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Integrating APOL1 Kidney-risk Variant Testing in Live Kidney Donor Evaluation: An Expert Panel Opinion

Doshi, Mona D. MD1; Gordon, Elisa J. PhD, MPH2; Freedman, Barry I. MD3; Glover, Craig4; Locke, Jayme E. MD, MPH5; Thomas, Christie P. MD6,7

Author Information
doi: 10.1097/TP.0000000000003641
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INTRODUCTION

Live kidney donors (LKDs) of African ancestry have a higher risk for developing end-stage kidney disease (ESKD) than demographically matched healthy nondonors.1 Retrospective data from the general population reveal that having 2 apolipoprotein L1 gene (APOL1) kidney-risk variants (KRVs) (ie, G1G1, G2G2, or G1G2) contributes to this risk.2 Two APOL1 KRVs vary in frequency around the world with approximately 11%–32% in African Americans (AAs), sub-Saharan Africans, and Western Africans, 5%–22% in Afro-Brazilians, Afro-Caribbeans, or Black Hispanics/Latinx, and approximately 0% in European Americans.3

APOL1 genetic testing is available, and in the absence of prospective data, the role of APOL1 genotyping in LKD candidate selection remains uncertain. Recent survey data reported wide variation in genetic testing practices and clinical use of results during the donor selection process.4 There are several ethical issues concerning the use of genetic testing to determine donor eligibility, which are central to development of policy around APOL1 genetic testing, release of results, and counseling.5 The National Institutes of Health initiated the prospective multicenter U01 “APOL1 Long-term Kidney Transplantation Outcomes Network” (APOLLO) to help understand the impact of APOL1 KRVs on long-term kidney function of donors and recipient outcomes.6 As the transplant community awaits the results of definitive research, the American Society of Transplantation’s Living Donor Community of Practice commissioned a workgroup to develop interim recommendations for APOL1 genetic testing. The workgroup, comprising a transplant nephrologist, a transplant surgeon, a nephrologist with expertise in genetics, a former LKD of African ancestry, a general nephrologist, and a bioethicist, produced this report.

APOL1 and Native Kidney Disease

The discovery of the association of APOL1 KRVs and chronic kidney disease (CKD) revealed that unrelated forms of nondiabetic nephropathy comprise a spectrum of APOL1-related diseases, including hypertension-attributed nephropathy, focal segmental glomerulosclerosis, HIV-associated nephropathy, and severe lupus nephritis.7 However, most people with 2 APOL1 KRVs do not develop ESKD. Second hits or modifying factors such as viral infections are required to initiate kidney disease.8

APOL1 and Deceased Donor Kidney Transplantation

Kidneys transplanted from deceased donors with 2 APOL1 KRVs are associated with premature allograft failure and a ~2-fold increased risk of allograft loss compared with kidneys from donors with 1 or 0 APOL1 KRVs.9 Similar to native kidney disease, a second insult may be required to develop allograft failure after transplanting kidneys from AA deceased donors carrying 2 APOL1 KRVs.

APOL1 and Former Living Kidney Donors

A cohort of 136 AA LKDs with postdonation follow-up information was stratified by APOL1 genotype.10 Donors with 2 APOL1 KRVs had lower predonation and postdonation estimated glomerular filtration rates (eGFRs) and faster annual declines in eGFR than donors with 0 or 1 KRV (1.19 versus 0.4 mL/min/1.73 m2 per y; P = 0.02). Of 19 donors carrying 2 APOL1 KRVs, 2 (11%) developed ESKD. However, the 11% frequency of ESKD in LKDs with 2 APOL1 KRVs in this study may not be an accurate estimate because of the small sample size and inability to genotype all eligible participants.

