The complement system is part of your immune system and is an essential component of your defense against infections. It consists of a group of proteins that are normally in an inactive state.
Complement proteins are activated in response to some type of stimulus. For example, when you’re exposed to an infectious bacteria, these proteins will “turn on” in a chain reaction, or cascade. This contributes to your overall immune response to fight off the infection. But if complement activation is excessive, it can cause problems such as tissue damage.
The complement system becomes dysfunctional in both IC-MPGN and C3G. This results in a buildup of deposits in the kidneys’ filtering system, called the glomeruli. C3G causes complement proteins to break down, including one called C3. The protein fragments accumulate in the kidneys, leading to inflammation and damage to the glomeruli. In IC-MPGN, deposits of C3 accumulate in the glomeruli along with other protein fragments and antibodies. Together, they form “immune complexes” that damage the kidneys.
It remains unclear what causes the complement system to malfunction. In C3G, it’s believed that the complement system is triggered by genetic changes or antibodies that target and attack your own body’s healthy cells and tissue (autoantibodies). In IC-MPGN, complement system dysfunction is often associated with other health conditions, including autoimmune diseases like rheumatoid arthritis, certain cancer types, and chronic infections.
Complement inhibitors, on the other hand, actually target the complement system, and reduce the damage caused by C3 deposits in the kidney filters. Two drugs have been approved to date, and others are currently being studied in clinical trials:
Iptacopan (Fabhalta) was approved by the FDA in March 2025 to treat C3G. It’s an oral medication that blocks one signaling pathway in the complement system, which prevents the breakdown of some C3 and disrupts the rest of the chain reaction. The clinical trial that led to its approval showed that iptacopan reduced proteinuria at both 6 and 12 months (35 and 37 percent, respectively). It also helped stabilize eGFR decline.
Pegcetacoplan (Empaveli) was approved July 2025 for both C3G and IC-MPGN. It’s a twice-weekly injection that blocks all three signaling pathways in the complement system, preventing the breakdown of additional C3. FDA approval was based on a clinical trial in which patients taking pegcetacoplan saw a 68 percent reduction in proteinuria at 26 weeks compared with a placebo.
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