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Kidney / Renal Last reviewed:

APOL1-Mediated Kidney Disease

Also known as: AMKD, APOL1 nephropathy

Reviewed by the Black Health editorial team Last reviewed

~13% of African Americans carry two high-risk APOL1 variants

About 1 in 8 Black Americans

Overview

For decades, the higher rates of chronic kidney disease and kidney failure among Black Americans were attributed to hypertension and diabetes alone. Then in 2010, researchers discovered something more specific: two variants of a gene called APOL1, found almost exclusively in people with recent West African ancestry, account for the majority of excess kidney failure risk in Black Americans from non-diabetic causes. (Genovese G et al., Science. 2010;329(5999):1564-1568. PMID: 20647424) This is a genetic risk factor that clinicians and patients often don't discuss, partly because genetic kidney testing is still not routine. This page explains what APOL1 is, what the risk actually means, and what to do about it.

How APOL1-Mediated Kidney Disease affects Black patients

This condition is, by genetics, almost entirely a Black diagnosis, and the reason traces back thousands of years to West Africa. The G1 and G2 variants of APOL1 are protective against Trypanosoma brucei, the parasite that causes African sleeping sickness. People who carried one copy survived outbreaks at higher rates, so the variants spread through West African populations. The trade-off only became visible centuries later: two copies of the variant damage the filtering cells of the kidney (podocytes), especially when a second stressor is present (HIV, COVID-19, interferon therapy, lupus, severe hypertension).

Because the trans-Atlantic slave trade carried West African ancestry into the Americas, the variants travel with that ancestry today. Allele frequency in African Americans is roughly 35%; about 13% inherit two high-risk copies. The variants are also common in Afro-Caribbean and some Hispanic Black populations. They are rare to absent in people without recent West African ancestry, which is part of why race-based eGFR equations were misleading: race was being used as a noisy stand-in for a genetic difference that only some Black patients actually carry, while inflating estimated kidney function for everyone classified as Black and delaying referrals for transplant and specialty care.

Clinically, Black patients with two high-risk APOL1 alleles tend to present earlier, progress faster, and lose kidney function at a steeper rate than peers without the variants. In the AASK trial (African American Study of Kidney Disease and Hypertension), Black patients with the high-risk genotype reached end-stage kidney disease or doubled their creatinine at 58.1% versus 36.6% in those with low-risk genotypes (Parsa et al., NEJM 2013). The variants are also a leading explanation for why Black kidney transplant donors are more likely to develop CKD post-donation when they unknowingly carry two copies.

Symptoms

  • Foamy or bubbly urine (a sign of protein in the urine, often the first clue)
  • Swelling in the ankles, feet, hands, or around the eyes
  • Fatigue that does not improve with rest
  • High blood pressure that is hard to control, especially before age 50
  • Reduced urine output, dark urine, or urine that looks tea-colored
  • Itchy skin, muscle cramps, or trouble sleeping in later stages
  • Shortness of breath from fluid buildup
  • Nausea, loss of appetite, or a metallic taste in the mouth as kidney function drops

Early disease is usually silent. Many people have no symptoms until proteinuria is found on a routine urine test or kidney function has already dropped significantly.

When to see a doctor

Make an appointment with a primary care doctor or nephrologist if you notice foamy urine that persists for more than a few days, new or worsening swelling, or if blood pressure is climbing without an obvious reason. If you have a family history of kidney disease, dialysis, or kidney transplant on the Black side of your family, ask your doctor for a urine albumin-to-creatinine ratio and a basic metabolic panel even if you feel fine. Go to the ER for sudden severe swelling, chest pain or shortness of breath with low urine output, or confusion paired with very high blood pressure.

Screening

There is no consensus that every Black person should be screened for APOL1 variants, and the medical community is openly working through that question. The current state in 2026:

Who is offered testing. A 2024 clinical review in JAMA by Hopper and Olabisi summarized the field consensus that population-wide APOL1 screening is not yet recommended, but testing should be offered to people with recent West African ancestry who have non-diabetic CKD, unexplained proteinuria, FSGS on biopsy, or a family history of kidney disease. The American Society of Transplantation's 2025 living-donor guidance recommends discussing APOL1 testing with any prospective living kidney donor who self-reports recent African ancestry, well before the donor evaluation closes, and supports shared decision-making rather than automatic exclusion if two high-risk variants are found.

