C3G and IC-MPGN both cause protein deposits that reduce kidney function. Overactive proteins in the immune system lead to these different conditions.
C3G and IC-MPGN are rare kidney conditions. They occur when a part of the immune system, called the complement system, doesn’t work as it should.
Although these conditions are similar, they result from a breakdown of different parts of the complement system. As researchers learn more, new treatments give hope to people with these diseases.
Both IC-MPGN and C3G are types of membranoproliferative glomerulonephritis (MPGN). Both conditions occur when proteins in the immune system break down. This breakdown causes deposits to build up in the glomeruli, the parts of the kidneys that filter out waste and excess water.
Researchers once defined types of MPGN based on where the deposits build up in the glomeruli. Now, experts distinguish IC-MPGN and C3G based on the material in the deposits.
IC-MPGN
The deposits in IC-MPGN consist of parts of immune system proteins. The proteins in these deposits are both
C3G
The deposits in C3G are primarily complement system proteins, specifically C3 proteins. There are little or no immunoglobulin deposits. C3G is further divided into two types: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).
In DDD, the deposits appear dense and ribbon-like in the glomerular basement membrane (GBM), another part of the kidneys’ filtering barrier. In C3GN, the deposits are less dense and less well-defined.
IC-MPGN and C3G have many similarities. However, they lead to kidney deposits in different ways. These differences are important for researchers developing new treatments for both conditions.
Causes
Both IC-MPGN and C3G are due to an abnormally controlled complement system.
When the complement system is working as it should, proteins connected to the system stay inactive until they encounter an invader like a virus or bacteria. At this point, the proteins become active and set off a series of events called a cascade. This cascade wakes up different types of proteins in a chain so they can find and fight the invader.
The first stages of the complement system work through
- classical pathway
- alternative pathway
- lectin pathway
Each of these pathways activates different proteins. The pathways converge in the final stage to attack invaders. This last stage is called the lytic pathway.
In both IC-MPGN and C3G, the proteins that should stay inactive become overactive. This causes the complement system proteins to not function correctly, which leads to a buildup of deposits in the kidney’s filtering system.
The critical difference between IC-MPGN and C3G is which part of the complement system is impacted. With C3G, immunofluorescence (IF) imaging shows excess C3 deposits. In IC-MPGN, IF imaging shows too many C3 and immunoglobulin (Ig) deposits.
Other conditions, like autoimmune diseases or infections, can cause IC-MPGN. However, the cause of IC-MPGN is often unknown. Many people with C3G have genetic abnormalities in the complement system. Researchers are still trying to determine the exact cause of the condition.
Diagnosis
Doctors will perform IF imaging to examine cellular proteins to diagnose C3G and IC-MPGN. They will use this along with a kidney biopsy. These images show whether the deposits in the glomeruli contain immunoglobulin, complement protein, or both. The makeup of the deposits is critical in the diagnosis of either C3G or IC-MPGN.
Before you reach this stage of diagnosis, you might have some physical symptoms like:
- blood in the urine (hematuria)
- fatigue
- swelling of ankles, hands, or feet (edema)
A doctor can also perform blood and urine tests to check your kidney function. Some signs of C3G or IC-MPGN are:
- protein in the urine (proteinuria)
- reduced ability of the kidneys to filter blood (reduced glomerular filtration rate)
A doctor might also perform a kidney biopsy to help diagnose these conditions. The biopsy can show a buildup of complement proteins.
Outlook
Over time, the buildup of deposits in the glomeruli makes it harder for the kidneys to filter out waste. This can lead to
The course of these conditions varies from person to person. Some people can have stable kidney function for many years, while others experience rapid progression to kidney failure.
About 30% to 35% of people with C3G or primary IC-MPGN have kidney failure within 10 years of diagnosis.
Treatment
There’s no cure for C3G or IC-MPGN. Treatment options are limited because these conditions progress differently in each person.
The first line approach is to protect the kidneys from damage, starting with diet changes and medicines to reduce blood pressure and cholesterol. If kidney function declines, doctors recommend systemic measures to suppress the immune system, called
For this treatment, you would take a drug that would slow activity in the immune system. Immunosuppressive therapy helps with conditions where parts of the immune system are overactive.
Several new and emerging treatments are being studied that target the complement system itself.
To help treat C3G and IC-MPGN, doctors might recommend:
- Lowering blood pressure: Taking medication such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs).
- Maintaining healthy cholesterol: This can involve lifestyle changes and medication such as statins.
- Lowering sodium intake: This can mean making lifestyle changes that restrict daily salt consumption.
- Lowering blood sugar: Taking medication such as
sodium-glucose transport protein 2 (SGLT2) inhibitors that stop the kidneys from reabsorbing glucose. - Suppressing the immune system: This can involve a combination of immune-suppressing medications such as mycophenolate mofetil (MMF) and steroids.
- Slowing the complement system activity: Taking medications such as eculizumab can reduce complement system activity.
In addition to these therapies, several trials are currently underway of medications that target different aspects of the complement system. These might provide hope for people living with C3G or IC-MPGN.
C3G and IC-MPGN are two distinct but closely related kidney conditions. Both cause protein deposits in the kidneys’ filtering system. C3G has excess C3 deposits, while IC-MPGN has extra immunoglobulin deposits and C3 deposits.
Current treatment methods, medication, and lifestyle changes help slow or prevent kidney damage. If kidney damage progresses, your doctor might suggest immunosuppressive therapy to help slow immune system activity.
Emerging research targets the unique immune system pathways at play in these conditions.