APOL1 Risk Variants, Acute Kidney Injury, and Death in Participants With African Ancestry Hospitalized With COVID-19 From the Million Veteran Program | Acute Kidney Injury | JAMA Internal Medicine | JAMA Network
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Figure 1.  Flowchart for Patient Eligibility
Flowchart for Patient Eligibility
Figure 2.  Incidence of Acute Kidney Injury (AKI) and AKI Stages by APOL1 Risk Group
Incidence of Acute Kidney Injury (AKI) and AKI Stages by APOL1 Risk Group
Table 1.  Participants Clinical Characteristics According to APOL1 Genotype Risk Group
Participants Clinical Characteristics According to APOL1 Genotype Risk Group
Table 2.  Participants Clinical Characteristics According to Acute Kidney Injury (AKI) Status
Participants Clinical Characteristics According to Acute Kidney Injury (AKI) Status
Table 3.  Association of APOL1 High-Risk Group, AKI, AKI Stages, and Death in Veterans With African Ancestry Hospitalized With COVID-19a
Association of APOL1 High-Risk Group, AKI, AKI Stages, and Death in Veterans With African Ancestry Hospitalized With COVID-19a
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    Original Investigation
    January 28, 2022

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

    Author Affiliations
    • 1Tennessee Valley Healthcare System, Nashville Campus, Nashville
    • 2Division of Nephrology & Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee
    • 3GI Section, VA San Diego Healthcare System, San Diego, California
    • 4Division of Gastroenterology, University of California, San Diego, San Diego
    • 5Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
    • 6Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
    • 7Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
    • 8VA Cooperative Studies Program Epidemiology Center, Durham VA Health Care System, Durham, North Carolina
    • 9Department of Psychiatry, Yale University School of Medicine, West Haven, Connecticut
    • 10VA CT Healthcare Center, West Haven, Connecticut
    • 11Division of Nephrology & Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
    • 12Division of Rheumatology and Division of Clinical Pharmacology, Vanderbilt University Medical Center, Rheumatology Section, Veterans Affairs, Nashville, Tennessee
    • 13Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston
    • 14Department of Epidemiology and Biostatistics, University of Arizona, Phoenix
    • 15Phoenix VA Health Care System, Phoenix, Arizona
    • 16Division of Endocrinology, Department of Medicine, University of Arizona, Phoenix
    • 17Epidemiology Research and Information Center (ERIC), VA Palo Alto Health Care System, Palo Alto, California
    • 18Department of Medicine, Stanford University School of Medicine, Palo Alto, California
    • 19Division of Aging, Brigham & Women’s Hospital, Boston, Massachusetts
    • 20Center for Population Genomics, Massachusetts Veterans Epidemiology Research & Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts
    • 21Cardiology Section, Veterans Affairs Boston, Boston, Massachusetts
    • 22Division of Cardiovascular Medicine, Brigham & Women’s Hospital, Boston, Massachusetts
    • 23VA Portland Health Care System, Portland, Oregon
    • 24Knight Cancer Institute, Oregon Health & Science University, Portland
    • 25Department of Population and Quantitative Health Sciences, Case Western Reserve University and Louis Stoke, Cleveland VA, Cleveland, Ohio
    • 26Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio
    • 27The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania
    • 28Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts
    • 29Departments of Biomedical Informatics, Biostatistics, and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee,
    • 30GREEC, TVHS VA, Nashville, Tennessee
    • 31Cardiology, VA Boston Healthcare System, Boston, Massachusetts
    • 32Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 33Novartis
    • 34Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania
    • 35Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    • 36Tennessee Valley Healthcare System, Nashville VA Medical Center, Nashville, Tennessee
    JAMA Intern Med. 2022;182(4):386-395. doi:10.1001/jamainternmed.2021.8538
    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.

    Abstract

    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.

