What Is C3G? Glomerulopathy | Kidney Disease | WeC3G.com

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What Is C3G?

C3 refers to a key protein in the complement system, which is part of your immune system.

Glomerulopathy means that something is not working properly in the glomeruli, which are small units in the kidneys that filter blood.

 

C3G glomerulopathy (glo-MER-u-LOP-ah-the) or C3G is a rare, chronic disease in which experts believe that a specific part of the immune system, the alternative pathway of the complement system, is not well controlled, often resulting in damage to the kidneys.

In 2013, doctors and experts created a new classification to identify C3G as its own disease. This change was made in order to reflect an improved understanding of the cause of disease. Currently, it includes two subtypes—dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).

If you were diagnosed prior to 2013, you may have been told you had membranoproliferative glomerulonephritis (mem-BRAY-no-PRAH-lif-er-ah-tiv glo-MER-u-lo-nah-FRI-tis) or MPGN and the type of MPGN (type I, II, or III). These are older terms that do not account for what may be causing the disease.

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image shows two arrow pointing in different directions with 2013 in the center, below shows a chart for understanding the relationship of MPGN and C3G. MPGN Type 1 - shows 3 people out of 10 would have C3G. Next line shows MPGN Type 2 – shows 9 in 10 people have C3G. Last line shows MPGN Type lll – shows 4 in 10 people have C3G.

If you have been diagnosed with MPGN Type I, II, or III, you may actually have a type of C3G. Most patients with an MPGN Type II diagnosis have DDD. While some patients with MPGN Type I or III diagnoses may actually have C3GN. It is important to discuss your diagnosis with your healthcare team.

C3G is estimated to affect 8 to 12 individuals per million people worldwide, including nearly 4,000 people in the United States.

There is nearly 1 person with DDD to every 3 people with C3GN.

C3G affects males and females equally. People with DDD generally present at a younger age (childhood or adolescence) compared to people with C3GN (adulthood).

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What Are Kidneys?

Your kidneys are 2 bean-shaped organs that sit on either side of the spine, above your waist.

They are constantly working to remove waste and extra water from the blood.

 
4 images are shown, the first image shows the anatomy of both kidneys  with the artery and vein blood flow, the second image shows the anatomy of the kidney so that all the parts can be seen. The third image shows a cross-section of the glomerulus and nephrons of the kidney, and the fourth image shows the parts of the nephron and how that works.

Each kidney has nearly a million workhorses known as nephrons.

4 images are shown, the first image shows the anatomy of both kidneys  with the artery and vein blood flow, the second image shows the anatomy of the kidney so that all the parts can be seen. The third image shows a cross-section of the glomerulus and nephrons of the kidney, and the fourth image shows the parts of the nephron and how that works.

Each of these nephrons has filtering units called glomeruli (glo-MER-u-lie).

4 images are shown, the first image shows the anatomy of both kidneys  with the artery and vein blood flow, the second image shows the anatomy of the kidney so that all the parts can be seen. The third image shows a cross-section of the glomerulus and nephrons of the kidney, and the fourth image shows the parts of the nephron and how that works.

Blood enters these glomeruli and gets filtered to form urine, keeping the body in balance.

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WHEN YOUR KIDNEYS DON'T WORK PROPERLY, WASTE AND FLUID
CAN BUILD UP IN THE BODY CAUSING SERIOUS SIGNS AND SYMPTOMS.

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The Alternative Pathway and C3G

The complement system is part of your body’s immune system.

It consists of a group of proteins circulating in the body working to protect you from threats like bacteria and viruses.

There are 3 distinct parts (pathways) of the complement system, known as the classical, lectin, and alternative pathways, each with their own roles and responsibilities.

image show 3 cooking pots on a stove depicting how the Classical and Lectin Pathways work. The image shows the gas is turned off when there is no bacteria invading, the 2nd pot has the gas flame on under the pot to show how the systems work when an invader enters the system, and the third pot has a high flame showing how the systems respond to C3G

The classical or lectin pathways are turned "on" or "off," as needed. They help the body fight a threat like an infection, either directly, or by recruiting other parts of the immune system.

