The kidneys are like the body’s personal filtration system. They work by cleaning the blood and removing waste through urine, but what happens when they’re not working correctly?

Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are two examples of chronic (long-term) kidney diseases that involve the immune system.

C3G and IC-MPGN are glomerular diseases. Glomerular diseases are kidney diseases that damage the filtering units in your kidneys, called glomeruli. Damage to these filters causes abnormal kidney function and waste buildup, which is harmful for your body.

Treating the symptoms of these diseases may help, but finding and treating the underlying cause can slow or stop long-term damage and prevent disease progression.

What Are C3G and IC-MPGN?

Both C3G and IC-MPGN occur due to problems with the immune system. In C3G, a part of the immune system called the complement system becomes too active and starts to damage the tiny filters in your kidneys. This makes C3G a complement-mediated disease. In IC-MPGN, clumps of immune proteins build up in the kidneys, and these clumps then activate the complement system.

Both of these conditions are rare and serious, and they usually require long-term care. However, there are key differences that may affect treatment choices, which you and your doctor should be aware of.

C3G Causes

C3G is estimated to affect between 2 and 3 people out of every 1 million. It’s caused by an overactivation of a specific part of the immune system called the complement system. The complement system is like your body’s first line of defense. It’s made up of about 50 proteins that circulate in your blood. These proteins activate other proteins like a chain reaction or cascade when they identify foreign intruders. The complement system:

• Helps you heal from injuries
• Cleans damaged cells throughout the body
• Prevents infection
• Finds and removes bacteria and viruses

The complement system can be switched on in three main ways. You can think of these pathways as three different “on” switches that start the same chain reaction. When this system misfires, it can damage your kidneys instead of germs.

In C3 glomerulopathy, one switch — the alternative pathway — becomes too active. This can happen because of genetic changes or because the body makes autoantibodies (immune proteins that mistakenly attack the body) that interfere with how this pathway is controlled. When the alternative pathway is overactive, the body makes too many breakdown fragments of a protein called C3. These pieces can build up in the kidneys’ tiny filters (the glomeruli) and damage them. Damaged filters don’t work properly, which can lead to:

• Inflammation
• Proteinuria (protein in the urine)
• Hematuria (blood in the urine)

The two main subtypes of C3G are C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), based on where these deposits show up in the glomeruli.

IC-MPGN Causes

IC-MPGN is different from C3G because it usually starts when the immune system is too active. It makes immune complexes (clumps of antibodies stuck to other targets), and these clumps can turn on the complement pathway. IC-MPGN often happens in people who already have a long-term infection, an autoimmune disease, or cancer. But sometimes, it develops with no clear cause.

Normally, your immune system makes proteins called antibodies or immunoglobulins. Antibodies find and attach to foreign molecules or unhealthy cells (antigens) and act like flags to tell your body that it needs to destroy these invaders or unwanted cells. When you have IC-MPGN, your immune system has some issues. It produces large amounts of antibodies that bind to antigens to form immune complexes, which then activate complement pathway proteins (including C3). These immune complexes and some C3 proteins get stuck in the glomeruli when the blood flows through the kidneys. When these complexes and C3 proteins build up in the glomeruli, they can cause inflammation and damage, leading to kidney problems.

Symptoms of C3G and IC-MPGN

The signs and symptoms of C3G and IC-MPGN are similar, though not identical. Symptoms common to both diseases include:

• Hematuria
• Foamy urine (due to proteins in the urine)
• Less urine output
• Swelling in the feet and hands and around the eyes
• Hypertension (high blood pressure)
• Fatigue (extreme tiredness that doesn’t improve with rest)

Beyond these symptoms, some people also develop gout. Gout is sudden, painful swelling in a joint, often the big toe, caused by uric acid crystals. It can happen with any significant kidney problems, including C3G and IC-MPGN. It is mentioned more often in C3G resources, but current evidence does not show it is more common in C3G.