    Introduction

    A recent study of US veterans hospitalized with COVID-19 showed that acute kidney injury (AKI) was more common in non-Hispanic Black veterans compared with non-Hispanic White veterans.1 Importantly, AKI in non-Hispanic Black veterans was also associated with a higher risk of death.1 Studies suggest that African ancestry-specific kidney risk genetic variants may play a role in the risk of AKI in patients infected with COVID-19.2,3

    Clinically relevant risk variants in the gene encoding for apolipoprotein L1 (APOL1) are common in individuals with African ancestry in the US, where approximately 45% carry at least 1 high-risk variant (RV) and 12% to 13% carry 2 RVs.4-9 The 2 RVs, termed G1 and G2, are common in individuals of West African descent owing to positive genetic selection. Individuals with at least 1 RV are resistant to lethal Trypanosoma brucei infections.9-12 However, having 2 RVs is associated with chronic kidney disease (CKD). The APOL1 RVs partially explain the disparities observed in the risk of end-stage kidney disease (ESKD) among individuals with African ancestry.13-15 In addition, APOL1 RVs are associated with several forms of nondiabetic kidney disease.16 Whether APOL1 RVs are associated with AKI in general has not been established.17-19

    The pathophysiology of AKI in individuals with COVID-19 is poorly understood and likely multifactorial, particularly with respect to patients with APOL1 risk variants. Expression of APOL1 in kidney cells is upregulated by inflammation,3,10,20,21 which has been observed in several forms of kidney disease, including focal segmental glomerulosclerosis (FSGS), now well described in the COVID-19 literature.22-25 However, it appears that most cases are owing to acute tubular injury during critical illness, where the exaggerated inflammatory response and robust immune activation may be a second hit.3,20,26,27

    In this study, we leveraged a national cohort of US veterans hospitalized with COVID-19 with genetic information and with African ancestry through the VA Million Veteran Program (MVP)28 to evaluate the association of APOL1 high-risk group (2 RVs) in African ancestry participants with AKI. Because AKI is a strong predictor of mortality in patients with COVID-19,1 our secondary goal was to evaluate the association of APOL1 genotypes with the risk of death.

    Methods
    Study Population and Design

    We identified 5046 MVP participants hospitalized with COVID-19 between March 11, 2020 and January 11, 2021. Of these, 4226 had genetic information. APOL1 RVs, our exposure of interest (individuals with 2 RVs were considered high-risk group), are found in individuals of recent West African ancestry.29,30 Consistent with this knowledge, we examined but found no participants without African ancestry who carried a high-risk APOL1 genotype. Hence, the cohort consisted of (1) MVP participants hospitalized with COVID-19, (2) those with genetic information available, and (3) those with African ancestry.28 After applying other exclusion criteria needed for AKI assessment as specified, our study sample size was 990 individuals (Figure 1).

    Data were obtained from the VA Corporate Data Warehouse (CDW), the MVP Study Mart, the Observational Medical Outcomes Partnership version 5, and the COVID Share Data Resources.31-33 COVID-19 was diagnosed based on a positive polymerase chain reaction test result for SARS-CoV-2 from a nasopharyngeal specimen between March 1, 2020 and January 11, 2021 (eFigure 1 in Supplement 1). Participants entered the cohort if they had positive SARS-CoV-2 testing results and were hospitalized 14 days prior or 14 days after the positive test result. The distribution of the date of admission with regard to test positivity are presented in eFigure 2 in Supplement 1. Overall, 934 (95%) of the individuals had a positive test within the first 3 days of hospitalization or prior to the admission date. The MVP received approval by the VA Central institutional review board (IRB), the IRB of each site, and the MVP COVID-19 Scientific Steering Committee. Written informed consent was obtained from all participants. Data analysis was conducted between February 2021 and April 2021. This study was performed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement guidelines for observational research.34

    Cohort Exclusion Criteria

    Participants were excluded if they had a preadmission history of ESKD, defined as previous dialysis or kidney transplant and those with a baseline estimated glomerular filtration rate (eGFR) lower than 15 mL/min/1.73 m2 (n = 160) (eTable 1 in Supplement 1) or did not have serum creatinine levels measured during hospitalization (n = 13). We also excluded patients with no baseline outpatient serum creatinine level measurement used to characterize AKI, defined as the mean outpatient creatinine levels within the 7 to 365 days prior to hospitalization (n = 87)35 (Figure 1). Participant AKI assessment was restricted to the first qualifying hospitalization during the study period.

