Version July 2025
INTRODUCTION —
This monograph discusses implications of genetic test results for the APOL1 gene, which encodes apolipoprotein L-1 (ApoL1), part of the ApoA1 lipoprotein component of high-density lipoprotein (HDL) [1]. Apol1 contains a membrane pore-forming domain that can create an anion channel.
APOL1 variants developed under evolutionary pressure to help defend against parasites such as trypanosomes in sub-Saharan Africa (similar to protection against malaria by sickle cell trait) [2].
APOL1 variants
●Risk alleles – Two specific APOL1 risk alleles (haplotypes) are associated with increased kidney disease risk [2]:
•G1 – G1 contains two single nucleotide variants that each create an amino acid substitution. The Ser342Gly variant (rs73885319) substitutes glycine for the typical serine at amino acid 342, and the Ile384Met variant (rs60910145) substitutes methionine for the typical isoleucine at amino acid 384. These variants are adjacent to each other and are in linkage disequilibrium, meaning they are inherited in the same haplotype. Approximately 21 percent of Black individuals carry this haplotype.
•G2 – G2 contains the rs71785313 variant, a 6 base-pair deletion that eliminates two amino acids, asparagine 388 and tyrosine 389 (designated delAsn388 and delTyr389). Approximately 13 percent of Black individuals carry this haplotype.
Co-occurrence of the rs73885316 missense variant, which causes a single amino acid change (N264K), ameliorates or negates the effects of G2; approximately 4.3 percent of African Americans have this combination [3]. Most laboratories are not testing for N264K.
•G0 – G0 refers to a low-risk haplotype that does not contribute to chronic kidney disease (CKD) risk.
●Biallelic versus heterozygous – Each individual has two APOL1 alleles: one inherited on the paternal chromosome and one on the maternal chromosome. For each allele, the patient may inherit the G0, G1, or G2 haplotype; G1 and G2 will not be present on the same allele [4].
•Biallelic – Biallelic risk haplotypes (G1 and G1, G1 and G2, or G2 and G2) markedly increase the risk of CKD and end-stage kidney disease (ESKD); this is referred to as a high-risk genotype [5]. (See 'CKD risk in the United States' below.)
•Heterozygous – The G1 or G2 haplotype on one allele and G0 on the other allele is considered a heterozygous carrier state in the United States (US). An increased risk of CKD has not been identified in the US but has been identified in an African cohort from Nigeria and Ghana [6]. (See 'CKD risk in the United States' below.)
Evolutionary pressure for heterozygosity is noted above. (See 'Introduction' above.)
CKD risk in the United States — Black individuals constitute 13 to 14 percent of the United States (US) population and 30 percent of the ESKD population. The high-risk APOL1 genotype accounts for approximately 70 percent of the excess ESKD risk [7]. Approximately 13 percent of Black individuals (>5 million people) have a high-risk APOL1 genotype, with biallelic G1 and/or G2 haplotypes.
Individuals with a high-risk APOL1 genotype have a 15 to 30 percent chance of developing ESKD over their lifetime [2]. In a case-control study of 1825 Black individuals in the US, 6.7 percent with a high-risk genotype had an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 versus 1.7 percent of Black individuals without the high-risk genotype [8].
However, two-thirds of individuals with a high-risk genotype will not develop ESKD. Additional acquired and/or genetic factors may contribute. Co-occurrence of the p.N264K variant adjacent to the G2 allele will negate or substantially ameliorate the effect of G2. (See 'APOL1 variants' above.)
A high-risk genotype confers increased risk for certain forms of CKD, often before age 50 years [2,5,6]:
●Human immunodeficiency virus (HIV) nephropathy – 29- to 89-fold increased risk compared with HIV-positive controls [9,10].
●Hypertension and hypertension-associated CKD or ESKD – Sevenfold increased risk [5].
●Focal segmental glomerulosclerosis (FSGS) – 17-fold increased risk [9].
●Microalbuminuria – Two- to threefold increased risk [8].
High-risk genotypes were documented in approximately 79 percent of US Black individuals with HIV nephropathy, 50 percent with hypertensive CKD, 75 percent with FSGS, and 17 percent with microalbuminuria [2,5,8,10]. In kidney transplant recipients, APOL1 genotype did not affect graft survival in one study and was associated with decreased allograft survival in another [11-13].
Inflammation may be a triggering factor for APOL1 nephropathy in individuals with high-risk genotypes. Collapsing FSGS has been described in an infant with STING syndrome (stimulator of interferon genes-associated vasculopathy) and in adults following parvovirus infection or coronavirus disease 2019 (COVID-19), or rarely after COVID-19 vaccination (two cases) [14-18]. The risk from COVID-19 greatly outweighs the risk of a vaccine complication. (See 'Prevention and management interventions' below.)
