How Rare Is Complement 3 Glomerulopathy?

Complement 3 glomerulopathy (C3G) is a very rare disorder, affecting just 1-2 million people globally. It’s an umbrella term for a group of kidney diseases that occur when part of the immune system becomes overactive. More research is needed to understand causes and treatment options for C3G.

C3G encompasses multiple kidney diseases that are caused by dysfunction of the complement system, which is part of the immune system.

The complement system is composed of proteins that help the body fight pathogens, such as bacteria and viruses. However, when someone has C3G, their complement system goes into overdrive, making too many of these disease-fighting proteins.

These complement proteins travel through the bloodstream and are broken down by the body. Then, the protein pieces are deposited in the kidneys, where they injure the glomeruli, or the kidneys’ filtration system.

With damaged glomeruli, the kidneys can’t function normally, leading to symptoms and complications such as blood in urine, swelling, and more.

C3G is a very rare condition that affects about 1 to 2 people per million worldwide. In the United States, experts estimate there are about 1-3 C3G cases per every one million people.

There are two main types of C3G:

• Dense deposit disease (DDD): People with this condition have long, ribbon-like or sausage-like protein deposits in their kidneys. Children and adolescents are more likely to be diagnosed with DDD.
• C3 glomerulonephritis (C3GN): People with C3GN also have protein deposits in their kidneys, but under a microscope, these deposits are less concentrated and are lighter in color. Diagnoses are more common among adults and kidney symptoms tend to be less severe in the beginning. However, C3GN is more likely to progress to end-stage renal disease, where the kidneys can no longer support the body.

DDD makes up about one-third of cases, while C3GN accounts for the other two-thirds.

C3G is very rare, and the exact cause is unknown. However, it could be driven by:

• Genetic mutations: For many people with C3G, genetic changes affect the complement system and cause it to go into overdrive, in turn, harming the kidneys. For example, research has shown that people from Cyprus, a small island in the Mediterranean, are at risk for C3G due to a genetic mutation in the CFHR5 gene, which affects the complement system. Experts have also linked mutations in the C3 and CFH genes to C3G.
• Autoantibodies: Normally, the body creates antibodies to fight foreign pathogens such as bacteria and viruses. However, it can also create autoantibodies, which target cells produced by the body itself. Many people with C3G have autoantibodies called complement 3 nephritis factor (C3NeF), which attack the complement system. This could spur the complement system dysfunction that leads to C3G.

Certain risk factors are known for C3G, however most cases are sporadic. This means C3G doesn’t usually run in families, and cases aren’t often linked to a person’s family medical history. Many people with C3G risk factors never develop the condition.

There may be some link between C3G and autoimmune diseases that run in families, but more research is needed.

Because the cause is usually unknown, there are no proven ways to prevent C3G or lower your risk of developing it.

However, there are several treatment options available to help people with C3G manage their symptoms and reduce the risk of complications.

Signs that you may be experiencing C3G could include:

• Changes in urine: When complement proteins build up in the kidneys and damage their filtering system, the kidneys aren’t able to produce urine as they normally would. People with C3G may notice blood in their urine (which can appear pink, red, or brown). Urine may also look cloudy or foamy, which is a sign of too much protein in the urine. With C3G, people may also have significantly less urine output.
• Fatigue: Damaged kidneys may struggle to filter out waste from the bloodstream, which can cause these waste products to build up in the body. This often causes tiredness or issues concentrating.
• Swelling: C3G often causes puffiness in the hands, feet, ankles, or around the eyes because kidney damage causes fluid retention.

See your healthcare provider right away if you develop any signs or symptoms of C3G. Promptly recognizing symptoms allows you to seek early treatment and reduce your risk of serious complications.

C3G symptoms tend to get worse over time and may lead to end-stage renal disease, which is a life-threatening condition. See your doctor if you are concerned that you may be experiencing C3G symptoms. It is helpful to remember that this disease is very rare, and many of its symptoms could have other causes.