    Outcomes and Follow-up

    The primary outcome was AKI, defined using a modified Kidney Disease Improving Global Outcomes (KDIGO) creatinine-based criterion as a 0.3 mg/dL or 50% increase in serum creatinine levels from baseline using the peak serum creatinine during hospitalization (eTable 2 in Supplement 1).36

    Our secondary outcomes included a modified KDIGO AKI severity stages result (stage 1, 0.3 mg/dL or 50% increase from baseline; stage 2, 100% increase from baseline; and stage 3, 200% increase from baseline or acute kidney replacement therapy [KRT]) or death. In this study, KRT was identified by diagnostic and procedural codes37 (eTable 3 in Supplement 1). Dates of death were obtained from the VA vital status files of the CDW.38,39

    Because our goal was to capture AKI events that were proximally related to COVID-19 infection, participants were followed until discharge or up to 30 days because late AKI occurring after 30 days may be more likely owing to hospital complications. For the death outcome, participants were followed for up to 30 days after admission, consistent with other VA studies.39-41

    Exploratory analysis included dipstick proteinuria and hematuria measurements at baseline and on admission,42 mechanical ventilation, and vasopressors.

    APOL1 Genotype Exposure

    APOL1 RVs G1 (rs73885319 p.S342G; rs60910145 p.I384M) and G2 (rs71785313, a 6-base pair deletion that removes amino acids N388 and Y389) were directly genotyped on the Affymetrix Axiom Biobank Array on DNA extracted from whole blood.4 Participants were defined as 2 RV carriers if they were homozygotes for G1/G1, homozygotes for G2/G2, or compound heterozygotes for G1/G2. The genotyping was completed by the MVP Genomic Core.43 The G1 and G2 genotypes were in Hardy-Weinberg equilibrium.

    Subgroup Analysis

    A subgroup analysis was planned for all outcomes, restricted to the population with baseline eGFR levels of 60 mL/min/1.73 m2 or higher, to evaluate if the effect of APOL1 high-risk genotypes in the risk of AKI in the context of COVID-19 was independent of CKD.

    Covariates

    Characteristics reported include demographics, comorbidities, hospitalization characteristics, laboratory tests, and medications. Determination of ancestry was based on a unified classification algorithm developed by MVP.44 This algorithm integrates genetically inferred ancestry based on the top 30 principal components of ancestry (PCs) with self-identified race/ethnicity (SIRE). The HARE (Harmonizing Genetic Ancestry and Self-identified Race/Ethnicity) algorithm classifies an MVP participant as “African” if their genetic ancestry is consistent with “African ancestry” and it informs ancestry in those with missing SIRE information.44 In MVP African ancestry assignment is population level and is derived from projecting the genetic PCs of MVP to those in the 1000 Genomes Project reference panel.43

    Baseline comorbidities were obtained up to 730 days before the SARS-CoV-2 positive test. In-hospital risk factors for AKI were collected during the hospitalization prior to peak AKI. Drug exposures associated with high-risk of AKI were documented if they were administered prior to the peak creatinine using the bar-coded medication administration (BCMA) in the inpatient setting. Outpatient ACE inhibitors or ARB exposure was defined as a prescription fill within 180 days prior to admission by assessing outpatient VA pharmacy files. Diagnoses were defined using the International Classification of Diseases, Ninth Revision, Tenth Revision (ICD-9, ICD-10) procedures codes ICD-9/ICD-10 and Current Procedural Terminology (CPT) codes (eTable 3 in Supplement 1). Levels of eGFR were calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.45

