An Overview of Complement 3 Glomerulopathy (C3G)

Causes

C3G is caused by unusual immune activity in your body’s alternative complement system.

The complement system is responsible for your innate immune activity. Its alternative pathway is always active, working to mark pathogens (such as viruses and bacteria) and damaged tissue for your immune cells to destroy.

In C3G, the alternative complement system becomes overactive with C3 complement protein, which is responsible for marking cells for destruction.

Excess C3 travels to your kidneys, where it builds up in filtration structures called glomeruli. C3 buildup triggers inflammation, leading to kidney damage, scarring, and loss of kidney function over time.

The exact cause of C3G is complex. In some people, genetic mutations contribute to the overactivation of C3, while in others, autoantibodies are responsible.

Autoantibodies are antibodies that mistakenly target healthy components in your body. For unknown reasons, some people develop C3 nephritic factor (C3NeF), an autoantibody that binds to enzymes responsible for regulating the C3 complement component. This allows C3 to remain active longer than it should.

Types

C3G has two primary subtypes, which are defined by the pattern of C3 deposits visible under a microscope:

• Dense deposit disease (DDD): dense, ribbon-like deposits
• C3 glomerulonephritis (C3GN): small, scattered clusters or clumps

DDD is typically diagnosed in children and teenagers, while C3GN is generally diagnosed in adults.

According to a 2023 study, a diagnosis of C3GN comes with a higher risk of progression to end stage renal disease (ESRD) than a diagnosis of DDD does. However, kidney failure progresses more slowly in adults with C3GN than in youth with DDD.

Symptoms

Not everyone with C3G will develop symptoms, particularly in the early stages. C3 deposits in the kidneys can take a considerable amount of time to affect kidney function, and the rate of buildup can vary significantly from person to person.

When symptoms do occur in either C3G subtype, they can include:

• repeated infections
• drusen (a buildup of complement proteins and fat in the retina of your eye)
• uneven body fat distribution
• hematuria (blood in your urine)
• proteinuria (protein in your urine)
• edema (swelling due to fluid buildup)
• gout
• oliguria (low urine output)
• hypertension (high blood pressure)
• fatigue
• brain fog

Diagnosis

A doctor will diagnose C3G by evaluating your symptoms, your medical history, and any relevant test results.

A urinalysis can detect blood and protein in your urine. Your doctor can then verify the results by checking your estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR).

The only test that can definitively diagnose C3G is a kidney biopsy. During this surgical procedure, a doctor takes a sample of your kidney tissue for evaluation under a microscope. A biopsy can help doctors find out whether you have DDD or C3GN and how much kidney damage you have.

Treatment

Treatment for C3GN can vary depending on the severity and progression of the disease. Overall, doctors will work to preserve your kidney function and address underlying issues with the complement system.

Therapies and medications can reduce proteinuria, help manage factors that may compound kidney damage (such as high blood pressure), and slow down the progression of C3G to chronic kidney disease (CKD) and ESRD.

Medications your doctor may prescribe include:

• angiontensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)
• immunosuppressants, such as corticosteroids or mycophenolate mofetil
• complement-targeted therapies, such as eculizumab or ravulizumab

In 2025, the Food and Drug Administration (FDA) approved Fabhalta (iptacopan), a small-molecule inhibitor drug that prevents the overactivation of C3 by blocking a part of the complement activation pathway.

In addition to medication, lifestyle changes that support kidney health are an important part of managing C3G. Your doctor may recommend strategies such as:

• quitting smoking if you smoke
• avoiding nonsteroidal anti-inflammatory drugs (NSAIDs)
• eating a low sodium, moderate-protein diet
• getting regular exercise
• limiting alcohol intake
• staying hydrated
• finding healthy ways to manage stress
• making efforts to lose weight or avoid weight gain

If your kidney function becomes too compromised, dialysis or a kidney transplant may be necessary.

Outlook

Up to 70% of children and 30% to 50% of adults with C3G will experience progression to ESRD within 10 years of diagnosis. In about half of people who receive a kidney transplant for C3G, the condition returns, often within the first year.

Many people can live a typical life span with C3G. But only about 35% of people survive for 5 years after developing ESRD and receiving long-term dialysis treatment.

Effects on quality of life

C3G may not affect your quality of life right away. Kidney damage can take years to affect your kidney function and cause symptoms.

But when C3G progresses to CKD, your quality of life may decrease.

A 2024 study based on data from 385 people found that many people living with C3G-related CKD experienced:

• fatigue
• depression
• anxiety
• difficulty with everyday tasks
• mobility challenges

Fatigue was the most commonly reported symptom, and as many as 77% of the participants said that they needed to sleep during the day.

Takeaway

C3G is an immune system-related kidney disease caused by unusual activity in your body’s complement system. The alternative complement system is responsible for your body’s innate, background immune functions, such as marking damaged tissue and pathogens for destruction.

Over time, C3G can lead to kidney damage and loss of kidney function. Timely treatment with medications, lifestyle changes, and supportive therapy is important for preserving your kidney function.