Using Genetic Testing to Address Disparities in Care for Kidney Disease

July 8, 2022

African Americans are four times more likely than Whites to suffer from end-stage kidney disease. In part, that’s because of genetic causes underlying kidney-disease being more common in people of African descent. A recent study suggests that genetic testing and genetic counseling to patients of African ancestry changed behaviors and lowered their risk of developing kidney disease. We spoke to Maggie Westemeyer, a genetic counselor with the clinical genetic testing company Natera, about the genetic risks of kidney disease, racial health disparities, and how genetic testing can be used to address that and improve outcomes for patients.


Daniel Levine: Maggie, thanks for joining us.

Maggie Westemeyer: Hi Daniel, thank you for having me today. I’m excited to be here.

Daniel Levine: We’re going yo talk about chronic kidney disease, health disparities, and the role genetic testing and counseling can play in addressing these. Llet’s start with chronic kidney disease. How big a healthcare problem does this represent today and how broad a range of conditions does this encompass?

Maggie Westemeyer: Chronic kidney disease or CKD is a major healthcare problem. It affects close to 40 million Americans, or one in seven adults, and this number is expected to rise. Another statistic is that nine out 10 adults with CKD are unaware they have the disease according to the CDC. And this is where genetic testing can make a huge difference. If people are aware that CKD runs in their family, their chances of catching it early and making meaningful interventions are way better. Though there’s a lot of causes of the disease, CKD is often caused by diabetes or high blood pressure, and it usually worsens with time. It can progress to end stage kidney failure at which point a patient will need to undergo dialysis or kidney transplant. And it’s also worth mentioning that children can be affected by CKD. In the U.S., about 10,000 people younger than age 20 have kidney failure.

Daniel Levine: This is a condition that disproportionately impacts the African American community? What’s known about the role of genetics and the impact of these conditions in the African American community?

Maggie Westemeyer: So, the ClinGen Consortium and others have identified hundreds of genes for kidney disease. And according to published research, African Americans experience CKD at roughly three times the rate of European Americans and are two to four times more likely to experience kidney failure. So, although African Americans make up just over 10 percent of the population, they account for roughly a third of people receiving dialysis, and you might ask, why do African Americans have such a high risk for CKD? Much of this disparity, up to 70 percent, can be attributed to genetic variants in the APOL1 gene, which are found only in individuals with African ancestry. So APOL1 drastically increases the risk of CKD and end stage kidney disease and 13 percent, or one in eight, African American individuals have these APOL1 risk variants. To make a comparison, this is more common than the sickle cell trait in individuals of African American descent.

Daniel Levine: What is the APOL1 gene and what’s its function?

Maggie Westemeyer: Sure. APOL1 codes for a protein that’s called Apolipoprotein L1, that’s a component of our HDL or our good cholesterol that is synthesized in our liver and also in many other tissues in our body. Everybody inherits two copies of the APOL1 gene, one from each biological parent, but there’s two risk variants in APOL1 that are known to be associated with CKD. And these two genetic variants arose in humans in Sub-Saharan Africa several thousand years ago. And then the frequency of these variants rose quickly in African populations because they confer enhanced protection against trypanosomes that cause African sleeping sickness. Because these risk variants arose after the “out of Africa” expansion that populated the rest of the world, the APOL1 kidney risk variants are observed in individuals with recent African ancestry.

Daniel Levine: How do variants in the gene cause chronic kidney disease?

Maggie Westemeyer: They’re surprisingly little consensus about the specific molecular mechanisms that drive APOL1 kidney disease, or really even what cell types are injured by APOL1. A leading hypothesis is that APOL1 risk variants create pores in the kidney cell membranes, similar to how APOL1 punches holes in those trypanosomes related to sleeping sickness. Other hypotheses include that risk variant over-expression in the body leads to mitochondrial dysfunction injury. And so, what we really know is that people with two high risk APOL1 variants have an increased lifetime risk for CKD. And according to research, the lifetime risk of CKD in African Americans who have these two risk alleles is 15 percent and the lifetime risk of kidney failure is 7.5 percent. Of note, people that have these variants who have high blood pressure or untreated HIV, lupus, sickle cell anemia, or even COVID 19 infection have even greater risks of developing kidney disease.