APOL1 and Risk of Kidney Disease in Young, Healthy Potential Donors

A cohort of 3438 individuals aged 18–30 y who were deemed medically suitable to donate was retrospectively assessed for development of CKD stage 3 or higher after 25 y.11 Among the 18-y olds, the 25-y projected CKD risk was higher in AAs than Whites and varied by sex. The risk of CKD increased further among those with 2 APOL1 KRVs. The risk of CKD was much greater for individuals with 2 APOL1 KRVs who presented with relative contraindications for donation, including impaired fasting blood sugar, body mass index >30 kg/m2, eGFR 90–99 mL/min/1.73 m2, smoking, and a family history of hypertension and diabetes. Based on the risk calculator in this article, an 18-y-old male individual with 2 APOL1 KRVs and no other risk factors was anticipated to have an equivalent risk of CKD as a 30-y-old AA female individual with a family history of diabetes and 0 APOL1 KRVs. The risk of CKD associated with APOL1 KRVs was similar to some of the other risk factors that routinely appear during donor evaluation and generally do not raise similar concerns among transplant professionals.

Providers’, AA LKDs’, and Community Members’ Attitudes About APOL1 Testing

In a recent survey of transplant nephrologists, transplant surgeons, and community nephrologists, most physicians believed that all potential AA LKDs should be informed about the option of APOL1 testing.12 Similarly, AA LKDs and members of the public recommended that APOL1 testing be routinely offered to donors in clinical care to foster informed decision making about donation.13,14 Half of the surveyed physicians would not proceed or strongly recommend against donation in potential LKDs carrying 2 APOL1 KRVs. However, both AA LKDs and members of the public opposed it as such a policy would violate donor autonomy.13,15 Instead, most community members preferred that the physician and potential LKD together make a shared decision about donation.14

Considering the Available Information, the AST LDCoP APOL1 Workgroup Proposes the Following Guidelines:

  • 1. Who should be educated, by whom, and when?

All potential LKD candidates who self-report African ancestry (including AA, Afro-Caribbeans, and Hispanic/Latinx Blacks, Africans) should be informed about the APOL1 gene and risk of ESKD. Although individuals from North Africa and those with mixed ancestry are less likely to carry 2 APOL1 KRVs, they should still be informed about APOL1 and the lower likelihood of carrying 2 APOL1 KRVs. Providers should ask potential donors about their ancestry and ethnic identity rather than rely on their own perceptions or medical records. Counseling can be provided by a transplant team member under the guidance of a transplant nephrologist early in the evaluation process.

  • 2. Who should be tested?

AA LKD candidates with known independent risk factors for the development of ESKD such as young age (<44 y), male gender, history of smoking, obesity (body mass index >30 kg/m2), hypertension, low to normal eGFR (90–99 mL/min/1.73 m2), and a family history of ESKD, hypertension, or diabetes in a first-degree relative may be considered for testing. Among donor candidates with 2 or more of these risk factors, the absence of 2 APOL1 KRVs has not been reported to mitigate their future risk of ESKD; such individuals should be counseled about their elevated risk of ESKD before genetic testing.16 For LKD candidates who want to pursue donation after adequate discussion and their risk of ESKD is deemed acceptable by the transplant center, genetic testing for APOL1 KRVs may be offered for further risk stratification. Genetic testing should only be offered after appropriate counseling. LKDs who wish to donate, regardless of their genetic test result, should be allowed to proceed if their risk of ESKD does not exceed the acceptable threshold set by their transplant program.

  • 3. When should testing be offered?

If genetic testing is deemed appropriate, it should only be offered to candidates who have passed preliminary medical and psychosocial evaluation, preferably not during the initial screening. This approach is less expensive and provides physicians with the chance to counsel potential LKDs when they have a clinical or laboratory abnormality that may preclude them from donation, regardless of genotype. APOL1 testing may be performed before HLA typing, crossmatching, or computed tomography scanning, because these tests are less likely to rule out donors.

  • 4. What topics should be covered in counseling?

