CLN - Feature

The APO-L1 Testing Debate

Transplant community explores whether preop workups in African American Kidney donors should assess for risk-conferring variants

Heather Lindsey

Physicians have long known that African Americans have higher progressive nondiabetic rates of chronic kidney disease and end-stage renal disease than whites. Evidence shows that much of this increased risk is associated with two variants in the Apolipoprotein L1 gene (APO-L1). Emerging data suggest that patients who receive kidneys from deceased or living donors with these risk variants have worse outcomes. Some living donors with APO-L1 variants also experience functional declines in their remaining kidney.

Consequently, transplant surgeons, nephrologists, ethicists, and other providers are weighing the benefits and drawbacks of universal testing for APO-L1 risk variants in African American living kidney donors, and many are eagerly awaiting data from the APO-L1 Long-Term Kidney Transplantation Outcomes Network (APOLLO) study to inform discussions about genotyping with their patients.

APO-L1 in Kidney Disease

In 2010, researchers discovered that two APO-L1 risk variants cause kidney disease, said Barry Freedman, MD, a nephrologist at Wake Forest Baptist Health in Winston-Salem, North Carolina and principal investigator of APOLLO. About 13% of African Americans carry the high-risk alleles (Am J Kidney Dis 2018;72:S8-16).

APO-L1 proteins made in the kidney can damage the organ, explained Freedman. The protein attaches to cell and organelle membranes and “seems to punch holes in the mitochondrial membrane, and this process kills kidney cells,” he said. These same proteins damage the lysosomal membrane of the parasite trypanosome, which causes African trypanosomiasis and are likely why some people of African ancestry have APO-L1 risk variants.

Case reports show that transplant recipients of kidneys from African American living donors with two APO-L1 risk variants can develop focal segmental glomerulosclerosis disease, leading to graft failure. In addition, “the healthy donor can develop kidney failure,” said Freedman. Mechanisms that cause kidney disease in African American living donors may be the same mechanisms that lead to kidney disease in the recipients of those kidneys.

Additional data published in 2018 indicate that African American living kidney donors with the high-risk genotype have an increased risk of complications (J Am Soc Nephrol 2018; 29:1309-16). Researchers evaluated 136 African American living kidney donors, 19 of whom had two APO-L1 risk variants. Two of these donors were on dialysis at a median 12 years’ follow-up compared with no one in the low-risk group. High-risk living kidney donors also had a greater decline in post-donation kidney function.

While these data are concerning, “we also have to remember that the majority of people who don’t donate a kidney and who have two APO-L1 variants have normal kidneys their whole lives,” said Kenneth A. Newell, MD, PhD, professor of surgery at Emory University School of Medicine in Atlanta. This may mean a second genetic hit potentiates the risk inferred by the APO-L1 variance. “Until we really know what that second hit is, it’s difficult to know how important, in any given person, APO-L1 variants are,” he stressed.

Whether a person with two APO-L1 variants who donates a kidney has a higher risk of complications than someone with the variants who does not donate a kidney isn’t yet known, said Vasishta Tatapudi, MD, a nephrologist and assistant professor of medicine at NYU Langone’s Transplant Institute in New York City. “From the data we have, I can’t clearly say that donating heightens the risk any further,” he said.

While Testing Isn’t Universal, a Discussion Should Be

In 2017, a panel convened by the American Transplant Society on which Newell served published a guidance against universal screening for APO-L1 as part of living donor evaluations of African Americans (Am J Transplant 2017;17:901-11). However, the guidance encourages physicians to have a comprehensive and informed discussion with patients about APO-L1 genetic testing. At this point, there are no plans to update the guidance, according to Newell.

While doctors tend to agree that a discussion about APO-L1 should occur with African Americans who want to donate a kidney, the transplant community is still uncertain about what to do with test results indicating that a patient has a high-risk genotype, noted Newell. Generally, test results and risk should be discussed in the context of each patient’s individual risk profile. Specifically, APO-L1 variants likely need to be assessed alongside baseline fasting glucose, estimated glomerular filtration rate, obesity, smoking, and family and personal history of diabetes and hypertension, said Newell. “When you begin moving up the risk spectrum, I think that’s where a discussion about testing is really useful,” he said.

The donor’s age is another important risk factor. “We can’t say what will happen to the kidney function in younger donors with the high-risk genotype 20 and 30 years down the road,” said Tatapudi. “It may be wise to not donate.”

