Complement 3 glomerulopathy (C3G) or C3 glomerulopathy is a kidney disease affecting 2 to 3 out of every 1 million people. Although it’s very rare, there’s plenty of information and research surrounding C3G. Doctors and researchers continue looking for new ways to treat C3G to improve overall health and quality of life.

This article will cover seven facts about C3G, including its causes and symptoms. We’ll also discuss how researchers are looking for new ways to treat this disease.

1. C3G Is a Rare Kidney Disease Affecting the Kidneys’ Delicate Filters

Your kidneys filter 1 cup of blood every two minutes to remove wastes and toxins. They contain glomeruli (delicate filters) that choose what stays in your blood and what’s removed. The extra fluid and wastes make urine that eventually leaves the body. Glomerular diseases like C3G damage glomeruli and make it harder to filter blood.

Since there aren’t FDA approved therapies specifically for C3G yet, treatments focus on slowing disease progression and managing symptoms.

C3G affects people with overactive complement systems. The complement system is a key part of the immune system. It’s the body’s first line of defense against invading pathogens. There are roughly 50 complement proteins that play a role in protecting the body. Complement 3 (C3) activates the rest of the complement system to fight bacteria and viruses.

In people with C3G, the overactive complement system breaks down normal C3 proteins. As the kidneys filter blood, the tiny C3 fragments get stuck in the glomeruli. This creates inflammation that damages the kidneys. Over time, these organs lose their ability to remove wastes and make urine. Toxins build up in the bloodstream and lead to harmful effects on the body.

2. There Are Two Types of C3G

C3G is divided into two types depending on how it specifically affects the kidneys. Over 10 years ago, researchers renamed C3G from membranoproliferative glomerulonephritis (MPGN). The two types are now known as:

• C3 glomerulonephritis (C3GN)
• Dense deposit disease (DDD)

Doctors need to look at kidney tissue samples to make a final diagnosis. They use a powerful electron microscope to find C3 deposits in the kidneys. The patterns of inflammation and damage determine whether you have C3GN or DDD.

Both types of C3G are rare. Health experts estimate that the disease affects 2 to 3 per 1 million people in the United States. According to the Genetic and Rare Diseases Information Center, DDD affects fewer than 5,000 Americans. While C3GN affects individuals 30 years and older, DDD tends to occur in children and young adults.

3. C3G Has Genetic and Autoimmune Causes

Doctors and researchers have found that C3G has genetic and autoimmune causes. Your genes provide instructions for making new proteins. Some people with C3G have mutations (changes) in certain complement system genes.

The complement system usually stays inactive until it’s needed. This helps stop it from attacking your body’s cells and tissues. Certain genes make proteins that act like brakes in a car to keep the system under control. C3G develops in people with mutations that affect the “brakes.” Their complement system becomes overactive and starts breaking down normal C3 proteins.

Some mutations associated with C3G affect the CFH gene. Complement factor H plays a key role in controlling complement system activation. Specifically, it keeps the system turned off until you get an infection. Mutations in the CFH gene either stop the protein from being made or create a protein that doesn’t work. Some people have mutations in the C3 gene that makes C3 proteins.

Studies also show that some C3G cases are related to abnormal immune system proteins called autoantibodies. Antibodies normally protect you from infections, but autoantibodies attack you instead. Researchers think these abnormal proteins interfere with the “brakes” as well, leading to complement overactivation.

4. Common Symptoms of C3G Include Urine Changes and Swelling

Since C3G affects the kidneys, some of the most obvious symptoms are changes in your urine. Damaged glomeruli let larger molecules through that would normally stay in your body. When blood or protein leaks into your urine, it looks different than it usually does.

Blood can also escape into your urine with C3G. This is known as hematuria, and it may make your pee brown, pink, or red.

Protein in your urine (proteinuria) makes it foamy, dark, or cloudy. It may take a few times to flush all the bubbles down the toilet. Blood can also escape into your urine with C3G. This is known as hematuria, and it may make your pee brown, pink, or red.

Other signs of C3G to look out for include:

• Edema (swelling) in your feet, hands, and around your eyes from extra fluid buildup
• Hypertension (high blood pressure), which is usually caught during a doctor’s appointment
• Reduced urine production
• Fatigue and trouble thinking/concentrating from toxin buildup in your blood
• Changes in your vision from drusen (complement protein deposits in your eyes)
• Partial lipodystrophy (abnormal fat distribution or having areas with little fat)

Studies show that around 50 percent of people with C3G eventually develop kidney failure. Doctors diagnose kidney failure when your kidneys no longer work well enough to support your body on their own. Signs of kidney failure with C3G may also include:

• Nausea, vomiting, and loss of appetite
• Trouble sleeping from muscle cramping at night and toxin buildup
• Itchy or dry skin from chemical imbalances in your blood

5. Doctors Diagnose C3G With Urine Tests and Biopsies

If you’re experiencing symptoms of C3G, it’s a good idea to make a doctor’s appointment. Your primary care provider can refer you to a nephrologist (kidney specialist). They’ll know which tests to run to diagnose rare kidney diseases like C3G.

Doctors start to look for C3G or other kidney diseases with these common tests:

• Physical exam to check your blood pressure and look for swelling
• Urine tests to check for proteinuria and hematuria
• Blood tests to check the level of complement proteins and toxin buildup and to see how well your kidneys work (glomerular filtration rate, or GFR)

Your doctor will also ask about your personal and family history of kidney diseases. If you have a family member with C3G, your chances of developing it are higher.

The only way to know you have C3G is through a kidney biopsy. This test involves removing a small piece of kidney tissue to look at under a microscope. A tissue specialist will look for signs of inflammation and C3 protein deposits in the kidney tissue. You’ll be diagnosed with C3GN or DDD, depending on what the damage looks like and where it’s located.

6. C3G Treatments Focus on Treating Disease Symptoms

Unfortunately, the U.S. Food and Drug Administration (FDA) hasn’t approved any therapies specifically for C3G. Doctors instead focus on slowing disease progression and managing symptoms. It’s important to work closely with your doctor to prevent kidney failure.

Examples of treatments used for some people with C3G include:

• Medications to help lower your blood pressure, like ACE inhibitors, drugs that relax blood vessels and reduce strain on your heart
• Immunosuppressants that help calm your overactive immune system and inflammation, like corticosteroids
• Diet changes to treat high blood pressure, like low-sodium and low-protein diets

People with kidney failure need either dialysis or a kidney transplant to live healthier lives. Dialysis treatment filters your blood to remove toxins and extra fluid — just like healthy kidneys would. A kidney transplant involves surgery to replace your damaged kidneys with healthy ones from a donor.

7. Researchers Are Looking for New Ways To Treat C3G

Since there aren’t any approved C3G therapies, researchers are looking for better ways to target the disease. There’s currently ongoing research into medications known as complement inhibitors. These treatments block specific parts of the complement system to calm inflammation and prevent kidney damage.

Some complement inhibitors are FDA-approved for other complement-related diseases. These drugs include:

• Eculizumab (Soliris)
• Ravulizumab (Ultomiris)
• Iptacoplan (Fabhalta)
• Pegcetacoplan (Empaveli)

Talk to your doctor to learn more about rare kidney diseases like C3G. Researchers are running large studies known as clinical trials that are looking at these drugs for C3G. Another complement inhibitor drug, zaltenibart, will be tested in the future to see if it can help treat C3G. If you’re interested in joining a clinical trial, you may have the opportunity to try new treatments for your disease.

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