How testing is done. A simple blood or saliva test sequences the APOL1 gene for the G1 and G2 variants. Results return as one of three genotypes: 0, 1, or 2 high-risk alleles. Only two high-risk alleles confer the strong disease risk. One copy is essentially neutral for kidney disease.

The honest controversies. A positive result (two high-risk variants) means elevated lifetime risk, not a guarantee. Estimated lifetime risk of kidney disease in someone with two copies is around 15%, which means most carriers never develop the disease. That uncertainty creates real problems: the Genetic Information Nondiscrimination Act (GINA) bars health-insurance and employment discrimination based on genetic results, but it does not cover life insurance, disability insurance, or long-term care insurance. People considering testing should know this before they consent. Pre- and post-test genetic counseling is recommended by every major group that has weighed in. The race-based eGFR equation was retired in 2021 (NKF-ASN Task Force, Delgado et al., JASN 2021) in part because APOL1 made clear that race was being used as a poor proxy for a genetic risk only some Black patients carry. The replacement CKD-EPI 2021 equation removes race; many labs also report cystatin C-based eGFR for confirmation.

Treatment overview

There is no FDA-approved therapy specifically for APOL1-mediated kidney disease as of May 2026. Standard care is the same backbone used for other proteinuric kidney disease: tight blood pressure control (target generally below 130/80), an ACE inhibitor or ARB to reduce proteinuria, an SGLT2 inhibitor (dapagliflozin or empagliflozin) which now has strong evidence in non-diabetic proteinuric CKD, careful management of lipids and cardiovascular risk, and avoidance of nephrotoxic drugs including chronic high-dose NSAIDs.

Inaxaplin (VX-147) is the first APOL1-targeted therapy. Developed by Vertex, it is a small molecule that blocks the toxic activity of the APOL1 protein inside kidney cells. The Phase 2a open-label study (Egbuna et al., NEJM 2023; PMID 36920755) enrolled 16 participants with two APOL1 variants and biopsy-proven FSGS. After 13 weeks, the urine protein-to-creatinine ratio dropped 47.6%, with mild-to-moderate side effects and no discontinuations. The FDA granted Breakthrough Therapy designation.

AMPLITUDE is the ongoing Phase 2/3 adaptive trial (NCT05312879) testing inaxaplin 45 mg once daily versus placebo on top of standard of care in adults and adolescents with APOL1-mediated kidney disease. Vertex announced completion of the interim-analysis cohort enrollment in late 2025; a positive interim readout would support accelerated FDA approval. Anyone who fits the diagnostic criteria should ask their nephrologist about enrollment.

I could not verify the existence of trials named "AVANTI" or "ONELINER" in APOL1-mediated kidney disease, so this entry covers AMPLITUDE and the Egbuna Phase 2a study, which are the confirmed inaxaplin trials in the published record.

For people who progress to kidney failure, dialysis and transplant remain the mainstays. APOL1 testing of living donors is now part of standard transplant evaluation when the donor reports West African ancestry, because two high-risk variants in the donated kidney predict faster post-transplant function loss.

Questions to ask your doctor

Bring this list to your next appointment.

  • Should I be tested for APOL1 gene variants given my ancestry and kidney health history?
  • My urine has been foamy. Should I have a urine albumin test?
  • What is my eGFR trend over the past few years, and is it declining?
  • Am I on an ACE inhibitor or ARB, and if not, why not?
  • Am I a candidate for an SGLT2 inhibitor for kidney protection?
  • Are there APOL1-related clinical trials I should know about?
  • If I am considering donating a kidney, what does my APOL1 status mean for my own risk?