    Statistical Analyses

    The primary exposure variable was APOL1 variable high-risk group defined by the presence of 2 RVs (recessive model of inheritance). Logistic regression models were used to study the association of the exposure and the outcomes of interest. We also used a partial proportional odds (PPO) regression model to study the association of the APOL1 high-risk group and increasing severity stages of AKI.46 Nested multivariable models included (a) model 1, minimally adjusted (demographics, baseline eGFR and 10 PCs of ancestry) and (b) model 2, fully adjusted, also adjusted for preexisting comorbid conditions and inpatient risk factors. All logistic regression models passed the Goodness of fit test by the Hosmer-Lemeshow test (eTable 4 in Supplement 1). When conducting proportional odds regression analyses, proportional odds were assumed for all variables except for baseline eGFR, diastolic blood pressure, and remdesivir, as suggested by the Brant test and addressed by the PPO model46,47 (eTable 5 in Supplement 1). Nonlinear terms and secular effects were tested (eTable 6 and eTable 7 in Supplement 1). A subgroup analysis was done restricting the analytical file to individuals with a baseline eGFR level of 60 mL/min/1.73 m2 or higher. Sensitivity analyses restricted the outcome to AKI stages 2 and 3 (eTable 8 in Supplement 1). Exploratory analysis included other models of inheritance (codominant and dominant) (eTable 9 in Supplement 1) and dipstick proteinuria and hematuria. All statistical tests were 2-sided, where a P = .05 or a 95% CI that did not contain unity were considered statistically significant for the primary outcome. All analyses were conducted using R statistical software (version 3.6.1.; R Foundation, Inc).

    Results
    Baseline and Clinical Characteristics for the Participants

    We studied 990 veterans enrolled in the MVP hospitalized with COVID-19 infection between March 2020 and January 2021, genotyped for APOL1 risk variants, who were of African ancestry and satisfied cohort entry criteria for AKI assessment (Figure 1). Baseline cohort characteristics by APOL1 genotype risk-group were summarized (Table 1). Clinical characteristics were similar across the different APOL1 risk groups, including baseline eGFR levels and the proportion of individuals with eGFR levels lower than 60 mL/min/1.73 m2, diabetes, and hypertension.

    Demographics and participant characteristics overall and by AKI status were summarized (Table 2). Overall, 905 (91.4%) were men, median (IQR) age was 68 (60-73) years, 701 (71%) had a GFR level of 60 mL/min/1.73 m2 or higher, with 493 (51%) of the participants hospitalized September 2020 or later (Table 2; eFigure 1 in Supplement 1).

    The incidence of AKI was 392 (39.6%). Overall, AKI rates per month among study participants varied and are shown in eFigure 3 in Supplement 1. Of 392 individuals with AKI, 251 (25%) had stage 1, 59 (6%) stage 2, and 82 (8%) stage 3, including 28 (3%) who received dialysis due to AKI. Compared with individuals without AKI, individuals with AKI were older, and more likely to have eGFR levels lower than 60 mL/min, diabetes and hypertension, and positive baseline dipstick proteinuria.

    Mechanical ventilation and vasopressors were required by 141 and 98 individuals, respectively. One-hundred twenty-two individuals died. Individuals with AKI were more likely than individuals without AKI to require mechanical ventilation (29% vs 5%, P < .001), vasopressors (22% vs 2%, P < .001), and to die (26% vs 3%, P < .001) (Table 2).

    APOL1 Genotype

    One-hundred twenty-five study participants (12.6%) carried 2 APOL1 risk alleles, consistent with frequencies reported in other studies of individuals with African ancestry in the US.4-7 However, 64 of 392 (16.3%) with AKI had 2 APOL1 RVs compared with 61 of 598 (10.2%) without AKI (P = .005). Furthermore, we observed a dose relationship with more severe forms of AKI, with stages 2 and stage 3 having 22.0% and 20.7% high-risk genotypes, respectively, with only 13.5% with stage 1 AKI having the high-risk genotype (eFigure 4 in Supplement 1).

    The APOL1 high-risk genotype doubled the risk of severe stages 2 and 3 AKI, with incidences of stages 2 and 3 AKI in the APOL1 high-risk group of 7 (13.6%) and 13 (10.4%), respectively, compared with 65 (7.5%) and 46 (5.3%) in the APOL1 low-risk group. For stage 1, the incidence was 27.2% for the APOL1 high-risk vs 25.1% for APOL1 low-risk group (Figure 2) (Table 1).

