<i>APOL1</i>, Sickle Cell Trait, and CKD in the Jackson Heart Study

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Abstract

Rationale & Objective

Apolipoprotein L1 ( APOL1) high-risk variants are associated with an increased risk for chronic kidney disease (CKD) among African Americans. Less is known regarding the risk for the development of CKD and kidney failure (end-stage kidney disease [ESKD]) among African Americans with only 1 APOL1 risk variant or whether the risk is modified by sickle cell trait.

Study Design

The Jackson Heart Study is a community-based longitudinal cohort study.

Setting & Participants

Self-reported African Americans in the Jackson Heart Study (n = 5,306).

Exposures

APOL1 G1 and G2 genotypes and sickle cell trait.

Outcomes

Incident CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m ²), albuminuria (urinary albumin-creatinine ratio ≥ 30 mg/g), continuous and rapid kidney function decline (≥30% decline), and incident ESKD.

Analytical Approach

Multivariable linear and logistic regression, and Cox proportional hazards models adjusted for age, sex, hypertension, diabetes, ancestry informative markers, and sickle cell trait.

Results

Of 2,300 participants, 41.3% had zero, 45.1% had 1, and 13.6% had 2 APOL1 risk variants. Sickle cell trait was present in 8.5%. Compared with participants with zero APOL1 risk variants, those with 2 alleles had an increased risk for incident albuminuria (adjusted HR [aHR], 1.88; 95% CI, 1.04 to 3.40), ESKD (aHR, 9.05; 95% CI, 1.79 to 45.85), incident CKD (aHR, 1.65; 95% CI, 1.06 to 2.57), continuous decline (β = −1.90; 95% CI, −3.35 to −0.45), and rapid kidney function decline (OR, 2.21; 95% CI, 1.22 to 4.00) after adjustment for sickle cell trait, with similar results after adjustment for ancestry informative markers. Having 1 APOL1 risk variant was not associated with CKD outcomes and there was no interaction of APOL1 with sickle cell trait.

Limitations

Single-site recruitment of African American individuals with APOL1 and sickle cell trait.

Conclusions

The presence of 1 APOL1 risk allele was not associated with increased risk for CKD outcomes, whereas 2 risk alleles were associated with incident albuminuria, CKD, ESKD, and rapid and continuous kidney function decline. Additional studies are needed to determine factors that might alter the risk for adverse kidney outcomes among individuals with high-risk APOL1 genotypes.

Graphical abstract

Related collections

Most cited references 35

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Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. National Institute of Diabetes and Digestive and Kidney Diseases.

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Giulio Genovese, David J Friedman, Michael D Ross … (2010)

African Americans have higher rates of kidney disease than European Americans. Here, we show that, in African Americans, focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22 {FSGS odds ratio = 10.5 [95% confidence interval (CI) 6.0 to 18.4]; H-ESKD odds ratio = 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 (apolipoprotein L-1) is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans.

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Author and article information

Contributors

Bessie A. Young

Journal

Journal ID (nlm-ta): Kidney Med

Journal ID (iso-abbrev): Kidney Med

Title: Kidney Medicine

Publisher: Elsevier

ISSN (Electronic): 2590-0595

Publication date PMC-release: 15 July 2021

Publication date Collection: Nov-Dec 2021

Publication date (Electronic): 15 July 2021

Volume: 3

Issue: 6

Pages: 962-973.e1

Affiliations

[1 ]UW Office of Healthcare Equity, Justice, Equity, Diversity, and Inclusion Center for Transformational Research (UW JEDI-CTR), University of Washington, Seattle WA

[2 ]Nephrology Section, Hospital and Specialty Medicine, Center for Innovation, Veterans Affairs Puget Sound Health Care System, Seattle WA

[3 ]Kidney Research Institute, University of Washington, Seattle, WA

[4 ]Division of Nephrology, University of Washington, Seattle, WA

[5 ]Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA

[6 ]Fred Hutchinson Cancer Research Center, Seattle, WA

[7 ]Department of Epidemiology, University of North Carolina, Chapel Hill, NC

[8 ]Department of Medicine, University of Mississippi Medical Center, Jackson, MS

[9 ]Department of Obstetrics and Gynecology, University of Washington, Seattle, WA

Author notes

[∗ ] Address for Correspondence: Bessie A. Young, MD, MPH, Office of Healthcare Equity, UW Justice, Equity, Diversity, and Inclusion Center for Transformational Research (UW-JEDI), University of Washington, 1959 NE Pacific Street, Box 357237, Seattle WA 98195. youngb@ 123456uw.edu

Article

Publisher Item ID: S2590-0595(21)00157-6

DOI: 10.1016/j.xkme.2021.05.004

PMC ID: 8664705

PubMed ID: 34939005

SO-VID: 5e0946de-4146-4a14-92f4-689934d59c98

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

APOL1, Sickle Cell Trait, and CKD in the Jackson Heart Study

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