Find care for apol1-mediated kidney disease

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The numbers

  • Approximately 35% of African Americans carry one high-risk APOL1 allele and a higher proportion carry at least one copy. (NIDDK)
  • People with two high-risk APOL1 variants have an estimated 15% lifetime risk of kidney disease overall, with much higher risk in the presence of specific triggers. (NIDDK)
  • Among HIV-positive Black Americans not on antiretroviral therapy, having two high-risk APOL1 variants raises kidney disease risk to approximately 50%. (NIDDK)
  • Patients with two high-risk variants who develop focal segmental glomerulosclerosis (FSGS) begin hemodialysis at a mean age of 49 years, compared to 56 years for those with one variant and 62 years for those with none. That is 13 years earlier for the highest-risk group. (NIDDK)
  • APOL1 high-risk variants account for nearly all excess kidney failure in Black Americans from non-diabetic causes including FSGS and hypertension-attributed kidney disease (now increasingly called APOL1-mediated kidney disease rather than hypertensive nephrosclerosis). (Genovese et al., Science 2010, PMID 20647424)

What it is

APOL1 stands for Apolipoprotein L1. It is a protein produced primarily in the liver and also in kidney cells (podocytes). Under normal conditions, it circulates in blood and protects against certain parasites, specifically the trypanosome that causes African sleeping sickness. Two variants of the APOL1 gene, called G1 and G2, evolved within the past 10,000 years, likely because they provided superior protection against the Trypanosoma brucei rhodesiense parasite common in sub-Saharan Africa. This survival advantage explains why G1 and G2 are common in populations with recent West African ancestry and nearly absent in populations without that ancestry.

The tradeoff is kidney risk. When a person inherits two copies of high-risk variants (two G1 alleles, two G2 alleles, or one of each), the APOL1 protein that accumulates in kidney cells becomes toxic to those cells under certain conditions. The kidney cell type most affected is the podocyte: a specialized cell that filters blood in the kidney's filtering units (glomeruli). When podocytes are damaged, protein leaks into the urine, and kidney function can decline.

This is a "two-hit" model: the genetic predisposition (having two risk alleles) is the first hit. A second hit (viral infection, HIV, interferons, certain medications, or other stressors) appears to trigger or accelerate disease in many cases. Not everyone with two risk alleles develops kidney disease, which is why the 15% lifetime risk figure is important: it is substantially elevated but not a guarantee.

The most common APOL1-associated kidney disease patterns are: - Focal segmental glomerulosclerosis (FSGS): Scarring of parts of the glomeruli; can cause heavy proteinuria and rapid kidney function decline. - APOL1-mediated kidney disease (AMKD) / HIV-associated nephropathy (HIVAN): Collapsing FSGS pattern, historically documented in HIV-positive patients; now recognized in non-HIV contexts as AMKD. - Hypertension-attributed CKD: Many cases formerly attributed to hypertension in Black patients likely represent APOL1-mediated injury with hypertension as a cofactor, not the primary cause.

Why it affects people of West African ancestry

The G1 and G2 APOL1 variants are found almost exclusively in people with recent West African ancestry. They are present at high frequency in sub-Saharan African populations and in African American, Afro-Caribbean, and Afro-Latino populations that trace ancestry to the West African slave trade. They are rare or absent in populations from East Africa, Europe, Asia, and the Americas without West African ancestry.

This is not a marker of race as a social category; it is a marker of a specific geographic ancestry and evolutionary history. People who identify as Black but whose ancestry is primarily East African (Ethiopian, Somali, Kenyan) are much less likely to carry G1 or G2.

The implication: APOL1 genetic risk cannot be assumed based on self-reported race alone, though it is currently the best available clinical proxy in the absence of genetic testing.

Treatment, plainly

Until recently, there was no disease-specific treatment. Management focused on blood pressure control (ACE inhibitors or ARBs to reduce proteinuria), SGLT2 inhibitors (which have shown kidney-protective benefits across CKD populations including those with proteinuria), and avoiding nephrotoxic drugs and NSAIDs.

