Host: This podcast was made possible by Vertex Pharmaceuticals.

Welcome to this podcast where we dive into the intersection of cutting-edge science and practical health care, exploring the questions that shape patient outcomes and redefine how we approach complex diseases. I’m your host, Dr. Rachel Giles. Today we’re talking about a topic that’s critical for nephrologists and all health care professionals working with kidney disease, APOL1-mediated kidney disease, or AMKD.

What is AMKD and how does it differ from other forms of kidney disease why is it essential to recognize, diagnose, and treat AMKD? To help us unpack these vital questions, I’m thrilled to welcome Dr. Adriana Hung, a leading nephrologist at Vanderbilt University in Nashville, Tennessee. Dr. Hung will share her insights on what makes AMKD distinct, the role of the APOL1 gene in this condition, and the concept of the quote, second hit, end quote, that can trigger the disease. Whether you’re a practicing nephrologist, a genetic counselor, or someone just interested in the evolving understanding of genetic kidney diseases, this episode is packed with information you won’t want to miss.

Let’s get started. So thank you so much. I’ve got Dr. Adriana Hung here today and we’re going to talk about APOL1-mediated kidney disease. So thank you so much for joining.

Dr Hung: Thank you so much, Rachel. Yeah, so AMKD is APOL1-mediated kidney disease.

It is something that has been recognized over, I would say, the last two decades. And we have gained knowledge significantly more probably in the last couple of years.

It’s really heterogeneous. What’s important about AMKD is that it partially explains the excess risk of progressing to end-stage renal disease in individuals of African ancestry, and specifically recent African ancestry. And so what we have to understand is that it’s related to a high-risk genotype, which is known as G1 and G2.

And G1 and G2 came actually from West Africa. It arrives as a selective mechanism to protect ourselves against human trypanosomiasis. But unfortunately, individuals that had two copies of the allele that protected us against trypanosomiasis also acquire the risk of end-stage kidney disease and fast progression of kidney disease to end-stage renal disease.

When we think how is this different than other forms of kidney disease, it’s very hard actually to disentangle the clinical presentation. Even in patients with diabetes, they could present and they could have AMKD. It’s just if you have the high-risk genotypes, so these two alleles, G1, G1, G1, G2, G2, G2, you are at risk of having a faster progression.

And so that’s what’s most important. Something that we always talk about is that what is the prevalence of having a high-risk genotype? And really in the U.S., that is about 14 percent. So 12 to 14 percent, that’s current and contemporary, and that’s across the entire United States.

That’s been shown in the Million Veteran Program, which is a contemporary cohort. And that count was, that prevalence was estimated out of 123,000 individuals of African ancestry. But it’s very consistent with the BioVU, which is the Vanderbilt Biobank, and with many other cohorts like REGARDS or MESA or ARIC. 

So we’re certainly that that’s the number, the percent of individuals of recent African ancestry that will have a high-risk genotype. The good news is that not everybody’s going to suffer kidney disease. And that is where this second hit hypothesis becomes so important.

So there are certain conditions that are pro-inflammatory and that will increase gene expression of APOL1. These conditions can be several, as a matter of fact. We have recognized viral infections as probably the strongest of the stimuli.

So when HIV was really an epidemic and we didn’t have a good treatment, HIVANN was the most severe form of AMKD. But we saw it with COVID, right? And we can see it too with Parvovirus B19, with dengue, but really with any condition that will create a pro-inflammatory setting. Even a medication.

Nowadays, we’re seeing that with some of the immune checkpoint chemotherapy agents that will generate a cytokine storm and that will have the same effect. So medications like interferon can directly increase the expression, gene expression of APOL1 and generate one type of kidney disease that is absolutely typical for the most severe forms of AMKD. That is NFSGS and a very particular one called collapsing FSGS.

That’s the most severe form of AMKD and it’s really fast progressing. I think that over the last few years, we have recognized the mechanisms and pathways as how this is happening. And I think in the near future, we will have medications to treat AMKD.

One is on a phase 2 trial and one is on a phase three trial. Now, when we think about second hits, right? As I mentioned, it can be many things.

It can be medications. It can be viruses. It can be other disease conditions.

For example, lupus is one that we have been seeing as a frequent form of AMKD. Sickle cell disease. So there are other kidney diseases that may interact with APOL1 and generate an AMKD.

Now we’re also recognizing what we know as gene modifiers. And I had a beautiful publication in something recognized as another mutation and it’s N264K.

And this very particular variant is actually protective. It actually mimics, we’ll say it’s the gene proxy of the APOL1 blockers now. Why am I mentioning that? Because at the end, when I emphasize the relevance of genotyping, is because if you are a kidney donor and you’re going to give your kidney to your loved one, that’s gone into an stage renal disease because they had APOL1 high-risk genotype.

Genotyping will be very important to tailor treatment to risk and justify the patient.

But in the case of the family member that’s going to serve as a donor, genotyping will be also important to understand their risk of suffering AMKD, but also understand if they are protected against AMKD and they can have the opportunity to donate their kidneys

Host: Terrific. Thank you so much.

Dr Hung:  Thanks to you.

Host: Thank you for joining us on this podcast episode. A big thank you to Dr. Adriana Hung for her valuable insights into APOL1-mediated kidney disease, the importance of early diagnosis for this condition, and the genetic underpinnings that make this condition so unique. If you’d like to learn more about AMKD and the role of the APOL1 gene, there are some resources available, and we’ll include links into the show notes to help you dive deep.

Stay informed and stay healthy. This podcast was made possible by Vertex Pharmaceuticals. Thank you for listening.