Other studies have reported a greater risk of progression to ESKD from FSGS and worse outcomes in individuals with high-risk APOL1 genotypes [19,20]. In a study of 138 children and young adults with FSGS, a high-risk APOL1 genotype was associated with a greater risk of progression to ESKD but did not affect the response to cyclosporine or mycophenolate [19]. In another study, individuals with a high-risk APOL1 genotype had worse outcomes that were not improved with aggressive blood pressure control [20].
CKD risk in Africa — A 2025 case-control study of 8355 Black participants from Ghana and Nigeria that included 4712 individuals with CKD stages 2 to 5, 866 with glomerular disease, and 2777 with no kidney disease, reported that having biallelic APOL1 risk haplotypes increased CKD risk by 25 and having heterozygosity for the APOL1 risk genotype on one allele increased CKD risk by 18 percent [6]. This differs from findings in Black individuals from the US, in whom only biallelic risk haplotypes is associated with increased CKD risk and heterozygosity is not.
The reason for this difference in risk is unclear. Given the higher allele frequency of APOL1 variants in Africa and a possible increased exposure to other factors that could cause CKD (infectious, genetic, environmental), individuals in Africa may be at more risk, or there may have been more statistical power to identify an effect of the heterozygous high-risk haplotype [21].
The prevalence of APOL1 high-risk variants in African Black subpopulations varies by ethnolinguistic groups, likely based on selection pressures from trypanosome infection and migration patterns [6]. Thus, the approach to patients who are heterozygous for the APOL1 risk haplotype may be different for Black individuals in Africa versus those in the US. Further investigation is needed.
COUNSELING AND DISCLOSURE OF RESULTS
Pre-test considerations — Testing may be done for several reasons:
●Evaluation of kidney disease
●Consideration to enter a clinical trial for APOL1-related nephropathy
●Potential kidney donor
●Evaluation for an unrelated condition
●Testing after a finding in a relative
Clinicians should not order a genetic test if they are not comfortable and proficient at discussing results or if they lack a predetermined plan for delivering results.
Prior to testing, clinicians should discuss risks, benefits, and alternatives to testing, and the option not to receive the results. Kidney donors may not want to know they have a high-risk genotype. (See 'Kidney donation' below and "Secondary findings from genetic testing", section on 'Informed consent'.)
Some companies that perform genetic testing provide genetic counseling that can be very helpful.
Reviewing genetic test results — Verify the result applies to the tested individual and testing was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified or other nationally certified laboratory (table 1). Determine if a risk variant (G1 and/or G2) is present on one or both APOL1 alleles. (See 'APOL1 variants' above.)
Information for the tested individual — While disclosure of actionable genetic test results is well-accepted, uncertainty is greater for disclosure of results such as APOL1 genotype since kidney disease may not develop and management interventions are limited. However, clinical trials to identify new treatments are underway, and several promising therapeutic agents are under study that may increase the range of available treatments [22,23].
Learning the results of APOL1 genotype may improve outcomes; in a randomized trial involving >2000 participants with hypertension, those assigned to disclosure had greater improvements in blood pressure control and biomarkers of CKD [24].
If a patient undergoes testing for APOL1 or is referred for explanation of genetic results, the provider should ascertain that pre-test counseling was performed and provide counseling if not done previously (see 'Pre-test considerations' above). Even after testing, the patient can decline to receive the results, though in some cases the result may be entered into the medical record and inadvertently disclosed in the future.
For individuals who wish to receive the results, a clear and supportive discussion of the findings, implications, and potential management strategies is essential. The algorithm (algorithm 1) and table (table 2) summarize important considerations and information to provide, which include:
●Delivery of the information by a health professional who has a relationship with the patient and is knowledgeable about the testing.
●Communication of results realistically, with empathy, hopefulness, and an understanding of the patient's basic genetic knowledge.
●The discussion must consider the historical mistreatment of Black individuals in research, clinical care, and genetic testing.
●The term "mutation" is discouraged; "genetic variant" or "risk variant" is more appropriate.
●Patients should be aware of legal protections against health care discrimination, as well as areas in which they are not protected. (See 'Life insurance coverage (in the United States)' below.)
Psychological effects — Patients may develop anxiety after learning they have a high-risk APOL1 genotype. This usually dissipates over several months.
In a study of 76 African American community members, stakeholders strongly supported returning results, but risks include misunderstanding, psychological burdens, and stigma [25].
Life insurance coverage (in the United States) — Patients with known kidney disease may be denied life insurance coverage or have higher costs. Additional information about a high-risk APOL1 genotype is unlikely to further increase these costs.
However, patients without known CKD who undergo genetic testing are at risk for adverse consequences when trying to obtain life insurance and long-term care insurance. This is especially concerning for potential kidney donors, who are trying to perform an altruistic act. Patients tested for unrelated conditions who are found to have APOL1 risk alleles may also be at risk.
