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APOL1 Risk Variants, Acute Kidney Injury, and Death in Participants With African Ancestry Hospitalized With COVID-19 From the Million Veteran Program

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Are APOL1 high-risk genotypes observed in individuals with African ancestry associated with acute kidney injury (AKI) and death following hospitalization for COVID-19?

Findings  In this cohort of 990 veterans with African ancestry hospitalized with COVID-19, 1 in 8 had APOL1 high-risk genotypes. Of those with high-risk genotypes, 51.2% had AKI, and 19.2% died, suggesting that high-risk genotype may be associated with a 2-fold increase in the odds of severe AKI and death; this increased risk was observed even in patients with normal kidney function prior to COVID-19.

Meaning  APOL1 high-risk genotypes were associated with increased odds of AKI, AKI severity, and death in individuals with African ancestry hospitalized with COVID-19.


Importance  Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates.

Objective  Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19–associated AKI and death.

Design, Setting, and Participants  This retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information.

Exposures  The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group).

Main Outcomes and Measures  The primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m2).

Results  Of the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021.

Conclusions and Relevance  In this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.

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Article Information

Accepted for Publication: December 25, 2021.

Published Online: January 28, 2022. doi:10.1001/jamainternmed.2021.8538

Corresponding Author: Adriana M. Hung, MD, MPH, Tennessee Valley Healthcare System, Division of Nephrology and Hypertension, Vanderbilt University, 1611 21st Ave S, S3223 MCN, Nashville, TN 37232 (adriana.hung@vumc.org).

Author Contributions: Adriana Hung, Otis Wilson, Zhihong Yu, and Hua Chang Chen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Design and conduct of the study: All Authors

Collection, management, analysis, and interpretation of the data: Hung, Siew, Wilson, Zhihong Yu, Hua Chang Chen,

Drafting the manuscript: Adriana M. Hung, Siew, Bick, Tuteja, Hunt.

Critical revision of the manuscript for important intellectual content: All authors

Statistical Analysis: Zhihong Yu, Ran Tao, Hua Chang Chen, Robert A. Greevy

Decision to submit the manuscript for publication: All Authors.

Statistical analysis: Hung, Yu, Chen, Wendt, Wilson, Greevy, Akwo, Zhou, Iyengar, Robinson-Cohen, Tao.

Obtained funding: Hung, Gaziano, Chang.

Administrative, technical, or material support: Hunt, Ho, Huffman, Chang, Cho, Susztak, Robinson-Cohen, Tuteja.

Supervision: Hung, Polimanti, Gaziano, Luoh, Casas.

Conflict of Interest Disclosures: Dr Hung reports grants from Veterans Health CSR&D Merit Grant CX001897 and grants from Veterans Health MVP035 MVP COVID-19 Science Program during the conduct of the study; grants from Vertex Pharmaceutical outside the submitted work. Dr Bick reports personal fees from TenSixteen Bio outside the submitted work. Dr Hunt reports other from Akebia Therapeutics, Inc. Safety adjudication in COVID-19 clinical trial during the conduct of the study. Dr Wendt reports grants from NIMH outside the submitted work. Dr Akwo reports grants from American Heart Association Postdoc Award #20POST35210952/Akwo/2020 during the conduct of the study. Christopher J O'Donnell: Dr O'Donnell reports income from Novartis Institute for Biomedical Research as a salaried employee outside the submitted work. Dr Susztak reports grants from GSK, Regeneron, Bayer, BiPI, Novo Nordisk, Maze, Novartis, Gilead and other from AZ, Pfizer, Bayer, GSK Consulting outside the submitted work. Dr Siew reports grants from Veterans Health Services Research and Development Grant SDR 18-194 Million Veteran Program Gamma Program during the conduct of the study; personal fees from Akebia Therapeutics, Inc. Consultant on and personal fees from Da Vita, Inc. Honorarium for an invited educational talk on AKI epidemiology at the Da Vita Annual Physician Leadership Conference outside the submitted work; and Serves on the editorial board for the Clinical Journal of the American Society of Nephrology; and has received royalties as an author for UptoDate.

Funding/Support: This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award #MVP035 (MVP COVID-19 Science Program) and VA Clinical Science Research and Development-investigator grant CX001897 (Dr Hung) Genetic of Kidney Disease and Hypertension-Risk Prediction and Drug Response in the MVP. Drs Siew’s and Matheny’s time was covered by grant HX002489 (Drs Siew and Matheny).

Role of the Funder/Sponsor: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: A complete list of investigators and staff in the the VA Million Veteran Program COVID-19 Science Initiative is provided in Supplement 2.

Disclaimer: This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

Data Sharing Statement: The protocol, statistical code, are available from Dr Hung. However, data will require approval from the Office of Research Development and the Million Veteran Program.

Additional Contributions: We thank the MVP leadership and MVP COVID-19 Science Program. The MVP COVID-19 Science Initiative core acknowledgment and the MVP program core acknowledgment are included in eTable 9 in Supplement 1.

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