    Association of APOL1 With Incident AKI and AKI Severity

    In the minimally adjusted model (model 1), individuals with the APOL1 high-risk group had significantly increased odds of incident AKI (odds ratio [OR], 1.80; 95% CI, 1.21-2.69; P = .004). This association was also observed in the fully adjusted model (model 2) that included outpatient comorbidities and inpatient risk factors for incident AKI (OR, 1.95; 95% CI, 1.27-3.02; P = .002) (Table 3). For the association with AKI severity, we observed an increase of 88% in the odds of more severe stages of AKI (OR, 1.88; 95% CI, 1.30-2.71; P = .001) in model 1. The association was also observed in model 2 (OR, 2.03; 95% CI, 1.37-2.99; P < .001) (Table 3).

    Association of APOL1 With AKI and AKI Severity in the Subgroup of Individuals With Normal Baseline Kidney Function

    Among individuals with baseline eGFR levels of 60 mL/min/1.73 m2 or higher (n = 701), participants in the APOL1 high-risk group had significantly increased odds of experiencing AKI in both model 1 (OR, 1.88; 95% CI, 1.18-2.99; P = .008) and in model 2 (OR, 1.93; 95% CI, 1.15-3.26; P = .01) (Table 3). There was also an increase in the odds of more severe stages of AKI in model 1 (OR, 1.98; 95% CI, 1.28-3.06; P = .002) and in model 2 (OR, 2.11; 95% CI, 1.31-3.39; P = .002) (Table 3).

    Sensitivity Analysis

    In the sensitivity analysis restricting the outcome to AKI stages 2 and 3, a 2-fold increase in the odds of AKI stages 2 and 3 in the APOL1 high-risk group was also noted, consistent with the primary analyses, both for the entire cohort and the subgroup with normal eGFR levels (eTable 8 in Supplement 1).

    Association of APOL1 Risk Variants With Death, Mechanical Ventilation, and the Use of Vasopressors

    There were 122 (12.3%) deaths overall; 24 (19.2%) in the APOL1 high-risk and 98 (11.3%) in the APOL1 low-risk group. The APOL1 high-risk group was associated with a 1.92 fold increase in the odds of death in model 1 (OR, 1.92; 95% CI, 1.13-3.17; P = .01) and in model 2 (OR, 2.15; 95% CI, 1.22-3.72; P = .007) (Table 3). This association was also present in the subgroup with normal eGFR levels, in model 1 (OR, 2.54; 95% CI, 1.32-4.72; P = .004) and model 2 (OR, 2.51; 95% CI, 1.21-5.05; P = .01). Overall, 102 (84%) individuals who died experienced AKI.

    APOL1 high-risk genotype was not associated with mechanical ventilation (OR, 1.51; 95% CI, 0.86-2.55; P = .10) or a vasopressor requirement (OR, 1.61; 95% CI, 0.85-2.89; P = .10) in the fully adjusted models.

    Exploratory Analyses
    Association of APOL1 Risk Variants With Proteinuria and Hematuria

    Urine dipstick proteinuria data were available in 614 participants at baseline. There was no association in the APOL1 high-risk group with outpatient baseline proteinuria in those with available measurements (OR, 1.12; 95% CI, 0.68-1.80; P = .60). Dipstick proteinuria data were available in 357 participants on admission. Ninety-six of 357 (27%) had new-onset proteinuria and 24 people had worsening dipstick proteinuria results. The APOL1 high-risk group was associated with proteinuria of 1+ or more on admission (n = 357) (OR, 2.20; 95% CI, 1.21-4.10; P = .01). There was no association of APOL1 high-risk group and hematuria defined as 1+ or more at baseline (n = 608) (OR, 0.95; 95% CI, 0.53-1.64; P = .90) or on admission (n = 351) (OR, 1.32; 95% CI, 0.74-2.31; P = .30).

    Other Models of Inheritance

    Other models of APOL1 inheritance were performed also as exploratory analyses. We observed significant associations with 2 RVs and AKI, AKI severity, and death in the codominant model, consistent with the recessive model. No associations were observed with a single RV (eTable 9 in Supplement 1).

