Does the APOL1 gene increase the risk of kidney disease in African Americans with diabetes?

APOL1 is one of six APOL genes on chromosome 22. Everyone inherits one from each parent. During evolution, the gene developed to protect people against trypanosome parasites.

Scientists identified two APOL1 kidney risk variants in 2010, which are known as G1 and G2. These variants developed in sub-Saharan Africa to provide extra protection against the trypanosome parasite that causes African sleeping sickness. Therefore, scientists have only identified these variants in individuals with African ancestry.

Having two risk variants increases the risk of kidney disease. An estimated 13% of African American people in the United States have the high risk genotype.

APOL1 gene variants can cause damage to certain cells in the kidney.

The rate of severe kidney disease is higher among Black individuals than among most other ethnic and racial groups. Research suggests that these variants play a big role in this disparity, accounting for almost 70% of the excess risk of kidney disease in African Americans.

Focal segmental glomerulosclerosis (FSGS) is a disease that involves scarring of the kidneys. A high risk variant is present in about 75% of Black individuals with FSGS.

Diabetic and end stage kidney disease

In the United States, non-Hispanic Black people are nearly twice as likely as non-Hispanic white people to develop type 2 diabetes. Over time, this disease can damage the kidneys. The primary cause of kidney failure in the U.S. is diabetes-associated end stage kidney disease (ESKD).

Diabetes and APOL1-associated kidney disease are both fairly common, and an individual can develop them independently. The conditions share obesity as a risk factor. It can be difficult to determine whether kidney disease is related to diabetes or APOL1.

A 2021 research article describes the relationship of APOL1 risk variants to diabetic kidney disease as “puzzling.” APOL1 risk variants do not seem to increase the prevalence of diabetic kidney disease. However, they do appear to speed the rate of progression.

ESKD affects about 750,000 people in the U.S., and the incidence is three times higher among Black people than among white people. About 50% of Black people with ESKD due to hypertension carry the high risk genotype.

Two facts are worth noting. One is that only a small number of people who carry the risk variants develop ESKD. The other is that not all cases of ESKD in African American people are associated with the gene.

These facts mean that there are likely other significant risk factors.

Some other factors that may contribute to outcome disparities are:

• socioeconomic status
• racism and discrimination
• distrust of the medical community
• lack of access to healthcare due to having no or insufficient insurance

People who have two risk variants plus chronic kidney disease lose kidney function faster than those who have only one or neither variant. It also tends to occur at a young age, typically before a person is 55 years old.

It is not clear exactly how the variants speed disease progression.

APOL1 is also associated with a faster decline in kidney function in children and young adults. This is particularly true of those with:

• kidney diseases that affect the small filtering units of the kidney called glomeruli
• sickle cell disease
• HIV

There are currently no therapies that target APOL1 activity related to kidney disease. However, there is a lot of ongoing research in this area, and recent clinical trials show promise.

For example, a phase 1 trial assessed the safety and tolerability of antisense oligonucleotide (AZD2373) against APOL1. The study involved 48 healthy men of African ancestry. It ended with enough data to support the proposed dosing in future studies. Reactions at the injection site limited the testing of higher doses.

A phase 2 trial evaluated the efficacy and safety of an oral small molecule inhibitor of APOL1 activity (VX-147). The study involved 16 adults, all of whom had FSGS associated with APOL1. The results were encouraging, and researchers are recruiting for phase 2/3 trials.

Another phase 2 trial is set to begin in June 2022. The goal is to determine whether a Janus kinase (JAK) inhibitor called baricitinib can reduce albumin in the urine. Albumin is a protein that the liver makes. High albumin in the urine is a sign that the kidneys are not functioning well.

The trial participants will be African American people with APOL1-associated FSGS or nondiabetic CKD due to hypertension.

Other areas of research include:

• interferon antagonists
• direct potassium channel inhibitors
• mitogen-activated protein kinase inhibitors

CKD is a progressive condition.

Currently, there are no targeted therapies for APOL1-associated kidney disease. However, there are other treatments that can help slow disease progression. It is worth mentioning that not everyone progresses to kidney failure.

For those who do experience kidney failure, the treatment options may include dialysis or a kidney transplant.

Certain APOL1 gene mutations can increase the risk of kidney disease. They can also speed up disease progression. Only people of African descent inherit these variants.

African American people also have an increased risk of developing type 2 diabetes. Over time, diabetes can damage the kidneys.

The high risk variants do not necessarily increase the risk of kidney disease in African American people with diabetes, but they do speed up disease progression.

Researchers do not know why some carriers of the variants develop kidney disease while others do not. Various environmental, lifestyle, and societal factors may play a role.

Currently, there are no targeted therapies for APOL1-associated kidney disease. However, ongoing research suggests that change is on the horizon.