Daniel Levine: There’s been growing recognition of health disparities tied to race. What’s known about the effects of these disparities on people with chronic kidney disease? Is there evidence that it takes longer for them to get a diagnosis, that the treatments they receive are different, or it takes longer to get treated, or are outcomes worse in some way because of that?

Maggie Westemeyer: Yes, there are definitely health disparities in CKD that are tied to race and other factors. There’s notable discrepancies in who develops CKD and who has more severe progression in outcomes. So, when we look at data from the National Kidney Foundation, African Americans represent 13 percent of the population, but make up 35 percent of those experiencing kidney failure. Research has also shown that the incidence of kidney failure is three and a half times higher for African Americans and one and a half times higher for Hispanics than for whites. And we even know that other ethnic groups have a higher prevalence of kidney disease than whites. We also know there’s disparities in the quality of care, right? So, an individual who has higher quality of primary care or earlier referral to a nephrologist may have a better outcome. And we do see in minority populations lesser degrees of care and early referrals to specialists, and that affects outcomes. One example I can give is that dialysis centers that have more minority patients tend to be bigger and less likely to offer a convenience of a home therapy that could make a patient more likely to be compliant with their treatment. African Americans and other minorities also have higher rates of COVID 19 transmission and risk of health problems and death related to COVID. We’ve even found out more recently through some data that people with two APOL1 risk variants and COVID 19 infection have increased incidence of acute kidney disease. When we look at things like kidney transplant, African Americans and Hispanics are less likely to receive deceased or living donor transplants. And so, while we still have a lot to learn about how the APOL1 gene works, studies have shown a definite association between the APOL1 gene status of an individual and their progression to kidney failure. While not solely attributable APOL1, the lifetime risk of kidney failure in the African American population is seven and a half percent compared to a 2.1 percent risk in whites. Not only is APOL1 a factor in the increasing incidence of kidney disease, it also impacts transplant considerations when we evaluate living donors of African ancestry. And really we know that living donors are more valuable in kidney transplant because a kidney transplanted from a living donor lasts longer than one from a deceased donor. So, donor kidneys that have two APOL1 risk alleles are associated with lower survival of the transplant. We call that graft survival, regardless of the recipient’s APOL1 genetics.

Daniel Levine: Natera has developed what it calls its Renasight test. What does the test do? How does it work? What is it actually seeking to determine?

Maggie Westemeyer: Yes. So, Renasight is our test that checks for variance in 385 different genes known to be associated with both common and rare forms of kidney disease that are genetic. To date, we’ve performed over 20,000 tests and we test for conditions that are commonly known in the kidney disease community, such as Alport syndrome or autosomal dominant polycystic kidney disease. And when we took a look at developing this panel, we wanted to do a good job. So, we worked with general nephrologists, pediatric nephrologists, and transplant nephrologists to help develop the panel, to be as thorough as we could be with the technology available today. And I want to say that it’s an exciting time to be a genetic counselor and work in a company where our technology allows us to test for a large number of genes and give results to clinicians and patients in a short amount of time, in a cost effective manner, based on our NGS technologies available today used in the test.

Daniel Levine: How does the test work? Does a physician send in a blood sample and what kind of result does the physician get?

Maggie Westemeyer: Yeah, so Renasight uses NGS [next-generation sequencing] sequencing and we accept samples that are either blood or saliva and those samples can even be collected in individuals’ homes and sent in, in the case of saliva samples. And then we go ahead and check in the lab for variants in those 385 genes to check for genetic forms of CKD. We can detect both single nucleotide variants, meaning individual changes in a given gene, in addition, we can detect deletions and duplications, which are chunks of extra or missing pieces of DNA in a gene or genes that cause kidney disease. So, the laboratory also uses confirmatory testing and goes on to do expert curation of any variant that’s detected with the test in order to ensure accurate results. One thing to note is that, in our first publication of a thousand cases done in Renasight, we found that about 21 percent of people had a positive result. But what was really interesting was to see the number of people that had more than one positive test result, meaning they had more than one gene finding. Among those that had multiple positive results, many had both APOL1 risk variants and a variant found in a second gene.

