What is the significance of Apolipoprotein L1 (APOL1)?

From the Guidelines

APOL1 gene variants, particularly G1 and G2, are associated with an increased risk of kidney disease in individuals of African ancestry, with a significantly increased risk of developing focal segmental glomerulosclerosis, HIV-associated nephropathy, and hypertension-attributed kidney disease, as reported in the most recent study 1.

Significance of APOL1

The APOL1 gene variants are thought to have evolved as a protective mechanism against African sleeping sickness but now contribute to higher rates of kidney disease.

• Individuals with two high-risk APOL1 variants (homozygous or compound heterozygous) have a significantly increased risk of developing kidney disease, with an odds ratio of ~ 7 for end-stage kidney disease and an odds ratio of 10 to 29 for focal segmental glomerulosclerosis (FSGS), including HIV-associated nephropathy, as noted in 1.
• The mechanism involves APOL1 risk variants causing podocyte stress, mitochondrial dysfunction, and inflammatory pathway activation, ultimately leading to kidney damage.
• Currently, there is no specific treatment targeting APOL1-associated kidney disease, so management focuses on standard kidney protective measures, including:
  • Blood pressure control (target <130/80 mmHg)
  • Use of ACE inhibitors or ARBs
  • Diabetes management if applicable
  • Lifestyle modifications such as low-sodium diet, regular exercise, and smoking cessation

Genetic Testing for APOL1 Variants

Genetic testing for APOL1 variants may be considered for individuals of African ancestry with unexplained kidney disease or a strong family history of kidney failure, though testing is not routinely recommended for the general population, as discussed in 1 and 1.

• The APOL1 risk alleles 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, highlighting the importance of considering APOL1 testing in high-risk individuals, as reported in 1.
• However, the decision to offer APOL1 genetic testing should be individualized, taking into account the potential benefits and drawbacks, including the risk of anxiety, stigma, or apathy, and the lack of evidence-based interventions, as noted in 1.

From the Research

Significance of Apolipoprotein L1 (APOL1)

• APOL1 is a gene that has been associated with an increased risk of chronic kidney disease, particularly in individuals of African descent 2, 3, 4, 5, 6.
• The APOL1 gene has two variants, G1 and G2, which are found only in people of West African origin and are thought to have been genetically selected due to the protection they afford against African sleeping sickness 5.
• APOL1-associated kidney disease includes a group of related phenotypes, such as proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy 2, 4.
• Research has shown that APOL1 renal-risk variants are associated with glomerulosclerosis in African Americans, which can lead to secondary hypertension 2.
• Studies have also investigated the potential of targeted therapies, including APOL1 small molecule inhibitors, APOL1 antisense oligonucleotides, and inhibitors of APOL1-associated inflammatory pathways, for the treatment of APOL1-associated nephropathy 4, 6.

Role of APOL1 in Kidney Disease

• APOL1-mediated kidney disease is a subtype of proteinuric kidney disease that is caused by the G1 and G2 variants in the APOL1 gene 3, 6.
• The APOL1 gene has been shown to play a role in the development of kidney disease, with APOL1 channel activity driving podocyte injury and contributing to kidney damage 6.
• Inhibition of APOL1 channel activity has been shown to stop APOL1-mediated cell death and kidney damage in a transgenic mouse model, suggesting potential therapeutic applications for APOL1 inhibitors 6.

Treatment Approaches for APOL1-Associated Nephropathy

• Current treatment approaches for APOL1-associated nephropathy are suboptimal, with aggressive hypertension control, renin-angiotensin system blockade, steroids, and conventional immunosuppressive agents showing limited effectiveness 4.
• Targeted therapies, such as APOL1 small molecule inhibitors and APOL1 antisense oligonucleotides, hold promise for the treatment of APOL1-associated nephropathy 4, 6.
• Clinical trials are needed to further investigate the potential of these therapies and to determine their safety and efficacy in patients with APOL1-associated nephropathy 4, 6.