According to the 2020 Annual Data Report, 30% of patients with end-stage kidney disease (ESKD) in the US are Black individuals, although they comprise only 13% to 14% of the population. In 2010, researchers identified 2 common variants of the APOL1 (apolipoprotein L1) gene (G1 and G2), which account for much of the excess nondiabetic chronic kidney disease (CKD) risk among Black individuals in the US.^1,2 This review explains the evolutionary origin of APOL1 high-risk genetic variants, defines APOL1-mediated kidney disease (AMKD), and discusses recommendations for AMKD screening and management.

The wild-type APOL1 gene (G0) was identified in 2003 as the component of human serum that confers resistance to Trypanosoma brucei, the cause of African trypanosomiasis (sleeping sickness). The APOL1 gene encodes an innate immune pore-forming protein that inserts into the trypanosome’s lysosomal membrane, inducing osmotic stress and ultimately lysing the trypanosome. Approximately 10 000 years ago, 2 novel T brucei strains emerged in Africa that were resistant to the G0 immune response and therefore caused African sleeping sickness. The G1 and G2 variants of the APOL1 gene restored immune protection against the novel T brucei strains and underwent positive selection in West Africa.

The risk of kidney disease associated with the APOL1 G1 and G2 alleles follows a recessive inheritance pattern. Individuals who are heterozygous for a G1 or G2 variant (G1/G0 or G2/G0) are resistant to African sleeping sickness but do not have increased risk of kidney disease. However, individuals with 2 alleles of APOL1 G1 or G2 variants (G1/G1, G2/G2, or G1/G2) have an increased risk of kidney disease and are collectively known as the APOL1 high-risk genotype.¹

The allele frequencies of G1 and G2 vary across different populations worldwide. The prevalence of these high-risk alleles is highest in West African populations. In different populations in Nigeria, G1 allele frequency has been reported to be 37% to 45%, and G2 frequency has been estimated to be 7.5% to 17%.² Among Black individuals in the US, the G1 allele frequency is 22% and G2 allele frequency is 13%.² Approximately 13% of Black individuals in the US (more than 5 million people) have a high-risk APOL1 genotype.³ High-risk alleles are also found frequently in sub-Saharan African, Western African, Caribbean, Central American, and South American populations.⁴

Recent experimental evidence suggests that the G1 and G2 variants may cause kidney injury by increased transport of monovalent cations—similar to the mechanism by which G1 and G2 provide resistance to T brucei.^5,6

Individuals with a high-risk APOL1 genotype have been estimated to have a 15% to 30% lifetime risk of developing ESKD.³ The basis of this variable penetrance is currently unknown. AMKD is diagnosed when an individual with a high-risk APOL1 genotype develops nondiabetic kidney disease. There is no established glomerular filtration rate (GFR) cutoff to diagnose AMKD. Proteinuria (urine albumin to creatinine ratio >30 mg/g) is often present but is not a requirement for the diagnosis of AMKD.

Approximately 75% of Black individuals in the US with focal segmental glomerulosclerosis (FSGS) have been estimated to have a high-risk APOL1 genotype.⁴ Black individuals in the US with a high-risk APOL1 genotype are also more likely to develop hypertension-attributed ESKD, lupus nephritis–attributed ESKD, FSGS, and HIV-associated nephropathy compared with Black individuals who have a low-risk APOL1 genotype (Figure). A recent study reported that 25.8% of patients with COVID-19–associated kidney injury had collapsing glomerulopathy, and 91.7% of these patients had a high-risk APOL1 genotype.⁷

Screening of asymptomatic individuals in the US for high-risk APOL1 genotype is not currently recommended. Individuals identified as Black in clinical and epidemiological studies in the US represent a genetically diverse group, and the risk of a genetic variant is not evenly distributed in this population. However, individuals with recent West African heritage who have nondiabetic CKD, proteinuria, or a family history of kidney disease may be offered APOL1 screening. All individuals should receive genetic counseling before and after APOL1 genetic testing and be advised about potential for increased cost of health insurance that may be associated with detection of a high-risk APOL1 genotype. When individuals are noted to have a high-risk genotype, physicians may consider more frequent screening for reduced GFR and proteinuria to identify AMKD at an early stage.

Prospective kidney donors with recent West African heritage may be encouraged to undergo APOL1 genetic testing because preliminary data suggest that donors with a high-risk APOL1 genotype have a greater decrease in postdonation kidney function and are more likely to develop ESKD. A study of 136 Black living kidney donors who were evaluated at a median of 12 years after donation reported that compared with donors with a low-risk genotype, those with a high-risk APOL1 genotype had lower eGFR (mean [SD], 57 [18] vs 67 [15] mL/min per 1.73 m²; P = .02) and faster decline in eGFR after adjustment for predonation eGFR (1.19 [95% CI, 0-2.3] vs 0.4 [95% CI, 0.1-0.7 mL/min per 1.73 m² per year, P = .02).⁸

A study of 478 deceased donor kidney transplants from Black donors reported that after adjusted analysis, transplanted kidneys from deceased donors with a high-risk APOL1 genotype had shorter allograft survival compared with a low-risk APOL1 genotype (absolute rates not reported; hazard ratio, 2.05; P = 3 ×â¶Ä‰10^−4) but no difference in kidney recipient survival.⁹ A large ongoing National Institutes of Health–funded study, APOLLO () is evaluating the effects of APOL1 variants on outcomes for both kidney transplant donors and recipients.

Early identification of patients with a high-risk APOL1 genotype may be associated with beneficial lifestyle modifications and decreased blood pressure. A recent study¹⁰ randomized 2050 US adults with self-identified African ancestry and hypertension without CKD to immediate vs delayed reporting (12 months later) of APOL1 test results. At 3 months, patients identified with a high-risk APOL1 genotype had a significantly greater decrease in mean systolic blood pressure (6 mm Hg) compared with low-risk APOL1 genotypes (3 mm Hg) and the control group with delayed reporting (3 mm Hg). At 12 months, compared with individuals who had a low-risk genotype, patients with a high-risk APOL1 genotype self-reported significant improvements in diet and exercise (129/218 [59%] vs 547/1468 [37%]; P < .01) and increased use of blood pressure medication (21/218 [10%] vs 68/1468 [5%]; P = .005).

Although there is currently no approved treatment for AMKD, multiple therapeutic trials are ongoing. The JUSTICE trial () is testing baricitinib, a JAK-STAT inhibitor that reduces APOL1 gene expression. A phase 2/3 clinical trial () is evaluating the effect of inaxaplin, a small molecule APOL1 inhibitor, on proteinuria and the rate of GFR decline among individuals with a high-risk APOL1 genotype and proteinuric kidney disease.

Corresponding Author: Opeyemi A. Olabisi, MD, PhD, Duke Molecular Physiology Institute, Division of Nephrology, Department of Medicine, Duke University School of Medicine, 300 N Duke St, #50-104, Durham, NC 27701 (Opeyemi.Olabisi@duke.edu).

Published Online: April 25, 2024. doi:10.1001/jama.2024.2667

Conflict of Interest Disclosures: Dr Olabisi reported grants from NIH during the conduct of the study. No other disclosures were reported.