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American Journal of Kidney Diseases

Race, Ancestry, and Genetic Risk for Kidney Failure

Published:September 10, 2022DOI:https://doi.org/10.1053/j.ajkd.2022.08.008
      Commentary on Nadkarni GN, Fei K, Ramos MA, et al. Effects of testing and disclosing ancestry-specific genetic risk for kidney failure on patients and health care professionals: A randomized clinical trial. JAMA Netw Open. 2022;5(3):e221048.
      Racial and ethnic disparities in chronic kidney disease (CKD), up to and including kidney failure, have been well documented in the United States and globally.
      • Norton J.M.
      • Moxey-Mims M.M.
      • Eggers P.W.
      • et al.
      Social determinants of racial disparities in CKD.
      ,
      • Thurlow J.S.
      • Joshi M.
      • Yan G.
      • et al.
      Global epidemiology of end-stage kidney disease and disparities in kidney replacement therapy.
      There are myriad factors underlying these observations, including race-based inequities in the distribution of health-affirming resources and opportunities (eg, structural racism),
      • Eneanya N.D.
      • Boulware L.E.
      • Tsai J.
      • et al.
      Health inequities and the inappropriate use of race in nephrology.
      the cumulative burden of psychological and neurohormonal stress termed “weathering,”
      • Geronimus A.T.
      The weathering hypothesis and the health of African-American women and infants: evidence and speculations.
      and more, that contribute to the development and/or progression of major CKD risk factors (hypertension and diabetes), CKD, cardiovascular disease, and other chronic diseases.
      • Norton J.M.
      • Moxey-Mims M.M.
      • Eggers P.W.
      • et al.
      Social determinants of racial disparities in CKD.
      In addition to these factors, recent discoveries have shown that having 2 coding variants of the apolipoprotein L1 (APOL1) gene (G1/G1, G1/G2, G2/G2) is associated with an increased likelihood of developing CKD and kidney failure.
      • Genovese G.
      • Friedman D.J.
      • Ross M.D.
      • et al.
      Association of trypanolytic ApoL1 variants with kidney disease in African Americans.
      ,
      • Tzur S.
      • Rosset S.
      • Shemer R.
      • et al.
      Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene.
      This “high-risk”-for-CKD genotype is found almost exclusively in persons of West sub-Saharan African ancestry, thereby typically impacting a subset of persons who self-identify as Black or African American. These polymorphisms are hypothesized to have developed as a protective response to trypanosomiasis-induced sleeping sickness.
      • Genovese G.
      • Friedman D.J.
      • Ross M.D.
      • et al.
      Association of trypanolytic ApoL1 variants with kidney disease in African Americans.
      Notable features of the high-risk APOL1 genotype and associated “APOL1-associated nephropathy” include the following: (1) an ancestral heritage that primarily relates back to persons from West sub-Saharan Africa; (2) risk of kidney disease that is apparently only increased in persons with 2 APOL1 risk alleles (ie, high-risk genotype); (3) knowledge that not all individuals with a high-risk genotype develop kidney disease (only an estimated 20% do); (4) the incidence and progression of many forms of APOL1 nephropathies are associated with “second hit” triggers, such as HIV infection,
      • Kopp J.B.
      • Nelson G.W.
      • Sampath K.
      • et al.
      APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy.
      SARS-CoV-2 infection,
      • May R.M.
      • Cassol C.
      • Hannoudi A.
      • et al.
      A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19).
      ,
      • Wu H.
      • Larsen C.P.
      • Hernandez-Arroyo C.F.
      • et al.
      AKI and collapsing glomerulopathy associated with COVID-19 and APOL 1 high-risk genotype.
      systemic lupus erythematosus,
      • Freedman B.I.
      • Langefeld C.D.
      • Andringa K.K.
      • et al.
      End-stage renal disease in African Americans with lupus nephritis is associated with APOL1.
      other proinflammatory stimuli including iatrogenic interferons,
      • Markowitz G.S.
      • Nasr S.H.
      • Stokes M.B.
      • D'Agati V.D.