Inaxaplin (VX-147) is in Phase 3 trials specifically for APOL1-mediated kidney disease. This oral medication is a first-in-class APOL1 inhibitor designed to block the toxic effects of the APOL1 protein in kidney cells. Phase 2 data showed significant proteinuria reduction. A Phase 3 trial is ongoing; approval would be a major advance for this population. (Vertex Pharmaceuticals, VX-147 Phase 3 Trial)

Sparsentan (Filspari) received full FDA approval in April 2026 for reducing proteinuria in adults and children with focal segmental glomerulosclerosis (FSGS) who do not have nephrotic syndrome. FSGS is one of the main disease patterns associated with APOL1 high-risk genotype. Sparsentan blocks both endothelin-1 and angiotensin receptors. It requires liver function monitoring. (FDA, Filspari Full Approval, April 2026)

Standard of care today includes: - ACE inhibitor or ARB to reduce proteinuria and slow CKD progression - SGLT2 inhibitor (empagliflozin, dapagliflozin): demonstrated kidney-protective benefit in CKD with albuminuria regardless of diabetes status - Blood pressure control to target (typically less than 130/80 in proteinuric CKD) - Dietary protein moderation and low-sodium diet in consultation with a renal dietitian - Avoidance of nephrotoxic agents (NSAIDs, contrast agents, certain antibiotics) - For FSGS with nephrotic syndrome: high-dose corticosteroids and, in resistant cases, calcineurin inhibitors (tacrolimus, cyclosporine)

Genetic testing for APOL1 variants is commercially available and can inform care planning, though it is not yet standard practice in most nephrology or primary care settings. Testing is most relevant when: a Black patient has unexplained CKD or proteinuria, has FSGS on biopsy, or is considering donating a kidney.

Kidney donation: Black Americans with two APOL1 high-risk variants who donate a kidney face a substantially higher risk of themselves developing kidney failure than donors without risk variants. This is an active area of debate about informed consent in transplant evaluation.

When to seek urgent evaluation

Seek prompt nephrology evaluation for:

  • Protein in the urine (foamy urine, or proteinuria detected on a routine urine test)
  • Unexplained rise in creatinine or drop in eGFR
  • Blood in the urine not explained by infection or another cause
  • Swelling in the legs or face (possible nephrotic syndrome)
  • Blood pressure that is difficult to control despite multiple medications

Routine kidney function tests (creatinine, eGFR, urine albumin-to-creatinine ratio) are recommended at least annually for any Black adult with hypertension or diabetes, and on a case-by-case basis for those without established risk factors.

If you are experiencing a mental health crisis, call or text 988 (Suicide and Crisis Lifeline).

How to find care

The National Kidney Foundation maintains a kidney health check tool and a helpline: 855-NKF-CARES (855-653-2273).

Sources

  1. Genovese G, Friedman DJ, Ross MD, et al. Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans. Science. 2010;329(5999):1564-1568. PMID: 20647424. https://pubmed.ncbi.nlm.nih.gov/20647424/
  1. Parsa A, Kao WH, Xie D, et al. APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease. New England Journal of Medicine. 2013;369(23):2183-2196. https://www.nejm.org/doi/full/10.1056/NEJMoa1310345
  1. Ekrikpo UE, Kengne AP, Bello AK, et al. APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans. New England Journal of Medicine. 2024. https://www.nejm.org/doi/10.1056/NEJMoa2404211
  1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Story of Discovery: APOL1 Gene Variants, Unraveling the Genetic Basis of Elevated Risk for Kidney Disease in African Americans. 2017. https://www.niddk.nih.gov/news/archive/2017/story-variants-unraveling-genetic-basis-elevated-risk-kidney-disease-african-americans
  1. Kopp JB, Nelson GW, Sampath K, et al. APOL1 Genetic Variants in Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy. Journal of the American Society of Nephrology. 2011. PMC. https://pmc.ncbi.nlm.nih.gov/articles/PMC3752955/
  1. Vertex Pharmaceuticals. Vertex Advances Inaxaplin (VX-147) into Phase 3 for APOL1-Mediated Kidney Disease. https://investors.vrtx.com/news-releases/news-release-details/vertex-advances-inaxaplin-vx-147-phase-3-portion-adaptive-phase
  1. AJMC. FDA Approves Sparsentan (Filspari) for Focal Segmental Glomerulosclerosis. April 2026. https://www.ajmc.com/view/fda-approves-sparsentan-for-focal-segmental-glomerulosclerosis

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Medical disclaimer

This content is for informational and educational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider with questions about a medical condition. If you are experiencing a medical emergency, call 911 or your local emergency number immediately.

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