Q&A with Dr. Henry Cremisi of Vertex Pharmaceuticals Medical Affairs: What is the APOL1 gene and how is it related to kidney disease?

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Dr. Cremisi is a nephrologist working with Vertex Pharmaceuticals Medical Affairs. In this Q&A, he addresses patients' questions about the APOL1 gene and its connection to kidney disease.

What is the APOL1 gene and what purpose does it serve?

The apolipoprotein L1 (APOL1) gene is part of the APOL gene family, which plays a role in innate immunity, our body's built-in system to fight infectious threats.

Sometimes genes change, which then become known as gene variants or mutations. In the case of the APOL1 gene, mutations evolved in people who lived in parts of Africa several thousand years ago to provide protection against a parasite that caused African sleeping sickness (which had high rates of mortality and morbidity). As people from these regions of Africa migrated around the world, the mutations in the APOL1 gene came with them. Today, people of African descent across the globe may carry these APOL1 mutations, including people who identify as Black, African American, Afro-Caribbean, and Latina or Latino.

At one point, the APOL1 gene mutations served a very important protective benefit, but we now know that they are also the underlying cause of severe kidney diseases in some people (known as APOL1-mediated kidney disease).

Does everyone with the APOL1 genetic mutations get kidney disease?

No. About 13% of people of African descent carry two copies of the APOL1 high risk mutations (these are the ones that cause APOL1-mediated kidney disease), but most of these individuals will never develop kidney disease.

Some people have been diagnosed with kidney disease already (like focal segmental glomerulosclerosis, or FSGS), but do not know that the APOL1 gene mutations may have contributed to their disease.

Do the APOL1 genetic mutations impact other organs besides the kidneys?

The APOL1 gene circulates throughout the whole body, but scientists think the harmful effect of the APOL1 mutations is largely limited to the kidneys. However, the link between APOL1 gene variants and severe kidney diseases was identified in 2010, so there is still a lot that we need to learn about the mutations and their impact on the body.

Are people born with the APOL1 mutations, or do they develop later in life?

A person is born with the APOL1 mutations, but there must be an additional factor or environmental trigger that causes a person to get APOL1-mediated kidney disease. An environmental trigger is something a person can randomly or unintentionally encounter, such as a virus or an infection, that acts to trigger (or cause) the disease.

Research shows that an environmental trigger, also known as a "second hit," is needed to cause injury to the kidneys (which impacts the kidneys' ability to work). Most of the time this second hit is unknown to the patient, but it could be something as simple as an infection (like COVID-19) that serves as the trigger for the kidney disease.

So, while someone is born with the APOL1 high-risk mutations, they may not actually get kidney disease, or they may not get it until they are older.

Can the APOL1 mutations be triggered (or caused) by nutrition?

No. While the major causes of kidney disease – including diabetes, hypertension (high blood pressure) and heart disease – can be impacted by nutrition, APOL1-mediated kidney disease is not. Typically, APOL1-mediated kidney disease is triggered by an illness, infection, inflammation or even specific medicines in a person who carries two copies of the APOL1 gene mutations.

If you have the APOL1 mutations, are you destined to develop kidney disease?

No. An individual needs to have two "high-risk" mutations (these are the ones that cause kidney disease) of the APOL1 gene to be at risk for kidney disease — which means you would have received one gene from each parent. But even if a person does have two high-risk mutations of the APOL1 gene, they may not necessarily get kidney disease. Approximately 15% of individuals with the APOL1 high-risk mutations will ultimately develop kidney disease.

What should you do if you find out you have the APOL1 genetic mutations that can cause kidney disease?

APOL1-mediated kidney disease, like other chronic kidney diseases, presents a unique problem as it can progress quickly and without obvious symptoms. There are currently no approved treatments that address the underlying cause of APOL1-mediated kidney disease.

If you find out that you have the APOL1 high-risk mutations, you should talk to your doctor, so that together you can closely monitor the health of your kidneys. Early detection of kidney disease can help you and your provider choose appropriate care options, identify potential risk for other family members and assist with timely management of the disease. Some people diagnosed with the disease may also consider participating in a clinical trial.

If someone finds out they have the two mutations, what does that mean for their family and children? Do they also have the APOL1 genetic mutations?

The APOL1 mutations can be passed from generation to generation, so if someone has two APOL1 high-risk mutations, they might consider speaking to family members about getting tested. But remember: an individual receives one gene from each parent, and they must have two high-risk mutations to be at risk for APOL1-mediated kidney disease.

You can learn more about APOL1-mediated kidney disease on AKF's website.