      Treatment with IFN-{alpha}, -{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis.
      and reduced nephron endowment following kidney donation;
      • Doshi M.D.
      • Ortigosa-Goggins M.
      • Garg A.X.
      • et al.
      APOL1 genotype and renal function of black living donors.
      (5) a typical histologic profile of glomerular sclerosis accompanied by tubulointerstitial and vascular changes;
      • Freedman B.I.
      • Burke W.
      • Divers J.
      • et al.
      Diagnosis, education, and care of patients with APOL1-associated nephropathy: a Delphi consensus and systematic review.
      ,
      • Palmer N.D.
      • Freedman B.I.
      APOL1 and progression of nondiabetic nephropathy.
      and (6) although this APOL1-associated genetic risk is unrelated to societal differences, disease activation is grounded in many factors that are driven by societal inequities.
      The current lack of specific treatment for APOL1-associated kidney disease and the incomplete penetrance of kidney disease risk in persons with a high-risk APOL1 genotype raise the question regarding the utility of testing self-identified Black or African American persons for APOL1 genotype. For example, establishing that a patient with early-stage CKD also carries a high-risk APOL1 genotype may lead to the patient’s becoming worried and anxious about the possibility of progressing rapidly to kidney failure with no opportunity for treatment to potentially slow progression. Similarly, informing a healthy person who is currently free of kidney disease that they have a high-risk APOL1 genotype may also provoke anxiety about the future and may possibly lead to life or health insurance discrimination. Although the Genetic Information Nondiscrimination Act bars the use of genetic information in health insurance and employment, it does not bar its use for life insurance purposes, and such laws are not fully protective.
      • Freedman B.I.
      • Burke W.
      • Divers J.
      • et al.
      Diagnosis, education, and care of patients with APOL1-associated nephropathy: a Delphi consensus and systematic review.
      It is not surprising that recommendations from broad constituent groups have been equivocal regarding APOL1 genetic testing in the clinical setting (Box 1).
      • Freedman B.I.
      • Burke W.
      • Divers J.
      • et al.
      Diagnosis, education, and care of patients with APOL1-associated nephropathy: a Delphi consensus and systematic review.
      However, early surveys show that many people in the African American community are indeed interested in knowing their APOL1 genotype, and only a paucity have expressed concerns or worry about their results and the implications of those results.
      • Umeukeje E.M.
      • Young B.A.
      • Fullerton S.M.
      • et al.
      You are just now telling us about this? African American perspectives of testing for genetic susceptibility to kidney disease.
      • Young B.A.
      • Blacksher E.
      • Cavanaugh K.L.
      • et al.
      Apolipoprotein L1 testing in African Americans: involving the community in policy discussions.
      • Young B.A.
      • Fullerton S.M.
      • Wilson J.G.
      • et al.
      Clinical genetic testing for APOL1: are we there yet?.
      Whether disclosing APOL1-associated nephropathy testing results to patients and their clinicians may have a positive effect on patients’ health is unknown. The availability of such knowledge might better inform the decision to test persons at risk for APOL1-associated nephropathy.
      Adapted Excerpts from Consensus Statements on APOL1-Associated Nephropathy
      • APOL1-associated nephropathy should be considered in all patients with progressive kidney disease and a family history of CKD, particularly those with West African ancestry.
      • Regardless of ancestry, APOL1-associated nephropathy should be considered in all patients with kidney disease and a family member with a confirmed high-risk APOL1 genotype.
      • Clinical factors that are relevant to considering APOL1-associated nephropathy include hypertension, nondiabetic nephropathy, and rapid progression of CKD despite quality care.
      • For a patient with APOL1-associated nephropathy, important advantages of learning their APOL1 status may include:
        • a better understanding of the likelihood of rapid disease progression
        • an awareness that they are not to blame for their disease
        • greater knowledge about their ancestry
        • increased motivation to live a healthy lifestyle and control CKD risk factors
        • the potential for family members to learn their own APOL1 status and potential risk for CKD
        • the potential opportunity to participate in a clinical trial testing a treatment for APOL1-associated nephropathy
      • Clinicians will require confidence in communicating the findings from APOL1 testing to patients in a clear and effective way that minimizes patient confusion and misunderstanding of APOL1 testing in patients at risk.
      • Effective communication is necessary to minimize patients’ fear, distress, anxiety, or a sense of futility, as well as any confusion about the meaning of high-risk APOL1 status, as a potential outcome of APOL1 testing.
      • Potential concerns related to APOL1 testing that each patient should be aware of include:
        • cost associated with testing
        • implications of a positive test
        • fear of being diagnosed with APOL1-associated nephropathy
        • concern about disease progression
        • discrimination (eg, job, life insurance), as well as future health insurance access and cost
        • concern that there is no treatment and therefore no value in knowing
        • concern for family members who may have a high-risk APOL1 genotype
      • When health care professionals discuss APOL1 testing with their patients, they should be honest and transparent about our current understanding of APOL1, take time to discuss APOL1 with patients, listen to their concerns, answer questions, and provide information sources that are balanced, easy to use and understand, and reliable.
      Reproduced in modified form from Freedman et al
      • Freedman B.I.
      • Burke W.
      • Divers J.
      • et al.
      Diagnosis, education, and care of patients with APOL1-associated nephropathy: a Delphi consensus and systematic review.
      with permission of the copyright holder (American Society of Nephrology).
      Interestingly, not all studies have found that clinicians, researchers, and community members are equally positive about the use of APOL1. West et al
      • West KM
      • Cavanaugh KL
      • et al.
      Stakeholder perspectives on returning nonactionable apolipoprotein L1 (APOL1) genetic results to African American research participants.
      reported more than 80% of a group of 76 stakeholders (clinicians, researchers, and community members) expressed the opinion that research participants should be offered their APOL1 results, with the majority of those reluctant being clinicians and researchers. A study by Young et al
      • Young B.A.
      • Blacksher E.
      • Cavanaugh K.L.
      • et al.
      Apolipoprotein L1 testing in African Americans: involving the community in policy discussions.
      reported similar findings, with clinicians and researchers generally being more negative than community members about APOL1 testing in routine clinical care. These concerns ranged from possibly causing patient and family members psychological harm to potential provider frustration having to return a test result with important clinical implications for which there is no treatment.
      • Young B.A.
      • Blacksher E.
      • Cavanaugh K.L.
      • et al.
      Apolipoprotein L1 testing in African Americans: involving the community in policy discussions.
      ,
      • Young B.A.
      • Fullerton S.M.
      • Wilson J.G.
      • et al.
      Clinical genetic testing for APOL1: are we there yet?.
      Given these patient and provider concerns of a patient having knowledge of a high-risk APOL1 genotype, Nadkarni et al
      • Nadkarni G.N.
      • Fei K.
      • Ramos M.A.
      • et al.
      Effects of testing and disclosing ancestry-specific genetic risk for kidney failure on patients and health care professionals: a randomized clinical trial.
      examined the effects of testing APOL1 genotype in patients with hypertension and without CKD who self-reported as having African ancestry and disclosing the results to both patients and their providers.