In clinical practice APO-L1 testing appears to be limited, although interest in it seems to be growing. In 2018, a survey of 383 transplant surgeons and nephrologists found that 87% supported APO-L1 testing, but just 14% actually offered it. However, 63% said they planned on using APO-L1 testing in the next year.

“These findings and communication with members of the transplant community suggest that more clinicians are using APO-L1 testing,” said study author Elisa J. Gordon, PhD, MPH, a medical ethicist and professor of surgery at Northwestern University Feinberg School of Medicine in Chicago.

At NYU Langone Transplant Institute, all African American living donors are offered APO-L1 genotyping as part of predonation testing, said Tatapudi. At Wake Forest Baptist Health, the transplant team discusses APO-L1 testing with people with African ancestry who pass the initial donor screening process. “We don’t mandate testing, but we encourage a discussion about testing because we think it helps stratify risk,” Freedman said. Meanwhile, Newell discusses genotyping and risk with potential donors but APO-L1 testing at Emory University School of Medicine is not standard.

Ethical Considerations

Testing has numerous ethical considerations that doctors need to contend with, said Gordon. For one, physicians are obligated to prevent unnecessary harm in living donors, who are considering a surgical procedure that provides them no medical benefit.

Living kidney donors who find out they have two APO-L1 gene variants might decide not to donate, which is well within their ethical prerogative, said Gordon. However, not donating may magnify the already existing disparities in African Americans’ access to living kidney transplantation.

Informed consent is another ethical obligation to consider. Notably, kidney donors think APO-L1 genetic testing could help them make decisions about donation. A 2018 survey found that 87% of 23 African Americans who had already donated their kidney said they would have wanted to undergo testing had it been offered to them. “Many wanted to learn about their own risk for end-stage renal disease and to prepare for the potential harms,” said Gordon, lead author of this report.

Additionally, Gordon found that 96% of donor-respondents thought APO-L1 testing should be offered routinely, while 61% said being informed about having the two variants would not have impacted their decision to donate.

Of course, potential donors have the right to refuse testing, said Freedman. Individuals might not want to get tested because of the stress that surrounds knowing they have the mutations or because of fears of losing insurance, he said.

Awaiting APOLLO Results

Many doctors are waiting for the results from APOLLO, expected to conclude in 2023, to help guide discussions with donors about genetic testing and what the results say about risk. In APOLLO, Freedman and his colleagues at 13 clinical centers are prospectively investigating the effects of APO-L1 risk variants on outcomes in living donors with African ancestry, as well as outcomes in recipients of kidneys from deceased and living kidney donors with these variants.

“I think that trial will probably help establish what role APO-L1 genotyping plays in kidney transplant,” commented Anthony Gregg, MD, FACMG, president of the American College of Medical Genetics and Genomics. “This is one example of where we’re able to leverage our knowledge of genomics to, very likely, change testing policy.”

What’s Ahead for Labs

Medical centers that decide to offer APO-L1 genetic testing need to ensure that it occurs in a CLIA-certified lab that offers top quality genetic testing, said Freedman.

Gregg envisions immunology labs with next-generation sequencing technologies at transplant centers as making APO-L1 testing part of standard procedure.

Currently, transplant labs that perform human leukocyte antigen (HLA) testing may not be the best place for APO-L1 testing to occur, said Tiffany Roberts, PhD, a transplant immunologist at Trager Transplant Center at Kentucky One Jewish Hospital in Louisville, which is participating in the APOLLO trial but does not yet offer APO-L1 genotyping in routine clinical care.

HLA laboratories at transplant centers are highly specialized and have a firm grasp of testing in their niche area, “but they may not yet have the experience nor the expertise in molecular testing methodologies to be able to perform APO-L1 genotyping with the rigor that should be required,” said Roberts. Validation and quality control of APO-L1 testing should be much more stringent than is typically required of assays in an HLA lab, she explained. These issues are likely to be addressed sooner rather than later as “the evidence is in the process of being gathered at this point and suggests that APO-L1 testing in African American living donors is warranted.”

Disclosure: Dr. Freedman and Wake Forest Baptist hold a patent for APO-L1 gene testing in clinical transplantation.

Heather Lindsey is a freelance medical writer in Maplewood, New Jersey. Email: [email protected]