Daniel Levine: How actionable is that information? What would a physician do once he gets back the results and is informed that this patient has this mutation?

Maggie Westemeyer: Sure. We know that there are a number of things someone can do once they have a positive test result. An individual can take advantage of targeted therapies. They can enroll in clinical trials. We test for genetic conditions that cause kidney disease, as well as syndromes that are associated with kidney disease as a feature and can have extra renal manifestations. So, those are important findings in the test as well and mean that the patient needs to be referred for additional medical workup. When a syndrome’s identified, also really importantly, is that genetic testing allows for other family members to be tested. Once an individual in the family with the disease is identified with a specific genetic variant or variance, it allows them to then check if they’re going to or if they do have the disease, or if they’re going to develop the disease in their lifetime.

Daniel Levine: And what’s been done to validate the test? What’s known about its accuracy?

Maggie Westemeyer: So, accuracy is really a question you can ask when discussing genetic test results, but we usually tend to refer to an analytical detection in genetic testing. We know that with NGS, variants have a greater than 99 percent chance of being detected if present, right? It means that if the variants present in a sample, we will find it given the methods that we use and we’ll report it. What’s really important, I think to ask about the laboratory that you’re working with when you’re doing a genetic test, is what additional source of things are they doing to provide accuracy in their results? And I can tell you a little bit about our PKD1 analysis. For example, the PKD1 gene is a really tricky gene because it has a pseudogene of very similar sequence that can confuse the NGS analysis. And our lab has worked to optimize variant detection through optimization of our bioinformatic analyses to overcome those technical limitations. And again, make sure that if we detect a PKD1 variant, it’s actually in the PKD1 gene and not in the pseudogene, and then report it accurately.

Daniel Levine: When should a doctor order such a test and when should a patient ask about that? Do they consider things like family history or are they waiting for a patient to become symptomatic?

Maggie Westemeyer: Oh, absolutely. We are aware of a variety of risk factors or scenarios that make sense to think genetic. These include things like having an early age of onset of kidney disease, having a clinical diagnosis in an individual that’s based on their symptoms that suggest they have a certain genetic condition and could benefit from testing, particularly if someone has a syndrome that has kidney findings and other findings that’s suggestive of a genetic condition. Family history is very important and even things that you might not think about, like rapid progression of disease or atypical presentation of a particular kidney disease, are risk factors for a genetic condition.

Daniel Levine: If someone has a known variant, does it mean they’ll develop chronic kidney disease or are the variants just associated with a higher incidence of a disease and they should consider things like monitoring and lifestyle changes?

Maggie Westemeyer: That’s a great question. We get asked this all the time as well. To answer it, it’s important to understand a few things about genotype-phenotype correlations, and genotype-phenotype correlations mean the relationship between the variants detected on the test and the clinical findings that a person has. And there’s various factors that can influence that relationship and they think can affect things like the age of onset that someone will develop symptoms of their kidney disease, or even the degree of severity of their symptoms. So, generally aside from APOL1 positive, Renasight genetic test results are diagnostic. That means that someone who has a positive test result that identifies a variant in them means they’re expected to have the condition. And when it comes to families, it’s also important to think about if an at-risk family member has that test before they’re symptomatic and has a positive result. We expect that they’ll develop that condition in their lifetime.

Daniel Levine: Is there an example of a case you could point to, to illustrate how this works and how it’s impacted a patient?