      What Does This Important Study Show?

      The study by Nadkarni et al used a pragmatic randomized clinical trial design that enrolled more than 2,000 patients from 15 academic, community, and safety-net practices across 2 health systems. Inclusion criteria were patients who were English speaking, were 18-70 years of age with an electronic health record diagnosis of hypertension and/or taking antihypertensive medications, and were receiving primary care at a participating site in the past year. Exclusion criteria included diabetes, CKD, cognitive impairment, pregnancy, and moving away during the study period. Patients and providers were assigned to receive results immediately (intervention) or after a 12-month delay (wait-list control).
      Primary study outcomes included both the change in 3-month systolic blood pressure (BP) and 12-month urine kidney disease screening between intervention group patients with high-risk APOL1 genotypes compared to those with low-risk APOL1 genotypes. Secondary outcomes compared the same clinical outcomes between intervention group patients with high-risk APOL1 genotypes and wait-list controls. Exploratory analyses included psychobehavioral factors including lifestyle changes and medication adherence.
      Participants had a mean age of 53 years and a mean BP of 134/86 mm Hg. Patients received APOL1 genetic testing results from trained staff; in addition, their providers received results through electronic health records. In response to disclosure of APOL1 results, the study team found that patients with high-risk APOL1 genotype had a more robust response in taking positive action in almost all health domains compared to those with low- or no-risk APOL1 genotype. Those with high-risk compared to low-risk APOL1 genotype reported more positive lifestyle changes (eg, better dietary and exercise habits; 59% vs 37%; P < 0.001), increased urine testing for albuminuria (12% vs 7%), increased BP medication use (10% vs 5%; P = 0.005), and a trend toward a greater fall in systolic BP (6 vs 3 mm Hg; P = 0.01). Importantly, 97% of patients reported they would get tested again. In addition, the exploratory assessment of psychobehavioral factors found significantly more patients with high-risk APOL1 genotypes than patients with low-risk APOL1 genotypes reported making positive lifestyle changes and improved medication adherence.
      This study is the first to report that disclosing the presence of high-risk APOL1 genotype profile to patients with hypertension and their clinicians led to improved CKD prevention/early intervention actions without report of untoward psychologic effects from the knowledge of having a high-risk medical condition. These findings support the potential of implementing genetic testing in the primary care setting as well as the importance of using trained professionals to transmit sensitive genetic results.
      The study has some limitations. The study excluded patients with CKD, and their response as well as that of their providers may differ in that setting. There may have also been confounding (eg, kidney function, severity and treatment of hypertension, lifestyle factors) that could affect study outcomes. The study was unable to capture the impact of returning patient results on their family members. This study also had several strengths. Nadkarni et al used a unique approach by testing APOL1 status in patients with self-reported African ancestry and CKD risk (hypertension) treated in a primary care setting. With poor control of hypertension being both a traditional CKD risk factor and a potential accelerator of APOL1-associated nephropathy, the impact of knowledge regarding additional CKD risk on both patient and provider actions was assessed and found to be helpful. This has powerful implications for a large percentage of patients who may feel less internalized blame with this knowledge and thus be more motivated to do all they can do. Moreover, the use of trained staff supervised by a senior genetic counselor to return test results in a sensitive and consistent manner was another strength of this study.

      How Does This Study Compare With Prior Studies?

      The study by Nadkarni et al assessed the impact of testing of APOL1 status in a group of patients at risk for CKD, in contrast to most studies that have examined perceptions of APOL1 testing in patients with CKD (including kidney transplant recipients) and, to a lesser extent, kidney donors. Recent studies by Umeukeje et al,
      • Umeukeje E.M.
      • Young B.A.
      • Fullerton S.M.
      • et al.
      You are just now telling us about this? African American perspectives of testing for genetic susceptibility to kidney disease.
      Young et al,
      • Young B.A.
      • Blacksher E.
      • Cavanaugh K.L.
      • et al.
      Apolipoprotein L1 testing in African Americans: involving the community in policy discussions.
      and West et al
      • West KM
      • Cavanaugh KL
      • et al.
      Stakeholder perspectives on returning nonactionable apolipoprotein L1 (APOL1) genetic results to African American research participants.
      used a series of interview or focus group techniques that included African American community participants, scientific advisors, researchers, clinicians, bioethicists, patient advocates, and representatives from professional organizations and/or federal funding agencies. They found strong support from study participants for developing educational materials about APOL1 for community members and clinicians, the use of APOL1 testing in kidney transplant programs, returning APOL1 results to research participants, and the need to building trust between the African American community and the broader medical community.
      • Young B.A.
      • Blacksher E.
      • Cavanaugh K.L.
      • et al.
      Apolipoprotein L1 testing in African Americans: involving the community in policy discussions.
      However, given the lack of treatment and the potential risk of activating psychological burdens, such as stigma, discrimination, and more, there was mixed support offering APOL1 testing in a clinical care setting, though a trend to offer support was noted more so from patient stakeholders than from health professionals.
      • Umeukeje E.M.
      • Young B.A.
      • Fullerton S.M.
      • et al.
      You are just now telling us about this? African American perspectives of testing for genetic susceptibility to kidney disease.
      • Young B.A.
      • Blacksher E.
      • Cavanaugh K.L.
      • et al.
      Apolipoprotein L1 testing in African Americans: involving the community in policy discussions.
      • Young B.A.
      • Fullerton S.M.
      • Wilson J.G.
      • et al.
      Clinical genetic testing for APOL1: are we there yet?.
      Similar conclusions were reached by a multidisciplinary group that used a Delphi consensus process and conducted a systematic literature review regarding practical measures for caring for patients who may have APOL1-associated nephropathy.
      • Freedman B.I.
      • Burke W.
      • Divers J.
      • et al.
      Diagnosis, education, and care of patients with APOL1-associated nephropathy: a Delphi consensus and systematic review.
      They further suggested there was a need to increase awareness of both racial health disparities in CKD and of APOL1-associated nephropathy among key stakeholders, as well as an urgent need for research to develop a specific treatment.