What Symptom Treatment Includes

An effective way to manage the symptoms of C3G and IC-MPGN is to take medication that decreases blood pressure and reduces proteinuria. Symptom control typically involves reducing swelling and managing proteinuria.

Reducing Swelling

Diuretics, commonly known as water pills, help to decrease swelling by pulling extra salt and fluid from your body through your urine.

Managing Proteinuria

You may have heard of angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin-receptor blockers (ARBs), which are typically associated with blood pressure. ACE inhibitors lower how much angiotensin-2 (AT2) your body makes, and ARBs block AT2 from working. AT2 increases your blood pressure by narrowing your blood vessels. ACE inhibitors and ARBs help to lower blood pressure. They also relax the blood vessels in the kidneys and allow the kidneys to do less work to eliminate excess fluid.

Proteinuria happens when damaged glomeruli let protein leak into your urine. In kidney diseases like C3G and IC-MPGN, ACE inhibitors and ARBs help to reduce protein in the urine by reducing the pressure in the blood vessels and the filtration process.

Why Symptom Treatment Isn’t Enough

Symptoms are the physical results of a disease or sickness, but they don’t tell us why a disease is happening. Genetic testing and testing for other acquired causes like autoantibodies that affect the complement system can be crucial tools to uncover these hidden causes, especially in C3G. There are several ways to treat the symptoms of C3G and IC-MPGN.

To treat the underlying causes of C3G or IC-MPGN, your doctor must first understand what’s causing the immune system abnormalities. In C3G, the most common underlying cause is autoantibodies that attack certain proteins of the complement system. The less common cause is a genetic issue that affects how the complement system works. In IC-MPGN, the most common underlying cause is an infection, an autoimmune disease, or cancer. Idiopathic MPGN with no clear cause is less common.

Regardless of the reason, when you limit the immune system’s damage to the kidneys, the damage to the filters can be slowed.

Controlling the Immune System

To control the immune system, your doctor may use corticosteroids or complement inhibitors. Corticosteroids are medicines that lower immune activity and calm inflammation in C3G and IC-MPGN. This helps stop the immune system from attacking the kidneys. Complement inhibitors are a newer group of medicines — including monoclonal antibodies like eculizumab — that block parts of the complement system. Recently, the FDA approved two treatments to help lower protein in the urine:

• A complement factor B inhibitor called iptacopan (Fabhalta) for adults with C3G
• A C3 inhibitor called pegcetacoplan (Empaveli) for people 12 and older with C3G and primary IC-MPGN

Other complement blockers for these diseases are still being studied.

Controlling Infections

Sometimes, the cause of this overactive immune system is an infection with something like hepatitis C. This viral cause is more common in IC-MPGN than C3G. Antivirals are drugs used to treat viral infections, like hepatitis C. These medications are recommended based on which infection is identified and how severe the infection is.

Which Treatment Choice Is the Best for You?

Treatment choice isn’t always a straightforward decision. It requires an in-depth understanding of what is causing the problem. Multiple medications could be required. Each of these options should be discussed with your healthcare professional so you can determine the best option.

Diagnosing C3G and IC-MPGN

C3G and IC-MPGN are diagnosed through a biopsy (taking a tissue sample from the kidney and looking at it under a microscope). On a kidney biopsy, doctors see a lot of C3 in the kidney filters and little or no antibodies. On a kidney biopsy, doctors see mostly antibodies in the filters, with some C3 also present. Doctors may also test for genetic markers, like mutations (changes) in your complement system genes that can cause disease. Doctors may also look for underlying causes like hepatitis C, autoimmune diseases, or cancer.

Once the distinction is made between the diseases, additional testing may be necessary to help your provider identify the severity of the condition. Testing often includes blood tests that check the complement system, like C3 and C4 levels and complement activity tests. You may also get a complete blood count (CBC), which measures your red blood cells, white blood cells, and platelets. A urine test for C3G and IC-MPGN may be used to detect urine protein and how well the kidneys are functioning.

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