Protections against discrimination exist for health insurance and employment. (See "Genetic testing", section on 'Genetic discrimination'.)
Kidney donation — In kidney transplantation, the risk of graft failure is increased when the donor kidney has a high-risk APOL1 genotype, (almost fourfold increased risk of eventual graft loss) [26].
Given the increased risks of graft failure and end-stage kidney disease (ESKD) in the donor, many centers are not allowing individuals with the high-risk APOL1 genotype to donate, especially when young.
Kidney donors should have the option of not receiving APOL1 genetic test results; however, many will be curious as to the reason they are turned down for donation. (See 'Pre-test considerations' above.)
Positive results can cause uncertainty regarding the potential to develop CKD. Kidney transplant programs should have a protocol in place for delivering these results. (See 'Information for the tested individual' above.)
CLINICAL CARE —
Black individuals with relatives from European countries who have a high-risk APOL1 genotype (homozygous or compound heterozygous for risk alleles) are at increased risk of CKD, although the majority will never develop CKD.
Black individuals from Africa (particularly Ghana and Nigeria) who are homozygous or heterozygous for APOL1 risk variants, are at increased risk of CKD based on a recent study [6]. Further studies and guidelines are urgently needed in this area to determine their care; in the interim, one might consider care as described below for Black individuals who have European relatives and have the high-risk homozygous APOL1 genotype. (See 'CKD risk in the United States' above.)
Black individuals in the United States (US) or with relatives from Europe and who are heterozygous carriers of one APOL1 risk allele are not considered to be at increased risk. (See 'APOL1 variants' above.)
Evaluation and monitoring — Patients with a high-risk APOL1 genotype should receive reassurance and have their questions answered to alleviate anxiety. (See 'Counseling and disclosure of results' above and 'Psychological effects' above.)
Those with a high-risk genotype should undergo the following testing (algorithm 1):
●Kidney function – Serum creatinine, urinalysis, and urinary albumin (or microalbumin) to creatinine ratio at least annually (more frequently as needed for patient reassurance). Urinary albumin or microalbumin alone without urinary creatinine is insufficient.
●Blood pressure – All individuals should have blood pressure measured; the patient should buy a blood pressure cuff and check blood pressure at least monthly.
●Additional genetic testing for selected individuals – For individuals with at least one G2 allele, evaluation for the APOL1 p.N264K variant, which ameliorates the effect of G2, may be useful, although this testing is not widely available. (See 'APOL1 variants' above.)
It is also appropriate to evaluate all individuals at increased CKD risk for any chronic inflammatory conditions that might exacerbate CKD. (See 'CKD risk in the United States' above.)
Prevention and management interventions — There are emerging therapies for APOL1 nephropathy, and physicians should discuss participation in clinical trials with their patients [23]. The investigational Apol1 channel blocker inaxaplin appears promising [22].
General health guidelines should be followed:
●Avoid smoking
●Regular exercise
●Maintain a healthy body weight and body mass index
●Treat other health conditions
Hypertension should be treated with similar targets as in patients without a high-risk APOL1 genotype (algorithm 1).
In one study, Black individuals with a high-risk genotype had a twofold increased risk of acute kidney injury (AKI) and death from COVID-19 [18]. COVID-19 vaccination should be offered to individuals with a high-risk genotype. (See "COVID-19: Vaccines".)
Patients considering kidney donation should receive counseling about APOL1 testing and should consider being tested prior to donation, with counseling on the risks and benefits of testing. (See 'Counseling and disclosure of results' above.)
FIRST-DEGREE RELATIVES —
First-degree relatives may consider APOL1 testing. No specific treatments are available, but those with a risk allele may benefit from the measures discussed above. (See 'Evaluation and monitoring' above and 'Prevention and management interventions' above.)
RESOURCES
Locating a specialist
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG).
●Genetic counselors – National Society of Genetic Counselors (NSGC). Genetic testing laboratories may also provide virtual (online or telephone) access to a genetic counselor.
UpToDate topics
●Focal segmental glomerulosclerosis (FSGS) – (See "Focal segmental glomerulosclerosis: Genetic causes" and "Focal segmental glomerulosclerosis: Pathogenesis" and "Focal segmental glomerulosclerosis: Clinical features and diagnosis" and "Focal segmental glomerulosclerosis: Treatment and prognosis".)
●HIV-associated nephropathy – (See "HIV-associated nephropathy (HIVAN)".)
●Lupus nephritis – (See "Lupus nephritis: Diagnosis and classification" and "Lupus nephritis: Therapy of lupus membranous nephropathy" and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)
●Sickle cell nephropathy – (See "Sickle cell disease effects on the kidney".)
●Kidney transplantation – (See "Kidney transplantation in adults: Evaluation of the living kidney donor candidate".)
