Did you know there are around 150 types of rare kidney disease? A handful are caused by overactivation of the complement system — part of the immune system that fights bacteria and viruses. Two of these diseases include:

• Complement 3 or C3 glomerulopathy (C3G)
• Immune complex membranoproliferative glomerulonephritis (IC-MPGN)

In this article, we’ll discuss what causes C3G and IC-MPGN. We’ll cover how the immune system and genetics play roles in these rare kidney diseases. We’ll also explain the differences between these two conditions. Your nephrologist (kidney specialist) can answer any questions you have about C3G and IC-MPGN.

What Are C3G and IC-MPGN?

C3G and IC-MPGN are rare kidney diseases that are considered types of MPGN. Specifically, they’re called glomerular diseases. This means they affect the glomeruli, which are the filtering units in your kidneys. Normally, the glomeruli remove toxins and waste products from the blood. The kidneys make urine that gets rid of these substances.

C3G and IC-MPGN damage the glomeruli and affect kidney function. Each disease develops differently. Keep reading to learn more about what causes C3G and IC-MPGN.

What Is C3G and How Does It Develop?

C3G is a rare kidney disease caused by abnormalities with the protein C3. There are two types of C3G, and they’re divided based on how they affect kidney tissues. They’re known as dense deposit disease and C3 glomerulonephritis. According to Cleveland Clinic, C3G is an extremely rare condition. Studies show that it affects 2 to 3 out of every 1 million people.

The Complement System and C3G

The complement system is a complex part of the immune system that protects your body against bacteria and viruses. Usually, complement proteins remain inactivated until they’re needed. People with complement diseases like C3G have overactive complement systems that damage the body’s healthy tissues.

In C3G, complement proteins like C3 are broken down into smaller pieces. As the kidneys filter blood, the pieces of C3 become stuck in the tiny filters or glomeruli. This injures the kidneys and sets off reactions that lead to more damage. Because C3G damages the glomeruli, they can’t remove wastes and toxins as well as they should. These substances build up in the bloodstream and eventually damage the kidneys even more.

Why Does C3G Develop?

C3G develops when the complement system isn’t balanced properly. Researchers believe there are a few reasons why this happens.

The first is that some people have mutations (genetic changes) in proteins that control the complement system. Remember that the complement system is usually inactive until your immune system needs it. Certain proteins act like brakes that keep complement proteins under control. Some people have mutations that take away these brakes — letting the complement system run out of control.

Most people develop C3G randomly, meaning they usually don’t have a family history of the disease. For the most part, doctors can’t find the exact cause of the disease. Some people have mutations in genes that control the complement system. Affected genes include, but are not limited to, the C3 and CFH genes. Overall, these cases account for a small portion of C3G.

The overactive complement system in C3G may also be caused by autoantibodies. Autoantibodies are abnormal immunoglobulins (Igs) that mistake the body’s own cells and tissues for harmful invaders. Sometimes, the immune system accidentally makes antibodies that mistake your body’s cells and tissues as foreign. These are known as autoantibodies. These abnormal proteins attack the “brakes” in the complement system and lead to overactivation.

In some people with C3G, a specific autoantibody called C3 nephritic factor (C3NeF) keeps part of the immune system switched on for too long. This overactivity can damage the kidneys. Scientists know that C3NeF is important in some cases of C3G, but they are still studying whether other autoantibodies might also play a role.

Monoclonal Gammopathy and Kidney Disease

Cleveland Clinic explains that other health conditions can indirectly lead to C3G. Monoclonal gammopathy of renal significance (MGRS) refers to a set of conditions that affect the kidneys. MGRS develops when immune cells make abnormal copies of themselves. These cells then make defective Igs.

The defective Igs travel through your bloodstream and enter the kidneys. If these defective Igs collect in the kidneys, they can eventually cause damage. This process can affect part of the complement system and lead to C3G.

How Does IC-MPGN Develop?

