Gene test interpretation: APOL1 (chronic kidney disease gene)

INTRODUCTION — This monograph discusses implications of genetic testing for the APOL1 gene, which encodes apolipoprotein L-1 (ApoL1), a 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]. Heterozygous individuals are protected, but individuals with biallelic risk alleles have an increased risk for hypertension and chronic kidney disease (CKD) [2,3].

APOL1 variants — Two specific APOL1 risk alleles (haplotypes) are associated with increased kidney disease risk [2]:

●G1 – G1 contains two single nucleotide variants (rs73885319 and rs60910145) that each result in 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 located very close to each other and are in linkage disequilibrium, meaning they are inherited together in the same haplotype. Approximately 21 percent of Black individuals carry this haplotype.

●G2 – G2 contains the rs71785313 variant, a six base pair deletion that eliminates two amino acids, asparagine at amino acid 388 and tyrosine at 389 (designated delAsn388 and delTyr389). Approximately 13 percent of Black individuals carry this haplotype.

●G0 – G0 refers to a low-risk haplotype that does not contribute to CKD risk.

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 [3].

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 [4]. (See 'CKD risk' below.)

The G1 or G2 haplotype on one allele and G0 on the other allele is a heterozygous carrier state; increased risk of ESKD has not been identified. Evolutionary pressure for heterozygosity is noted above. (See 'Introduction' above.)

CKD risk — Black individuals constitute 13 to 14 percent of the United States population and 30 percent of the ESKD population. Approximately 13 percent of Black individuals (>5 million people) have a high-risk APOL1 genotype, with biallelic G1 and/or G2 haplotypes. High-risk APOL1 genotype accounts for approximately 70 percent of the excess ESKD risk [5].

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 African Americans, 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 [6].

However, two-thirds of individuals with a high-risk genotype will not develop ESKD. Additional acquired and/or genetic contributions may occur.

A high-risk genotype confers increased risk for certain forms of CKD, often before age 50 years [2,4]:

●HIV nephropathy – 29- to 89-fold increased risk compared with HIV-positive controls [7,8]

●Hypertension and hypertension-associated CKD or ESKD – Sevenfold increased risk [4]

●Focal segmental glomerulosclerosis (FSGS) – 17-fold increased risk [7]

●Microalbuminuria – Two- to threefold increased risk [6]

High-risk genotypes were documented in approximately 79 percent of Black individuals with HIV nephropathy, 50 percent of Black individuals with hypertensive CKD, 75 percent of Black individuals with FSGS, and 17 percent with microalbuminuria [2,4,6,8]. In kidney transplant recipients, APOL1 genotype did not affect graft survival in one study and appeared to be associated with decreased allograft survival in another [9-11].

Inflammation may be a triggering factor for APOL1 nephropathy in individuals with the high-risk genotype. Collapsing FSGS has been described in an infant with STING syndrome (stimulator of interferon genes-associated vasculopathy) and in adults following parvovirus or COVID-19, or rarely after COVID-19 vaccination (two cases) [12-16]. The risk from COVID-19 greatly outweighs the risk of a vaccine complication. (See 'Prevention and management interventions' below.)

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 response to cyclosporine or mycophenolate [17]. In another study, individuals with a high-risk APOL1 genotype had worse outcomes that were not improved with aggressive blood pressure control [18].

COUNSELING AND DISCLOSURE OF RESULTS

Pre-test considerations — Testing may be done for several reasons:

●Evaluation of kidney disease

●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. 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 chronic kidney disease (CKD) [19].

If a patient undergoes genetic testing for APOL1 or is referred specifically 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 [20].

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 from learning this information.

Protections against discrimination exist for health insurance and employment. (See "Genetic testing", section on 'Genetic discrimination'.)

Kidney donation — In kidney transplant, the risk of graft failure is increased when the donor kidney has a high-risk APOL1 genotype, with an almost fourfold increased risk of progression to graft loss over time [21].

Given the increased risk of graft failure and the increased risk of the donor developing end-stage kidney disease (ESKD), many centers are not allowing patients with the high-risk APOL1 genotype to donate, especially if the donor is 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 result in 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 — Individuals with 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. (See 'CKD risk' above.)

Individuals who are heterozygous for a risk allele are not considered 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.)

They 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.

It is also appropriate to evaluate for any chronic inflammatory conditions that might exacerbate CKD. (See 'CKD risk' above.)

Prevention and management interventions — There is no consensus for the care of patients with a high-risk APOL1 genotype. Many groups are evaluating potential treatments for APOL1 nephropathy and trying to identify inciting causes; the investigational Apol1 channel blocker inaxaplin appears promising [22].

Patients should be informed about ongoing research and potential new therapies (table 2).

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 haplotype (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 [16]. Vaccination to prevent COVID-19 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

●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 transplant – (See "Kidney transplantation in adults: Evaluation of the living kidney donor candidate".)