Understanding AMKD: Q&A with nephrologist Dr. Stacy Johnson

APOL1-mediated kidney disease (AMKD) represents a rapidly progressing form of chronic kidney disease (CKD) caused by inherited genetic variants of the APOL1 gene. Awareness of AMKD remains low. As a result, an individual might first be diagnosed with CKD before discovering their kidney disease may have a genetic cause. 

In this post, nephrologist Dr. Stacy Johnson shares her expertise to help you understand more about AMKD, as well as:

• Who is most at risk of carrying the genetic variants.
• Signs, symptoms and how AMKD is diagnosed.
• Current approaches to treatment and disease management.

What is AMKD?

APOL1-mediated kidney disease (AMKD) is a genetic form of chronic kidney disease caused by inherited variants of the APOL1 gene. Everyone inherits two copies of the APOL1 gene, one from each parent, which produces a protein that plays a role in the immune system to help fight off certain parasites. However, specific mutations in this gene (known as variants) can become harmful to the kidneys.

When a person inherits two variants of the APOL1 gene, the resulting protein can damage parts of the kidney responsible for filtering blood. This cellular damage leads to inflammation, protein leakage into the urine (pee) and a gradual decline in kidney function. 

It is important to understand that having these gene variants does not mean that you will develop kidney disease. It simply means you have a higher genetic predisposition. Other environmental factors or underlying health conditions, known as a "second hit," can trigger the actual onset of the disease. It's important to keep in mind that many people who develop AMKD aren't always sure what their "second hit" was that led to the development of AMKD.

Who is most at risk for developing AMKD?

The risk factors for AMKD are deeply tied to genetics and ancestry. The APOL1 gene variants that cause this disease evolved thousands of years ago in regions of West Africa. Originally, these variants provided a survival advantage by protecting individuals from certain parasites that cause African sleeping sickness. These genetic variants are now most commonly found in people of African ancestry, which can include individuals who may identify as African American, Black, Afro-Caribbean and Afro-Latino. 

Although African Americans constitute approximately 14% of the U.S. population, it's estimated that this community accounts for nearly 30% of kidney failure cases. Additionally, studies show that African Americans are up to four times more likely to develop kidney failure compared to white Americans.

While factors like differing rates of diabetes, hypertension (high blood pressure) and access to health care contribute to these disparities, scientific research now points to a genetic component as well, specifically, the APOL1 genetic variants. It's estimated that up to 13% of those in the Black community carry two copies of the APOL1 gene variants, which significantly increases their chances of developing kidney disease.

APOL1 gene variants are a key driver of this disparity, contributing to earlier onset and faster progression of kidney disease in people of African ancestry. Importantly, risk factors for kidney disease extend beyond genetics. A person carrying the variants typically needs a "second hit" or triggering event to develop AMKD. Common triggers may include:

• Severe viral infections, including COVID-19 and HIV-AIDS
• Uncontrolled high blood pressure
• Immune system disorders, e.g. lupus.
• Other existing kidney conditions

What are the common symptoms of AMKD?

In its early stages, AMKD can often present without any noticeable symptoms. The kidneys are highly resilient organs that can continue to perform their vital functions even when partially damaged; as a result, many people may remain unaware of their condition until the disease has progressed significantly.

As kidney function declines, individuals may begin to notice specific physical changes. The most common symptoms include:

• Swelling in the legs, ankles or feet due to fluid retention
• Foamy or bubbly urine, which indicates excess protein
• Unexplained fatigue and low energy levels
• Changes in urination frequency

Because these symptoms are common to many other medical conditions, they do not automatically confirm the presence of kidney disease, emphasizing the importance of seeking professional medical evaluation if you experience persistent symptoms. Timely medical intervention relies on identifying these signs before irreversible kidney damage occurs.

How is AMKD diagnosed?

The diagnostic process usually begins with simple blood and urine tests. A urine test can detect proteinuria, which is the presence of abnormal amounts of protein in the urine. Blood tests measure serum creatinine levels to calculate the estimated glomerular filtration rate (eGFR). The eGFR shows how well your kidneys are filtering waste from your blood.

To definitively diagnose AMKD, your doctor will need to conduct a genetic test, via a simple blood sample.  

If you have a family history of kidney disease and/or African ancestry, discuss genetic testing with your health care provider. A genetic counselor can help you understand the implications of the test results and guide your medical decisions. Education and awareness are powerful tools in the fight against genetic diseases.

What treatment options currently exist for AMKD?

Currently, there are no approved treatments that specifically target APOL1. Current treatment focuses on slowing the progression of kidney disease and managing secondary complications.

Standard care for individuals with AMKD involves several therapeutic strategies. Medical professionals prioritize blood pressure control, as hypertension can accelerate kidney damage. Doctors often prescribe medicines like ACE inhibitors or ARBs and SGLT2 inhibitors to protect the kidneys and reduce protein leakage. We also monitor people closely to manage other health parameters, such as cholesterol levels and blood sugar.

When AMKD progresses to kidney failure, treatment options become more intensive. At this stage, individuals require dialysis or a kidney transplant to sustain life.

The scientific community is actively working to change this reality. Ongoing clinical trials are testing investigational drugs designed to target the underlying cause of AMKD. 

What steps can individuals take to manage or prevent AMKD?

While you cannot change your genetics, there are proactive steps you can take to manage your kidney health. 

First and foremost, individuals in high-risk groups should schedule regular medical checkups. Routine screening for kidney disease involves simple blood and urine tests. Early detection allows for immediate intervention, which is critical for preserving kidney function over time.

Lifestyle modifications also play a significant role in improving kidney health, which may include the following:

• Maintain healthy blood pressure through diet and exercise
• Limit sodium intake to reduce fluid retention
• Avoid smoking, which constricts blood vessels and harms the kidneys
• Manage existing conditions like diabetes or autoimmune disorders
• Consult a doctor before taking over-the-counter pain medicines, as some can harm the kidneys

If you believe you may be at risk for AMKD, we encourage you to schedule an appointment with a health care provider to discuss kidney screening and ongoing clinical trials. You can also explore resources from the American Kidney Fund and other disease awareness campaigns like PowerForwardTogether.com to learn more about genetic kidney disease. Taking a proactive approach to your health is the first step toward a brighter and healthier future.

AMKD Awareness Day is observed the last Tuesday of every April, National Minority Health Month.

The American Kidney Fund's APOL1-mediated kidney disease education campaign is sponsored by Vertex Pharmaceuticals.