IC-MPGN is another type of rare kidney disease related to complement proteins, particularly C3. It’s caused by the collection of immune complexes in the kidneys that damage glomeruli.

Immune complexes are made of Igs and C3 proteins together. When these complexes get stuck in the delicate kidney filters, they turn on the complement system. This leads to inflammation that damages the kidneys.

Why Does IC-MPGN Develop?

Studies show that IC-MPGN usually develops with other diseases or infections. For this reason, these cases are called secondary IC-MPGN. For example, people with autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues, are more likely to have IC-MPGN. Autoimmune diseases related to IC-MPGN include:

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Mixed connective tissue disease
• Sjögren’s syndrome

Chronic (long-term) infections are also associated with IC-MPGN. Examples include hepatitis B and C and malaria. IC-MPGN develops in people with paraproteinemias as well. These blood disorders are caused by abnormal immune cells that make too many Igs called paraproteins. The abnormal Igs make immune complexes that become stuck in the kidneys, leading to damage.

Examples of paraproteinemias related to IC-MPGN include:

• Monoclonal gammopathy
• Blood cancers like chronic lymphocytic leukemia
• Waldenström macroglobulinemia

Sometimes, the cause of IC-MPGN is unknown. These cases are called idiopathic IC-MPGN.

How Are C3G and IC-MPGN Different?

Although C3G and IC-MPGN are related diseases, they have some key differences. Both diseases involve complement proteins, including C3. C3G develops when an overactive complement system breaks up C3 proteins that get stuck in the kidneys. On the other hand, IC-MPGN develops from immune complexes with C3 and Igs depositing together in the kidney tissue.

Complement Activation

Abnormal complement activation is seen in both C3G and IC-MPGN. However, each disease activates the complement system differently. There are three pathways within the complement system. Each works in its own way — but the ultimate goal is to activate C3 proteins. The complement pathways are:

• Classical — Triggered when Igs detect harmful invaders like bacteria
• Alternative — Activated directly by certain surfaces on bacteria without needing Igs
• Mannose-binding lectin — Starts when a specific protein binds to sugars on harmful microbes

Studies show that IC-MPGN activates the classical pathway. On the other hand, the alternative pathway is made unbalanced in C3G. Both pathways eventually turn on C3 and the complement system, but they use different proteins to do so.

Effects on the Kidneys

C3G and IC-MPGN both affect the kidney’s tiny filtering units. However, each disease looks different under a microscope. Doctors use tissue samples from a kidney biopsy to make a final diagnosis.

Immunofluorescence (IF) is a technique that stains target molecules or proteins in the tissue sample with special dyes and can be seen as a bright color under the microscope. This technique is used to distinguish between C3G and IC-MPGN by staining C3 and Igs in the kidney biopsy sample. C3 proteins in C3G look very bright with little or no Ig deposit. In C3G, the amount of C3 protein in the kidney tissue is about 100 times higher than any other protein, which makes it stand out clearly during testing. On the other hand, people with kidney samples that show C3 and Igs together in immune complexes and the IF intensity of C3 is not strong are diagnosed as IC-MPGN.

People with C3G and IC-MPGN can have similar symptoms. Examples are:

• Proteinuria (protein in your urine)
• Hematuria (blood in your urine)
• Reduced glomerular filtration rate (the ability to filter waste)
• High blood pressure
• Chronic infections

Talk to Your Doctor About Rare Kidney Disease

If you’re living with a rare kidney disease like C3G or IC-MPGN, be sure to work closely with your nephrologist (kidney specialist). They have the expertise to recommend treatment options and lifestyle changes to support your kidney health. Sticking to your treatment plan can help prevent kidney failure and avoid complicated therapies like dialysis.

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On MyKidneyDiseaseTeam, people with kidney disease and their loved ones come together to ask questions, give advice, and share their stories with others who understand life with kidney disease.

Are you living with a rare kidney disease like C3G or IC-MPGN? Do you have other questions about how these diseases develop? Share them in the comments below, or start a conversation by posting on your Activities page.