectively to determine who progresses and if there's an
increased risk of donation of kidney failure in people who
donate a kidney. There are also many studies that
are looking at new medications that are coming out and I think
we'll have another podcast on these.
There are studies that are looking at April one small
molecule inhibitors, anti censolago nucleotide inhibitors
and the Jack stat inhibitors that are currently in clinical
trials. And I also just wanted to point
towards there is one recent paper that is more of a
epidemiologic paper that really shows the high risk of April one
in Africa that was recently published that just showed the
very high rates in Western Africa.
So I think there are more trials out there, more research out
there that's being done. And so the story is not
completely known in terms terms of treatment, in terms of the
mechanisms and probably there's more that needs to be known in
terms of the epidemiology as well.
Yeah. Thanks for sharing those
resources. So, before we close Doctor
Young, are there any final messages you'd like to leave
with our listeners? Sure.
I would just like to say that the April 1 gene and knowledge
regarding pathophysiology and treatment are a major step
forward for modern medicine and research in stage.
Kidney disease is a deep disease that as you know effects African
Americans and other individuals who have recent African
ancestry. And we've been waiting for
something that really shows that it's not just lifestyle, but
there's really something intrinsic about either a gene or
something that is associated with end stage kidney disease.
And this, I think has really changed the way that we look at
kidney disease. This is a disease where you can
truly say that research changes lives.
I would say that the speed at which treatment was developed is
relatively swift, 15 years, but it still lags behind many other
diseases, you know, such as COVID, where a vaccine was
developed in 6 to 12 months. And so I'm hoping that the
treatment for April 1 kidney disease will advance very
quickly and that there will be more clinical trials to prevent
thousands of people from having to go on dialysis in the future.
There's certainly a lot of progress with more work to be
done to lead to direct patient benefit, but thank you so much.
Again, Doctor Young, I'd like to thank you for joining me.
It's great having you on the podcast.
Doctor Campbell, thank you again for inviting me.
This series will help our listeners understand April One
Kidney Disease a bit better and I really look forward to the
other sessions. I'm Doctor Kurt Campbell.
To access this and other episodes in our series, visit
kedego.org podcast. Thanks for listening.