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.