Maggie Westemeyer: So, as an example, I’d like to share a case story about the use Renasight to test a man who had kidney disease in his late seventies. He had kidney failure late in life that was thought to be secondary to diabetes and hypertension. And he actually underwent a kidney transplant where his adult child was a donor. And this family really had no known history of CKD or genetic conditions. After this individual had a transplant, his nephrologist was surprised to see that the creatinine remained elevated and they went ahead and pursued a biopsy of the transplanted kidney and also ordered Renasight at the same time. And the biopsy revealed some really specific findings in that transplanted kidney that were involving these tubular interstitial DHA crystal deposits and inflammation, and the Renasight test then identified two copies of a disease-causing variant in the APRT gene.

And this is for a condition called adenine phosphoribosyltransferase deficiency. That condition is a rare autosomal recessive disorder with prevalence of about 1 in 50,000 to 100,000 people. And the major features of this are recurrent kidney stones and crystal-induced kidney damage. Even though it is a rare condition, it’s an important cause of CKD because it’s potentially reversible with existing treatments called xanthine oxidase inhibitors, and these include medications like allopurinol or febuxostat that can improve kidney function, even in individuals with advanced CKD. So, identification of the genetic cause of this individual’s kidney disease led immediately to treatment with allopurinol, as well as recommended dietary changes. The treatment also helps prevent further injury to his transplant kidney. And then lastly, that diagnosis provided information about the familial risks and allowed family members to have genetic counseling and testing.

Daniel Levine: Are these tests generally covered by insurers, or is this something a patient would need to pay out of pocket?

Maggie Westemeyer: It’s also a great question because most folks are concerned about the cost of genetic testing and have heard things about genetic testing being expensive, but our tests are covered by insurance. So Renasight is covered by Medicare and Medicaid, and Natera also works to provide affordable testing options to patients through channels like our compassionate care program, commercial insurance billing, and some programs where we’ll contact the patient to determine their eligibility, determine if, based on federal income criteria, they could participate in the compassionate care program. And we find that most patients owe either $0 or a max of $349, depending on their plan. But if we find out a patient’s going to owe more than $349 to the lab, we’ll contact them to discuss options for payment, for cash pay as an example, as an alternative to billing insurance. Over the past two years since we started offering Renasight, it’s great to hear from nephrologists who couldn’t easily offer testing in the past because of how expensive genetic testing was in the past and our new NGS technologies really moved the needle toward affordability and testing.

Daniel Levine: As a genetic counselor, what’s the discussion like when you sit down with a patient who has gotten a result?

Maggie Westemeyer: So, we have a team of genetic counselors at Natera that work just on our Renasight test and they’ve had a lot of interesting experiences and great experiences counseling patients and families who’ve had Renasight. In genetic counseling, we really work to break down complex genetic testing information into something that’s digestible and understandable by patients and we try to focus on what the questions and concerns are of that individual patient, right? Genetic counseling is all about helping patients make decisions that are in line with their personal values and medical needs, and helping them understand what questions they should ask next of their nephrologist and what their treatment plan could look like. Based on some of the things we know about treatment for that individual condition, now it helps us identify who should be screened next in the family. Those are some really important discussions that we have.

Daniel Levine: What’s known about the outcomes for people who are tested? Is there a case that getting genetic testing in these conditions lead to better outcomes?

Maggie Westemeyer: Sure. So, we’re really starting to learn more about this in the past few years. Nephrology genetics lags a bit behind some other specialties. and a seminal paper came out in 2019 in the New England Journal of Medicine that showed 89 percent of patients who had a positive genetic test related to their kidney disease had actionable clinical implications. And Natera recently announced our Renacare study. Arenacare is our Renasight clinical application review and evaluation study that’s real world perspective and multicenter in order to assess the utility of our test. We want to know more about the outcomes of our patients after they have Renasight. Thus far, we’ve enrolled about 1700 patients across 25 sites, and we hope to have a publication about the outcome of this study in the next year.

Daniel Levine: Maggie Westemeyer, board certified genetic counselor, Natera. Maggie, thanks so much for your time today.

Maggie Westemeyer: Thank you.

This transcript has been edited for clarity and readability.

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