    Discussion

    We report a robust association between individuals in the APOL1 high-risk group and AKI development and severity among participants with African ancestry hospitalized with COVID-19. Half of the participants with 2 APOL1 high-risk group variants developed AKI and 24 (19%) died. Because 1 in 8 individuals with African ancestry have 2 APOL1 kidney risk variants, this inherited genetic difference may in part explain the excess risk of AKI described in previous studies in veterans with African ancestry hospitalized owing to COVID-19.1 This increased risk of AKI was present even among individuals without preexisting CKD and followed a recessive model of inheritance, consistent with other kidney phenotypes.9,11,48 These associations were further accentuated among individuals with increasing AKI severity.

    This study also identified an association of APOL1 high-risk group and death in participants of African ancestry hospitalized with COVID-19. Study participants baseline characteristics were similar between the APOL1 high-risk and low-risk groups. Recent studies report an association of APOL1 with endothelial cell defects, sepsis severity, and COVID-19 severity.3 Larger studies may further inform the association of APOL1 with death in the context of COVID-19.

    In the general population, the association of APOL1 and AKI and APOL1 and death has been controversial.18,19,49,50 Potential explanations for the different findings include variation in the populations studied, outcome ascertainment, or the potential effects of a second hit in a given study setting.27 For example, not all individual carriers of 2 RVs will develop kidney disease and a second hit, including environmental or genetic modifiers, have been considered as playing a role.27,29 In the case of COVID-19, the heightened inflammatory response has been hypothesized to be a second hit. Similar hypotheses have been made in the contexts of uncontrolled HIV where the high levels of interferon are associated with the development of HIV-associated nephropathy and the risk of ESRD,51 or that observed with the therapeutic administration of interferon (IFNs).21

    The pathophysiological mechanisms of APOL1 RVs remain incompletely characterized. Several studies have shown that APOL1 RVs represent gain of function variants with cytotoxic effects.52,53 When exposed to inflammatory triggers, podocytes and other specific cells overexpress APOL1, which compromises mitochondrial respiration, lysosome integrity, and autophagic flux resulting in cell death.54-57 Animal studies suggest that APOL1 variants impair mitophagy in endothelial cells, allowing the release of mitochondrial DNA that activates inflammasome.3 A second hit could also involve other genetic modifiers that can diminish cytotoxicity.48 The potential role of inflammation in the pathogenesis of AKI in the context of high-risk APOL1 and its relative contributions to different subtypes of AKI warrants further study.

    The strengths of our study include the use of a large national data set with genetic data on participants with African ancestry and carefully curated creatinine-based definitions of AKI and KRT. The use of longitudinal phenotype data prior to COVID-19 infection enabled rigorous adjustment for baseline conditions and inpatient exposures that might influence the risk of AKI and severe COVID-19. Our estimates were robust and consistent across nested multivariable models, subgroup and sensitivity analyses that included known comorbidities associated with worse outcomes in COVID-19 and AKI. Further, these results were consistent among individuals without known CKD.

    Limitations

    Limitations of this study include reduced generalizability to women, the lack of quantitative proteinuria measurements, which precluded a subgroup analysis by proteinuria, or the detection of severe forms of nephrotic syndrome. The study lacked histologic data, with only 1 patient having a kidney biopsy during a COVID-19 hospitalization. Socioeconomic status (SES) indicators were not available, and some covariates were defined using diagnosis and procedure codes. However, covariate ascertaiment should not be differential by genotype. Another limitation of our study is that we could not identify a comparable replication cohort, which most likely will be available in the near future. Finally, our limited follow-up period reduced the ability to examine longer-term consequences of COVID-19–associated AKI.

    Conclusions

    In this cohort of participants with African ancestry hospitalized with COVID-19 infection, APOL1 RVs were associated with an increased risk of AKI, severe AKI, and death, independent of CKD. Our findings suggest that genetic risk assessment can inform COVID-19 kidney risk prognostication in individuals with African ancestry. Because APOL1 RVs are highly prevalent in the population with African ancestry, studies evaluating the role of existing and novel therapies are needed to reduce poor outcomes in this population.

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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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