      What Are the Implications for Nephrologists?

      It is important for practicing physicians to recognize that a patient with unclear reasons for the development or progression of CKD may have an underlying high-risk genetic disorder such as APOL1-associated nephropathy.
      • Foster M.C.
      • Coresh J.
      • Fornage M.
      • et al.
      APOL1 variants associate with increased risk of CKD among African Americans.
      ,
      • Kopp J.B.
      • Winkler C.A.
      • Zhao X.
      • et al.
      Clinical features and histology of apolipoprotein L1-associated nephropathy in the FSGS clinical trial.
      A family history of CKD as well as a family history of West African ancestry would help to prioritize testing for the presence of a high-risk APOL1 genotype. However, the lack of such history should not preclude APOL1 genotype testing, especially in patients with glomerular sclerosis, because high-risk APOL1 genotype may be found in subsets of such patients who may not self-identify as Black or African American.
      • Kopp J.B.
      • Winkler C.A.
      • Zhao X.
      • et al.
      Clinical features and histology of apolipoprotein L1-associated nephropathy in the FSGS clinical trial.
      Thus, such testing should be included alongside the continued search for other causes of CKD progression, such as nonadherence, occult inflammatory disease, and autosomal dominant polycystic kidney disease, among other possible causes. Moreover, the significant benefits associated with reporting APOL1 genotype results to patients with hypertension without CKD in the study by Nadkarni et al argues in favor of returning APOL1 results to not only research participants but also patients at risk. The finding that providing APOL1 test results led to a reduction in systolic BP, increased kidney disease screening, and improved self-reported behavior changes in patients with high-risk genotypes was unexpected, given a prior Cochrane Review by Hollands et al
      • Hollands G.J.
      • French D.P.
      • Griffin S.J.
      • et al.
      The impact of communicating genetic risks of disease on risk-reducing health behaviour: systematic review with meta-analysis.
      that found communicating DNA-based risk estimates did not change behavior. This novel finding can, however, help to allay the previously reported concerns by some providers of there being no tangible clinical management action from returning APOL1 results to patients. If the APOL1 result is entered into a privacy-protected section of the patient’s electronic medical record, it may lessen concern about discrimination by life insurance providers. As providers, we also need to be cognizant of not only the potential impact of APOL1 testing for the patient but also the potential implications for family members. Such information from knowing a nonactionable risk result may also cause them anxiety and concern regarding potential stigma and discrimination and may cause them to possibly act upon the information inappropriately if misunderstood, especially if it is not transmitted by a trained professional. As our understanding evolves regarding CKD—including APOL1-associated nephropathy—and its treatment, we must remain diligent regarding the intersection of social and biological determinants of health if we are to bring the best care to all of our patients each and every day.

      Article Information

      Authors’ Full Names and Academic Degrees

      Opeyemi A. Olabisi, MD, PhD, Susanne B. Nicholas, MD, MPH, PhD, and Keith C. Norris, MD, PhD.

      Support

      Dr Olabisi is supported by NIH grant 5R01MD016401. Dr Nicholas is supported by NIH grants R01MD014712, P50MD017366, U2CDK129496, the Terasaki Institute of Biomedical Innovation , the Centers for Disease Control and Prevention , Goldfinch Bio , Bayer , and Travere Pharmaceutical , Inc. Dr Norris is supported in part by NIH grants UL1TR000124, P30AG021684, and P50MD017366.

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Peer Review

      Received July 1, 2022, in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form August 31, 2022.

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