APOL1-Mediated Kidney Disease Awareness

APOL1 gene variants are a major contributor to kidney disease risk among people of African ancestry. APOL1-mediated kidney disease (AMKD) is a form of kidney disease marked by rapid progression, proteinuria, and other factors.

Nephrology Times spoke with Pranav Garimella, MBBS, MPH, a nephrologist and the inaugural chief medical officer of the American Kidney Fund, about AMKD and APOL1 as the second annual AMKD Awareness Day approached on April 29, 2025.

Could you provide a few significant recent research highlights regarding the APOL1 gene variant?

APOL1-mediated kidney disease—or AMKD as it’s now more commonly known, perhaps—is caused by the genetic inheritance of two alleles, the G1 and the G2 allele. When people have both the high-risk alleles, they have an increased risk of kidney disease development and progressing to kidney failure.

Historically, this gene has been underdiagnosed, and we didn’t know about it, so people were not being diagnosed as having this condition. Perhaps a lot of what we previously thought was just hypertensive-associated kidney disease could now be attributed to some degree to the high-risk allele. In that sense, genetic testing advances and availability of genetic testing have really increased for APOL1-associated kidney disease.

The second thing that’s really exciting right now is, over the last few years, there have been clinical trials in humans targeting the APOL1 high-risk alleles. There are very promising data from early studies looking at the fact that this molecule reduces the protein levels in humans and possibly may reduce kidney function loss.

These are trials that are currently being enrolled, and this is really the first treatment that’s going to be available targeting people with this high-risk allele that doesn’t have any other treatment. I think that’s probably the most exciting advancement in understanding this allele and making sure that we have treatments available for these high-risk patients.

Could you discuss AMKD investigational therapies, such as Vertex’s VX-147 or AstraZeneca’s AZD2373?

There are at least two compounds out there right now. Inaxaplin, or Vertex’s 147 molecule, is an APOL1 channel inhibitor. This binds to the APOL1 protein and prevents the channel-mediated influx that happens. In mouse models, this directly shows that it prevents the cell death that happens in these transgenic mice models. Right now, there is phase 3 trial that’s ongoing, and they’re also looking to expand into younger populations. The primary end point of these trials is not going to be just proteinuria reduction, but also the GFR [glomerular filtration rate] slowing, which is going to be exciting.

There are no approved treatments for AMKD. So, what is the current approach to treatment?

How we approach patients who have AMKD is still a matter of debate. One of the reasons for that is because we have no clear guidelines. In fact, KDIGO [Kidney Disease: Improving Global Outcomes] convened a controversies conference, which is the first step in the development of a guideline on how we should test patients and perhaps what we should even do. Right now, if patients have African American, Central African, Caribbean [ancestry]—or perhaps even [in] some Latinx communities—if there is an undiagnosed cause of kidney disease, such as patients who don’t have uncontrolled diabetes or who have hypertension but that’s out of proportion to their kidney disease, and they have protein in their urine, some clinicians would refer them for genetic testing, but this isn’t yet prevalent.

The first thing is recognizing and being aware of the fact that we might be underdiagnosing AMKD. The second thing is not to attribute kidney disease to hypertension. I think we attribute far more kidney disease to hypertension than it does truly cause. Patients who have APOL1 kidney disease could have a spectrum of disorders. Understanding that patients who have FSGS [focal segmental glomerulosclerosis], patients who have HIV-associated nephropathy, and even what we used to call hypertensive kidney disease could all actually have AMKD is an important thing that we need to recognize.

Beyond that, [is] identifying patients who have early-onset proteinuria. Young adults or even schoolkids, if they’re undergoing physicals in schools and for employment and proteinuria is detected, making sure that these people are referred for further follow-up and testing and have nephrology care  at some point is really critical. I’ve heard of unfortunate stories where patients had some degree of protein in their urine, but this was attributed to either exercise or some kind of benign protein in the urine. These patients then went on to develop kidney disease and kidney failure. I think harmonizing how we approach AMKD, which would perhaps become more clear as the first KDIGO guidelines come out, is really the first step in recognizing and understanding the disease.

Apart from observing AMKD Awareness Day, what can the nephrology community do to raise awareness among people who may have APOL1 risk variants?

There’s a lot to be done still. AMKD Awareness Day, which is April 29, is an effort by the American Kidney Fund to raise awareness, but it’s really more than a recognition. It’s a real call to close the gaps in awareness and diagnosis and treatment and support. There are unmet needs in all these areas. For example, we really need to expand education and outreach, raise efforts in patient populations and among healthcare providers about the existence of APOL1-mediated kidney disease and how to diagnose it, ensure that there is the ability to send out for genetic testing when needed, and provide these patients and clinicians with the ability to speak with genetic counselors because unless you have those genetic counselors integrated into your care flow, there is really a gap in being able to provide excellent care to these patients.

There needs to be continued investment and research because this is still a relatively rare disease. Thirteen percent of people who have Central African ancestry carry the gene, but only one in five of them will actually develop kidney disease. It’s a relatively smaller proportion of all kidney disease. Understanding that these populations have historically not received the care that they deserve and that they disproportionately reflect kidney failure in our country really needs to be addressed. Developing the evidence-based guidelines that KDIGO will hopefully soon come out with would really empower clinicians and patients to ask for testing and understand what kind of interventions, outside of specific gene therapies, can be developed.

The last thing I’ll say is that we really need advocacy efforts to promote equitable research because again, this is a disease that disproportionately affects people of color and those who have Central African ancestry. Making sure that they have a stake in the clinical studies and research programs that are being developed and ensuring that they have a stake in securing funding would really be critical to move the needle on appropriate and accessible treatments for AMKD.