Apolipoprotein L1 (APOL1) Renal Risk Variant Genotyping 

This test uses bi-directional Sanger sequencing analysis to detect genetic variants in the APOL1 gene that increase the risk for renal disease. These variants, or risk alleles, include G1 (c.1024A>G & c.1152T>G) and G2 (c.1164_1169del). G0 indicates a non-risk allele. Each individual has 2 copies of the APOL1 gene, and testing for these risk alleles determines an individual’s genotype. Those with 2 APOL1 risk alleles (G1/G1, G1/G2, or G2/G2) have a “high-risk genotype” and have increased susceptibility to certain types of non-diabetic kidney disease compared to individuals with a “low-risk genotype” (G0/G0, G1/G0, G2/G0).^1,2

The G1 and G2 alleles occur at increased frequencies in populations with recent sub-Saharan African ancestry, such as African (particularly West African), African American, South American (particularly Brazilian), and African and Hispanic Caribbean.^3,4 Approximately 10% to 15% of African American individuals have a high-risk APOL1 genotype.⁴

The APOL1 status of the donor (not recipient) can impact post-donation renal function in the donor and recipient. Renal allografts taken from deceased donors with a high-risk APOL1 genotype have shorter survival compared to those from donors with low-risk genotypes.^2,5 However, many kidney transplants from deceased donors with a high risk APOL1 genotype function for prolonged periods.⁵ For living donor kidney transplants, no data are available on the impact of donor APOL1 genotype on the recipient allograft survival.⁶ However, living kidney donors with high-risk APOL1 genotypes may have greater declines in post-donation renal function compared to donors with low-risk genotypes. In one study, 11% of living kidney donors with 2 APOL1 risk alleles developed end-stage kidney disease (ESKD).⁷

The National Institutes of Health has initiated a multi-center study titled “APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO)” to prospectively determine the impact of APOL1 risk alleles on the long-term renal outcomes for donors and recipients. While awaiting the results of this study, the American Society of Transplantation’s Living Donor Community of Practice developed interim recommendations for APOL1 genetic testing in living kidney transplant evaluations.⁶ This expert panel opinion offers guidance on a variety of issues, including which donors should be educated and tested, when testing should be offered during transplant evaluation, topics to be covered in counseling, and how to approach the results of APOL1 genotyping.⁶

APOL1 testing is not common in routine clinical practice. There is currently no well-established algorithm for using APOL1 testing in kidney disease evaluations or best practice in counseling patients in APOL1 testing. A multidisciplinary group of experts and patient advocates recently issued consensus guidelines for diagnosis, education, and care of patients with APOL1-associated nephropathy.⁸ The group agreed that APOL1 testing should be considered in patients of African ancestry with kidney disease and any patient with kidney disease who has a family member with a confirmed high-risk APOL1 genotype.⁸ When offering APOL1 testing for renal risk variants, the clinician should discuss the risks and benefits of testing.⁸

Although APOL1 renal risk variant testing can provide information about the risk for APOL1-associated nephropathy, there are no current therapies specific for APOL1 kidney disease.⁸ In addition, there are no known interventions that may prevent onset of kidney disease in asymptomatic individuals.⁸ A consensus has not been reached regarding testing individuals with normal renal function who may have risk factors for APOL1 nephropathy, such as a family history of kidney disease. Preclinical studies as well as phase 1 and phase 2 clinical trials are ongoing for the development of an APOL1-specific treatment. If an effective therapy is identified, this could provide a stronger rationale for APOL1 testing in at-risk individuals.⁸

The typical clinical course varies from progressive chronic kidney disease (CKD) with stable low-level proteinuria to progressive albuminuria and decline in renal function. A subset of patients may also present with nephrotic syndrome and rapidly develop ESKD.²

The constellation of hypertension and CKD with subnephrotic proteinuria (hypertension-attributed kidney disease) is a common manifestation of APOL1-associated nephropathy.² In these individuals, renal biopsies have higher rates of global glomerulosclerosis in a solidified or disappearing pattern, thyroidization of atrophic tubules, and microcystically dilated tubules.⁹  

Individuals with high-risk APOL1 genotypes also have an increased rate of primary focal segmental glomerulosclerosis (FSGS), with an estimated odds ratio of 17 compared to those without.^1,4 Among individuals of African ancestry, approximately 50% of those with hypertension-attributed ESKD and 75% of those with primary FSGS have 2 high-risk APOL1 alleles.¹

Certain conditions that increase systemic interferon levels may increase renal expression of APOL1, which could result in sudden onset or exacerbation of APOL1 nephropathy.^2,10 Collapsing glomerulopathy is the most aggressive histologic pattern of APOL1-associated renal disease, manifesting clinically as rapidly progressive renal failure and heavy proteinuria.¹⁰ Conditions associated with high interferon levels can act as a second hit and trigger collapsing glomerulopathy in those with a high-risk APOL1 genotype. Commonly described high interferon conditions associated with collapsing glomerulopathy include certain viral infections, lupus, interferon treatment, and hemophagocytic lymphohistiocytosis.¹⁰ High rates of HIV-associated nephropathy with collapsing glomerulopathy (odds ratio=29 to 89) and lupus-associated collapsing glomerulopathy (odds ratio=5.4) have been documented in those with high-risk APOL1 genotypes.^1,4 COVID-19–associated nephropathy (COVAN) due to collapsing glomerulopathy is also a known complication of acute coronavirus infection in those with a high-risk APOL1 genotype.¹⁰   

While most individuals with a high-risk APOL1 genotype will have normal renal function throughout their lives, approximately 15 to 20% develop CKD.⁸  APOL1 high-risk genotypes increase the risk of developing CKD (odds ratio of 1.5 to 4), with the greatest risk in younger and middle-aged individuals.¹ Those with established CKD and a high-risk APOL1 genotype have a more rapid decline in renal function and progression to ESKD compared to those with CKD and a low-risk APOL1 genotype.^2,4 The age of onset of ESKD after developing APOL1 nephropathy is often before age 55.⁸ Other modifying environmental and genetic factors likely affect the onset and course of APOL1 nephropathy. Prediction models to help ascertain an individual’s personalized risk have not yet been developed.

The presence of a low-risk APOL1 genotype indicates that the individual is not at increased risk for APOL1-associated nephropathy. However, a low-risk genotype does not exclude the possibility of developing kidney disease due to other causes.

At Quest, we realize that offering this testing with the healthcare provider and patient in mind requires robust laboratory support with genetic counseling services and expert medical consulting. We are pleased to announce that we will support transplant centers with genetic counseling services, which can be reached via phone at 1.866.GENE.INFO (1.866.436.3463) or email at GeneInfo@QuestDiagnostics.com. For more information, visit QuestAdvanced.com/Transplant and click on the “What’s New—Now introducing APOL1: Contact a representative” icon to request follow-up from a Quest representative.