By contrast, the alternative pathway is always on and helping to deal with potential threats, but the body controls it to keep it running at a healthy level. Loss of control and overactivity of the alternative pathway can damage healthy cells in your body.

This is believed to be the key problem in patients with C3G.

It is important to know how the complement system may be impacting your kidneys and overall health.

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Cause and Risk Factors

The exact cause of C3G is not known, but research indicates that a loss of control of a specific part of the immune system, the alternative pathway of the complement system, may be the primary cause.

This loss of control leads to an alternative pathway that is continuously "turned up" too high, which is often called "overactivity. "

Overactivity of the alternative pathway results in a buildup of the key complement system protein "C3" in the glomeruli (filtering units), and, often, chronic damage to the kidneys.

There are some things that may increase your risk of getting the disease, including both genetic and acquired risk factors.

Icon of man, woman, and child depicting how hereditary factors work in  genetics

Genetic or Hereditary Risk Factors

Genetic risk is based on the DNA you inherit from your parents, which contains instructions for how your body works. This is also known as your genetic code. Different sections of DNA called genes contain instructions specific to different parts of the body. One way to think of DNA is like a book, with genes making up the chapters.

The immune system is a part of the body that may be influenced by genetics or hereditary factors. In some people, genes that are involved in control of the alternative pathway may have mistakes or mutations. These mistakes may make it hard for the body to adequately control the alternative pathway.

Besides genetic (also called hereditary) risk factors, there are other risk factors called acquired risk factors.

Acquired Risk Factors

Acquired factors are abnormalities in the body that are not inherited from your parents but that are picked up or occur after birth.

The complement system is one part of the body’s immune system. Antibodies, which are proteins, are another important part of the immune system. Antibodies normally help the immune system defend against harmful threats like bacteria and viruses. However, in some people, the body can also produce abnormal antibodies.

There are 2 types of abnormal antibodies that are believed to play a role in C3G:

  1. Autoantibodies: Antibodies that attack the body’s own cells and interfere with the body’s ability to control the alternative pathway.
  2. Paraproteins: Antibodies that don’t attack the body but may cause the alternative pathway to react as if these paraproteins were threats to the body.
note card giving information about C3G risk factors happen from childhood to adulthoods
note card giving information about C3G risk factors happen from childhood to adulthoods

Both of these types of antibodies may contribute to the overall loss of control and overactivation of the alternative pathway, which often results in kidney damage. It is not well understood why certain individuals acquire these risk factors.

Each patient with C3G may have his or her own risk factors, whether genetic or acquired. Some patients may not have any identified risk factors while some may have multiple. It is important to discuss your individual risk factors with your healthcare team.

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Signs and Symptoms

Many diseases affecting the kidneys can have signs and symptoms similar to C3G. Your healthcare team may perform additional tests to rule out other diseases and determine a diagnosis.

Signs and symptoms may include:

 
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Blood in the urine, called hematuria (HEME-ah-TOO-ree-ah)

Your urine color may appear pink, red, or cola-colored when visiting the bathroom.

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Dark foamy urine, from proteinuria (PRO-tee-NEW-ree-ah), meaning high protein levels in the urine

There may also be a cloudy appearance to urine during visits to the bathroom.

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Reduced amounts of urine

You may be visiting the bathroom less or producing less urine during those visits.

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Swelling, called edema (ah-DEEM-ah)

This is where fluid may build up under your skin in different areas of your body (for example, face, legs, and feet/ankles).

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High blood pressure

The force of the blood flowing through your body may be too high.

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Decreased general alertness

It may be more difficult for you to focus or concentrate.                          

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Fatigue or discomfort (malaise)

You may find yourself being more tired or having general feelings of discomfort.

Each patient's journey with C3G may be different. Signs, symptoms, and kidney function may get worse over time, as your kidneys are not able to filter fluids and waste from the body.