Transplant programs should address the pros and cons of APOL1 genetic testing before ordering the test. They should acknowledge the lack of robust data on the postdonation risk of ESKD in potential LKDs carrying 2 APOL1 KRVs and discuss the small study reporting an 11% risk of ESKD 12 y after donation. Programs should also inform potential LKDs that not all individuals carrying 2 APOL1 KRVs develop kidney disease and “second-hits” are required for deterioration in kidney function. Currently, the nature of second hits beyond certain viral infections is unknown. Transplant programs should inform LKD candidates about the national APOLLO study so that candidates can stay apprized of the study results in their decision to donate. The results of the APOLLO study will improve our understanding of the risks involved in donating among individuals with 2 APOL1 KRVs. Other topics of discussion should include, but are not limited to, the lack of specific treatments to prevent APOL1-associated kidney disease, the risk to themselves and to the potential recipient of not donating, and the possibility of psychological distress upon learning that potential LKDs have 2 APOL1 KRVs. Finally, counseling should discuss the role of the Genetic Information Nondiscrimination Act in protecting donors from employer and insurance-based discrimination. Counseling should be offered by a genetic counselor, nephrologist, or transplant team member trained to deliver counseling about APOL1 before donation and to deliver counseling with results thereafter.

  • 5. How should positive test results be approached?

The workgroup supports shared decision making between the transplant team and potential LKDs about donating in the context of APOL1 KRVs. Shared decision making entails 2-way communication between donors expressing their preferences and values and providers disclosing information about the procedure, its risks, benefits, and alternatives, out of respect for donor autonomy. As with other single risk factors, the isolated finding of 2 APOL1 KRVs should not be enough to automatically exclude the donor candidate. The presence of ≥2 baseline risk factors for future ESKD (including 2 APOL1 KRVs and other risk factors listed above) should be considered in the informed consent discussion.11 However, the team that recognizes the donor-recipient relationship may influence the donor’s decision. Some potential LKDs may wish to donate despite being informed of their increased future risk for ESKD; other LKDs may want the physician to decide for them. In either case, the risk of ESKD in the donor should be lower than the established acceptable threshold for the transplant center.

  • 6. Should recipients be informed of the living donor’s genotype?

To protect the donor’s privacy, the transplant team should not reveal the donor candidate’s APOL1 genotype to the recipient. Donors should decide whether they wish to discuss their genetic test results with the recipient and with family members. If the LKD candidate requests and the potential recipient agrees, transplant programs can jointly discuss genotype results and their implications with the pair.

  • 7. Should a donor with 2 APOL1 KRVs be discouraged to donate because of concerns about recipient outcomes?

Currently, no data exist on the impact of the living donor APOL1 genotype on recipient outcomes. The currently available data suggest that transplantation from a LKD, even with 2 APOL1 KRVs, is better for the recipient’s health than remaining on dialysis or waiting to receive a transplant from a deceased donor.

  • 8. Who should bear the cost of APOL1 genotyping?

Testing costs range from $300 to $500 and should be covered as a part of the Organ Acquisition Cost by the transplant center.

SUMMARY AND FUTURE DIRECTIONS

Results of the NIH-funded APOLLO study will not be available to inform clinical practice for several years. Until then, APOL1 genetic testing may supplement the already comprehensive donor evaluation process, as needed, for risk stratification and may be ordered after appropriate counseling has been provided. The decision to donate, in the case of a high-risk genotype, should be handled through shared decision making. Such an approach resonates with LKDs and community members because it addresses matters of consent and donor autonomy. These recommendations are intended to guide transplant centers in developing their own policies around APOL1 genetic testing and donor acceptance criteria. While the transplant community must await new findings and continue to improve its understanding of donor ESKD risk, there should not be a rush to pronounce judgment on the significance of APOL1 KRVs in living donors until firm data are available.

ACKNOWLEDGMENTs

This article is a work product of the American Society of Transplantation’s Live Donor Community of Practice.

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