What is the association between Apolipoprotein L1 (APOL1) genotypes and kidney disease, specifically regarding the risk of Focal Segmental Glomerulosclerosis (FSGS) and Human Immunodeficiency Virus (HIV)-associated nephropathy?

From the Guidelines

Apolipoprotein L1 (APOL1) genotypes are strongly associated with an increased risk of kidney disease, particularly Focal Segmental Glomerulosclerosis (FSGS) and Human Immunodeficiency Virus (HIV)-associated nephropathy.

Key Findings

• The APOL1 high-risk genotype, defined as G1G1, G2G2, or G1G2, is associated with a significantly increased risk of FSGS and HIV-associated nephropathy, with a more than 80-fold increased risk of developing HIV-associated nephropathy in black South Africans with untreated HIV and two APOL1 risk alleles 1.
• The magnitude of the risk associated with APOL1 variants varies significantly for different forms of nephropathy, with a 1.2 to 2-fold increased risk of CKD or non-diabetic kidney failure 1.
• APOL1 high-risk variants are being recognized as a strong predictor of adverse kidney outcomes from HIVAN, FSGS, and COVID-19–associated nephropathy in patients infected with SARS-CoV-2 1.

Clinical Implications

• Patients with APOL1 high-risk genotypes should be informed of the potential increased risk of kidney disease, particularly if they have a history of HIV or other viral infections.
• The use of APOL1 genotyping in living kidney donor candidates is controversial, with some studies suggesting that it may be useful in risk stratification, while others argue that it may exacerbate existing racial disparities in access to kidney transplantation 1.
• Shared decision-making is recommended for donors who elect to undergo APOL1 genotyping, rather than automatic exclusion for carrying high-risk APOL1 alleles 1.

Key Points

• APOL1 genotypes are an important risk factor for kidney disease, particularly FSGS and HIV-associated nephropathy.
• The magnitude of the risk associated with APOL1 variants varies significantly for different forms of nephropathy.
• APOL1 genotyping may be useful in risk stratification, but its use in living kidney donor candidates is controversial and requires shared decision-making.

From the Research

Association between APOL1 Genotypes and Kidney Disease

The association between Apolipoprotein L1 (APOL1) genotypes and kidney disease has been extensively studied, particularly in the context of Focal Segmental Glomerulosclerosis (FSGS) and Human Immunodeficiency Virus (HIV)-associated nephropathy. Key findings include:

• Individuals with two APOL1 risk alleles (G1 and G2) have a significantly higher risk of developing FSGS and HIV-associated nephropathy compared to those with zero or one risk allele 2, 3.
• The disease risk follows a recessive mode of inheritance, meaning that individuals must inherit two copies of the risk variants to develop the disease 2.
• Studies have shown that APOL1 risk alleles are associated with earlier age of onset and faster progression to end-stage renal disease (ESRD) in FSGS patients 3.
• The APOL1 risk alleles are found primarily in individuals of African ancestry, which may explain the higher incidence of kidney disease in this population 3, 4.

APOL1 Genotype and Renal Histology

Research has also investigated the relationship between APOL1 genotype and renal histology in Black HIV-positive patients undergoing kidney biopsy. Findings include:

• The APOL1 high-risk genotype is associated with a greater risk of FSGS and HIV-associated nephropathy in this population 5.
• The addition of APOL1 genotype to conventional clinical factors improves the prediction of non-HIV-associated nephropathy FSGS, but not HIV-associated nephropathy 5.
• APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in Blacks who are HIV positive 5.

Mechanisms of APOL1-Associated Disease

Studies have also explored the mechanisms of APOL1-associated disease, including:

• The localization of APOL1 in normal kidney and nondiabetic kidney disease, which suggests that APOL1 may play a role in the development of kidney disease 6.
• The potential role of APOL1 in arteriopathy, which may contribute to disease pathogenesis in patients of African ancestry 6.
• The need for further research to understand the cellular and molecular mechanisms of APOL1-associated disease, which may lead to new methods of treatment 4.