Dense Deposit Disease-Specific Conditions

There are some additional signs, symptoms, and conditions that affect people with DDD:

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Lack of fatty tissue under the skin in the upper part of the body called lipodystrophy (LIP-o-DIS-trah-fee)

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Buildup of deposits at the back of the eye, which may cause vision problems, known as drusen (DROO-zehn)

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Presentation and Diagnosis

For most patients, not feeling well will prompt a visit to the doctor. There are several ways that your doctor may determine that you have C3G.

In addition to talking to you about symptoms, your doctor will examine you and may conduct tests to evaluate your condition, including tests to evaluate the health of your kidneys.

Tests That Assess the Health of Kidneys

One way your doctor may assess the health of your kidneys is with a lab test to measure serum creatinine (cree-AT-i-nin), the level of creatinine in your blood. Creatinine is a waste product that comes from muscle. Under normal circumstances, the kidneys filter out creatinine; however, if the kidneys are not working correctly, creatinine is not filtered as well and may build up in the blood.

Your doctor may use your serum creatinine along with other factors like your age to calculate estimated glomerular (glo-MER-u-ler) filtration rate or eGFR, which lets your doctor estimate how well your kidneys are working.

Your doctor may also test your urine to see whether it contains protein. In patients with kidney problems, protein may leak into the urine, which is called proteinuria (PRO-tee-NEW-ree-ah).

test the health of kidneys, shows check mark next to measure serum creatinine, shows check mark next to calculate eGFR, shows check mark next to test urine

If these tests point toward a problem with your kidneys, your doctor may request that you get tests of your complement system and a biopsy of your kidneys.

Having more information can help you to understand your disease.

If these tests point toward a problem with your kidneys...


Image shows tests of the complement system with a checklist on one side and kidneys and a microscope on the other side of the image.

Complement System Tests

Because loss of control of the alternative pathway may be the basis for C3G, your healthcare team may want to get tests that look for problems with complement function.

There are several tests that check different parts of the complement system, including how the system is controlled by the body:

  • Complement proteins—Measuring the levels of certain complement system proteins in the blood may indicate if the alternative pathway is overactive
  • Autoantibodies—The presence of certain autoantibodies in the blood may reduce the ability of the body to control the alternative pathway. The most common autoantibody identified in C3G is called C3 nephritic factor, with approximately 80% of DDD and 50% of C3GN patients testing positive for this autoantibody
  • Paraproteins—The presence of these abnormal antibodies in the blood may cause the alternative pathway to continuously react as if these paraproteins were threats, contributing to overactivity. Paraproteins are more commonly found in older adults with C3GN
  • Genetic mutations—Mistakes in DNA may cause the body to lose control of the alternative pathway. About 1 in 5 C3G patients are found to have mistakes, or mutations, associated with C3G

These tests are looking for alternative pathway control and overactivity, as well as genetic changes and acquired factors.

Your doctor and healthcare team will help you decide which tests are most appropriate to help make the diagnosis.

For more information about complement system tests, register to receive the WeC3GTM Toolkit.

Image shows tests of the complement system with a checklist on one side and kidneys and a microscope on the other side of the image.

Kidney Biopsy

A biopsy is the removal and examination of a small amount of tissue from a kidney. It is used to find out what is happening in the glomeruli, the small units in the kidneys that filter blood. Biopsy is a standard part of the diagnosis for C3G. In some patients, a biopsy may not be possible and your healthcare team may have to rely on other tests to make the diagnosis of C3G.

Doctors and researchers look at the kidney biopsy under special microscopes to examine the glomeruli. An important test run during these examinations is called immunofluorescence (IM-u-no-flu-RES-ence), or IF. In IF, doctors use a special stain to make immune system proteins in the glomeruli "light up" under the microscope, including the C3 protein of the complement system.

Finding predominantly C3 deposits in the glomeruli indicates that the alternative pathway is overactive and may help your healthcare team to confirm a diagnosis of C3G.

Based on how the C3 is deposited in the kidney, C3G can be further divided into DDD or C3GN.

DDD or C3GN

In dense deposit disease (DDD), C3 deposits are bunched up in one area of the glomeruli and appear thick. In C3GN, C3 deposits are more spread out and less thick. In those cases in which the deposits don't look like DDD, C3GN is assigned as the diagnosis.

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