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Your immune system protects your body from germs, like bacteria and viruses. One part of the immune system is called the complement system. It’s made up of proteins that work together to help your immune defenses respond faster and more strongly.
In people with immunoglobulin A nephropathy (IgAN), the complement system can become overactive and cause harm instead of help.
IgAN is a kidney disease caused by problems with IgA, a type of antibody that helps fight germs. In IgAN, IgA can form clumps that get stuck in the kidneys. These clumps can turn on the complement system. When the complement system is overactive, it can cause inflammation and swelling. Over time, this can damage the kidneys and affect how well they filter blood. IgAN is a type of glomerulonephritis, meaning it affects the kidney’s filtering units (glomeruli).
In this article, we’ll explain how the complement system works and the important role it plays in IgA nephropathy.
The complement system is complex. It’s made up of around 50 proteins that work together to protect your body from invaders. These proteins act like helpers. They support other parts of the immune system and help the body respond quickly to infections. The complement system is part of the innate immune system. This means it’s one of the first defenses your body uses.
The complement system can be turned on through three main pathways:
When one pathway starts, it triggers a chain reaction, also known as a complement cascade. Each protein activates the next, like dominoes. This process triggers inflammation, which helps fight infection in the short term but can cause tissue damage if it goes on for too long.
In IgAN, the complement system becomes active mainly through the alternative and lectin pathways. These pathways can be triggered when abnormal IgA antibodies form clumps and settle in the kidneys.
All three pathways come together at a key protein called C3. C3 is split into two parts: C3a and C3b. C3a increases inflammation. C3b helps activate other proteins that damage unhealthy cells and the foreign invaders. In IgAN, too much C3 activity in the kidneys leads to ongoing inflammation and damage to healthy kidney cells, causing kidney injury.
Your kidneys clean your blood by removing waste and extra water, which leave your body as urine. Each kidney contains around 1 million nephrons, each of which is made of a tubule and a glomerulus (filter). The glomeruli are made of small blood vessels and support cells.
One important support cell is the mesangial cell. Mesangial cells help hold the glomerulus together, regulate blood flow within the filter, and clean up waste and debris. They also play a role in immune responses inside the kidney.
In IgA nephropathy, abnormal IgA antibodies form clumps called immune complexes. These immune complexes get stuck in the glomeruli, mainly in the mesangial cell area. This buildup triggers the complement system and, as a result, inflammation.
The complement protein C3 plays a key role in this process. C3 and its fragments collect in the glomeruli and activate mesangial cells. Over time, this ongoing inflammation damages the kidney filters, so they can’t clean the blood as well.
Problems with the complement system can affect many renal (kidney) diseases. However, for this article, we’ll focus only on how complement activation contributes to IgA nephropathy.
IgA nephropathy begins with changes in the structure of IgA itself. Most people with IgAN produce a form called galactose-deficient IgA1. Galactose is a sugar that normally attaches to IgA. When the sugar is missing, the IgA molecule looks abnormal to the immune system.
The body treats galactose-deficient IgA1 as a threat. It makes new antibodies that attach to it. This is what creates the immune complexes. These immune complexes circulate in the blood, eventually reaching the kidneys.
Once they arrive in the kidneys, the immune complexes settle in the mesangium. This area is especially important because it’s where most inflammation begins. Mesangial cells respond to the immune complexes by releasing chemicals that increase inflammation and attract other immune proteins.
The immune complexes in the mesangium strongly activate the complement cascade — mainly through the lectin and alternative complement pathways.
Studies show that complement components from the alternative pathway — including C5, C6, and C9 — are found in the glomeruli of people with IgAN. These proteins help form the membrane attack complex, which damages kidney cells.
The lectin pathway may be triggered when complement proteins bind to sugars on the abnormal IgA1. This leads to ongoing activation of C3, which fuels inflammation even when no infection is present.
As C3 breaks down, its fragments collect in the glomeruli. These fragments increase inflammation, stimulate mesangial cells, and damage surrounding kidney tissue. Over time, this process causes kidney dysfunction through scarring and loss of healthy kidney filters.
A kidney biopsy (tissue sample) is an important test for diagnosing IgAN. When doctors study the tissue under a microscope, they often see immune complexes made of IgA along with C3 deposits in the mesangium.
Finding C3 is important because it shows that the complement system is active in the kidneys. Studies have shown that people with higher levels of C3 deposits often have more severe disease and glomerular injury. They may lose renal function faster than those with less complement activation.
Researchers are studying new IgAN treatments that target the complement system. Many of these treatments are still investigational. This means they’re being tested in clinical trials and aren’t widely available yet.
One example is eculizumab (Soliris) — a type of recombinant monoclonal antibody (lab-made immune protein). It blocks C5, a protein involved in later stages of complement activation. Case reports show temporary improvement or stabilization in severe IgAN, but results have been mixed.
In August 2024, the U.S. Food and Drug Administration (FDA) approved the drug iptacopan (Fabhalta) for adults with IgAN. Iptacopan inhibits complement factor B, a major protein of the alternative pathway, and prevents the activation of C3.
Doctors may also use complement test results, like C3 levels in the blood or findings from a kidney biopsy, to track how active the disease is. However, most of the time, your blood C3 levels may show a normal test result.
If you have IgAN, talk to your doctor or a nephrology (kidney) specialist about how the complement system may be affecting your kidneys. Doctors often use several tests to monitor IgAN, such as:
Your doctor may also order a C3 complement blood test. This test measures C3 levels, which may be lower when the complement system is overactive due to inflammation or infection and the C3 proteins are used up. In IgAN and other autoimmune diseases, this test can help show whether complement-mediated inflammation may be contributing to kidney damage.
Your doctor can then develop a treatment plan to reduce inflammation and help prevent further tissue injury to your kidneys. If your IgAN progresses to chronic kidney disease or end-stage renal disease (kidney disease), you may need dialysis or a kidney transplant. Your doctor can help you better understand your options.
On myIgANteam, people share their experiences with IgA nephropathy, get advice, and find support from others who understand.
What questions do you still have about the complement system and IgAN? Let others know in the comments below.
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I believe I have Polycystic Kidney Disease which I inherited from my mother. Were did she get it? Her mother, my grandmother lived to be. almost 104!
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