Advancing Genetic Risk Assessment in Living Kidney Donation

Introduction

Clinical genetic testing has steadily increased in popularity with advances in available technologies and decreasing costs. ¹ As a result, there has also been a heightened interest in the potential impact of genetic testing in nephrology care, ¹ specifically surrounding living kidney donor (LKD) evaluation. However, the role of genetic testing in assessing the risk associated with living kidney donation varies widely, in policy and practice, among transplant centers. While LKD confers medical benefits to the recipient, it offers no direct medical benefit—and poses multiple risks—to the donor. Short-term risks are well-studied, and longer-term risks—most notably the development of ESKD—have been increasingly documented using registry databases. The lifetime risk of ESKD was estimated at 90 per 10,000 donors. ² When compared to matched, healthy non-donors, LKDs had an increased risk of ESKD over a median of 7.6 years. ² Though the estimated increased risk of ESKD attributable to donation is small, research has also shown that Black individuals are at a greater risk of developing this complication. ³ Genetic testing may have the potential to be an effective tool in screening LKDs, but its value in donor evaluation has yet to be proven. ⁴ Additionally, due to the lack of established, evidence-based guidelines, acceptance of genetic testing in donor evaluation is inconsistent, necessitating further research to assess the risks and benefits of LKD genetic testing. ⁴ This paper discusses the need for retrospective large-scale genetic studies on ESKD risk and explores the feasibility of conducting such research.

Current Limitations of Genetic Research with LKD

In 2010, Genovese et al., conducted an association analysis in African American individuals, comparing 1030 hypertension-attributed ESKD cases to 1025 geo-graphically matched controls, highlighting the significance of apolipoprotein L1 (APOL1) variants in the risk of CKD and ESKD among those of West African ancestry. ³ Possessing one kidney risk variant was associated with higher risk of CKD (odds ratio, 1.26; 95% confidence interval, 1.01 to 1.56), whereas possessing two kidney risk variants was associated with a stronger risk (odds ratio, 7.3; 95% confidence interval, 5.6 to 9.5) in the study's cohort. ³ Notably, over 30% of African American individuals have chromosomes that carry the APOL1 risk alleles associated with kidney disease (KD). ³ The large National Institutes of Health-funded APOL1 Long-Term Kidney Transplantation Outcomes Network study ^5,6 is currently being conducted to prospectively examine the effects of APOL1 kidney risk variants among Black LKDs. Though results are much anticipated, the APOL1 Long-Term Kidney Transplantation Outcomes Network study lacks the power to detect subtle differences in CKD/ESKD risk between those with high-risk and lower-risk variants. Furthermore, the follow-up period is not anticipated to be adequate in capturing long-term outcomes. However, the ongoing Living Donor Extended Time Outcome study, following 1100 African American donors over 20 years, may provide clearer insights into KD risk in those with two kidney risk variants. Nonetheless, other genetic KDs and potential markers may also play a critical role and deserve dedicated exploration, in parallel with efforts to study APOL1. Genetic testing is hindered by the lack of evidence to guide accurate risk-benefit analysis and interpretation of test results ⁴ and, in turn, a lack of ethical guidance on counseling LKD candidates about available genetic tests, their potential benefits, and possible consequences. ⁴

The Need for Comprehensive Genetic Risk Studies

In a recent exome-sequencing study of 3315 patients with CKD, diagnostic variants were found in over 300 patients. ⁷ These results were comparable to those seen in cancer cases, where genomic diagnostics are routinely used, demonstrating the potential utility of genetic testing in addressing diagnostic challenges. ⁷ Routine office workups and kidney biopsy findings are often used to diagnose CKD, however, in the early stages, CKD can be clinically silent. Consequently, the diagnosis of CKD and determination of its etiology may be delayed or remain inconclusive. ⁷ Of CKD patients, nearly one third report a family history of nephropathy, signifying a genetic component with the disease. ⁷ Genetic testing could help address this gap by improving our understanding of disease pathogenesis. ¹ Currently, there is limited research on how genetic and non-genetic risk factors interact to influence ESKD risk in LKDs. ⁸ Additionally, because ESKD takes many years to develop, prospective studies are largely impractical. As such, there is an urgent need for retrospective research initiatives that evaluate the role of a plethora of genes associated with CKD and their interaction with other risk factors. This will require partnerships with national registries to enable identification and contact of the entire population of LKDs, along with a well-designed retrospective case-cohort research plan and the collection of both genetic and non-genetic potential risk factors. Ultimately, this approach will yield improved accuracy of risk prediction methods, patient decision-making, and outcomes.

Challenges and Ethical Considerations

There are several challenges associated with conducting large-scale studies involving genetic testing (Figure 1). The success of a large-scale study is contingent on ethical and effective recruitment, coordination, and stakeholder collaboration to ensure feasibility and impact.

Figure 1. Challenges and ethical considerations in genetic testing.

A cluster map illustrating the main challenges and ethical considerations identified in genetic testing of LKDs. ^1,5,9,10 LKD, living kidney donor.

LKD Perspectives on Genetic Testing

In our preliminary research, approved by New York University Langone Health Institutional Review Board (i22-00888), we interviewed participants (N511) identified as LKDs. Each completed Natera's Renasight genetic panel, which analyzes 385 genes associated with CKD, and received genetic counseling. Among these participants, seven were related donors. Results suggested that participants were satisfied with their decision to undergo genetic testing for CKD risk variants and expressed no regret about their previous decision to donate, even after receiving test results. Participants also noted that genetic testing would be helpful to increase their understanding of donor and hereditary risks. While genetic testing may identify genetic risk factors for CKD, it can also lead to a change in lifestyle by encouraging patients to pursue environmental and/or clinical interventions to mitigate the risk following donation.

To support participants effectively, pre and post-test counseling was implemented. Before counseling, participants were asked to complete a survey on family history and relationship to recipient, allowing counselors to tailor strategies—especially for related donors, who may differ in risks and motivations. In the case that clinical questions arose during consent, participants would be referred for an additional counseling session. Once results were available, counselors created a care plan. Negative results were released automatically; for positive results, counselors attempted contact up to three times before release. All participants were given a visit summary with a defined clinical action plan which provides guidance on any actionable insights. Our preliminary research suggests that increasing access to trained genetic counselors provides individuals with the necessary support to cope with any psychological distress that may be experienced during and after genetic testing. Those who completed post-test counseling described it as “informative” and expressed satisfaction with the genetic counselor's ability to answer questions and explain results comprehensively. Genetic counselors are ideal for this role, because of their combined expertise in genetic testing and psychosocial counseling. ¹ These results highlight the importance of transparency, education, and communication with regard to genetic testing for LKDs.

Assessing ESKD genetic risk for LKDs should go beyond just genetic testing for APOL1. To more accurately assess the risk associated with living kidney donation, a large-scale study utilizing novel and retrospective methodology is required to validate genetic variants associated with CKD.

Data Availability Statements

Due to the sensitive nature of the questions asked in this study, interview respondents were assured raw data would remain confidential and would not be shared.