C3G Genetic Testing – Cleveland Clinic

We only know what we know, and when there’s something we don’t yet understand, we have to find ways to investigate the source of the issue in order to carve a path forward.

With kidney diseases like C3G, there can be many unknown variables about what causes the condition, what treatment options work and whether or not the condition is something that can be inherited genetically. For these reasons, getting a genetic test for C3G may be something to consider if you’ve recently received a diagnosis or someone in your family has.

Nephrologist Ali Mehdi, MD, explains how genetic testing works and why it might be helpful.

What is C3G?

C3G, or complement 3 glomerulopathy, is a rare glomerular disease that affects a specific network of blood vessels in your kidney, called glomeruli. Glomeruli are responsible for filtering waste and extra fluids from your blood. When these blood vessels get clogged, damaged or scarred over, toxins can build up in your blood and damage your kidneys. Over time, this damage could lead to end-stage renal disease (also known as end-stage kidney disease or ESKD) and kidney failure.

But how do your glomeruli get clogged or damaged in the first place? The answer starts in your complement system, a collection of proteins responsible for triggering inflammation and enhancing or “complementing” your immune system’s ability to fight off foreign invaders like bacteria and viruses.

If your complement system becomes overactive, specific proteins (called complement 3 proteins) build up and become trapped inside your glomeruli. Like food caught in a kitchen sink without a garbage disposal, your glomeruli become clogged with these proteins and lose their ability to filter waste and other toxins.

Healthcare providers don’t always know what causes your complement system to go into overdrive. But they do know that in 10% to 25% of people with C3G, the reason it remains activated is tied to specific mutations of certain genes linked to your complement system. These mutated genes can be inherited or mutated by some other cause. And roughly 30% to 50% of people who are diagnosed with C3G have an increased chance of developing the condition based on their genetic makeup.

Is there a cure for C3G?

There currently isn’t a cure for C3G. Like other kidney diseases such as IgA nephropathy, the goal of treatment is to focus on slowing the buildup of protein, addressing the complications caused by the condition and slowing down the level of damage that’s done to your kidneys. Some complications or side effects of having C3G include:

Because there’s no cure, it’s important to monitor your symptoms and any changes you experience along the way. This is important because C3G affects everyone differently. Some forms of the condition may be either slow developing or more aggressive depending on the condition itself and whether or not you have a genetic predisposition for the condition.

Half of all people who are diagnosed with C3G develop ESKD within 10 years of their diagnosis and need dialysis or a kidney transplant. As there are so many variables in play and your condition can change without warning, Dr. Mehdi advises seeing a nephrologist every three months for testing. He also recommends genetic testing for anyone who’s been diagnosed with C3G and close family members related to someone with the diagnosis.

“C3G is rare, and for the longest time, we didn’t have a lot of information or guidance about treating C3G because of the gravity of the disease,” Dr. Mehdi says. “As we understand more about these diseases at the molecular and genetic level, we’re seeing promising developments and we’ll hopefully be able to help our patients or guide them to get the right treatment.”

Genetic testing for C3G

If you’ve been diagnosed with C3G, you may wonder how a genetic test could play an important part in your recovery.

Genetic testing can identify mutations in your genes and whether or not these mutations are caused by a genetic condition. There is a variety of genetic tests for different conditions.

For people who have a condition like Huntington’s disease, genetic testing can help identify your risk for developing the condition, whether you’ll pass genetic mutations on to your children and the likelihood of your children developing the condition later in life.

With some conditions and certain cancers, details from a genetic test can tell providers which targeted treatments have a higher chance of being more effective. Some cancers respond better to different treatments than others. Having this information can be a tool in figuring out what treatment path could be best for you.

Research into C3G and its potential future treatments is ongoing. Clinical trials are currently happening to identify targeted therapies that may one day be U.S. Food and Drug Administration (FDA)-approved. But a genetic test can help your nephrologist determine the outlook for your condition and how aggressive your condition may be, the likelihood of C3G being inherited by your children and the possible length of time you may need treatment.

“It’s important for me to know whether or not you have a genetic predisposition because we have new therapeutic options now and many in the pipeline,” explains Dr. Mehdi. “If someone carries a genetic predisposition for C3G, that person might require lifelong treatment as opposed to someone who doesn’t have a genetic predisposition and somehow acquired the disease when their immune system ran array and caused this issue.”

How does genetic testing work?

If you’re interested in genetic testing, your nephrologist can send a referral to a geneticist who’ll work with you. The genetic test can be done at home or in-person and requires a saliva sample that’s then sent to a laboratory. When the test results are received, your nephrologist will schedule an appointment with you and go over the results.

“In this case, we’re looking for specific genes that affect your complement system,” says Dr. Mehdi. “If some of these genes are mutated, it might indicate that your complement system is just continuously activated in your body and it will continuously lead to inflammation in your body unless we block it.”

Using this information, your nephrologist might prescribe what’s called complement blockades to stop the overactive, ongoing process of inflammation that causes C3G. This means that you may need to take cascade blockers over the course of your life to ensure the inflammation process doesn’t start back up again.

“Many of the medications we offer suppress your immune system in an attempt to control the inflammation in your kidney. This will leave you immunocompromised,” notes Dr. Mehdi. “When this happens, you’re prone to infections. So, we focus a lot on preventative stuff like vaccinations and ways to avoid infection.”

Living with C3G comes with its own set of challenges and requires some lifestyle changes, but having a genetic test can help offer answers that might not otherwise be available.

“Ten years ago, if you came to see me, I could maybe control your blood pressure or perhaps take care of certain risk factors. I might put you on a high dose of prednisone to try and control the inflammation that’s happening in the kidney. But back then, we just had prednisone,” recounts Dr. Mehdi. “Now, we have more advanced targeted therapies that can hopefully help control the disease with minimal side effects.”