Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare kidney diseases that are caused by an overactive complement system. The complement system is part of your body’s natural immune defense. It’s made up of about 50 proteins that normally circulate through your body in an inactive state. When a foreign substance invades the body, such as an infection, the proteins activate, or turn on. Then they go after the invasive substances to destroy them and get them out of your body.
In C3G and IC-MPGN, the complement system triggers the over-activation of proteins including C3. That leads to an accumulation of C3 protein fragments in the kidneys’ filtering system, called the glomeruli. Over time, this will damage the glomeruli, and your kidneys will no longer be able to filter waste products efficiently from your blood.
C3 and C4
Among the proteins that make up the complement system, C3 and C4 are particularly important for detecting and eliminating pathogens. The complement system has three pathways: classical, lectin, and alternative. In C3G, the alternative pathway is disrupted, resulting in overactivation. C3 is broken down at a higher-than-normal rate, and the fragments become deposited in the glomeruli. This usually leads to low levels of C3 in the blood. But not everyone with C3G has low C3 levels, so normal levels do not rule out this disease.
The complement system’s major functions are to identify and eliminate foreign materials, and promote inflammatory and immune responses to those targets, explains Rossana Malatesta Muncher, MD, a pediatric nephrologist at Texas Children’s and an assistant professor at Baylor College of Medicine in Houston. “Sometimes these proinflammatory processes will target host tissues,” she says. “So when C3 is low, we know it is being consumed somewhere and when put in the right clinical context and using confirmatory testing, we can get to the right diagnosis. Low C3 can be seen in infections, angioedema, inflammatory, and autoimmune conditions.”
In C3G, levels of C4 are usually normal because it’s part of a different pathway. “C3 is on the alternative pathway and C4 is on the classic pathway,” says Dr. Malatesta Muncher. “Other complements like C1, C2, and C4 on the classic pathway are also not affected by C3G but are affected with other disease processes. Laboratory testing along with a kidney biopsy will help differentiate among the many different renal conditions.”
Serum Membrane Attack Complex (sMAC)
The end-product of all three complement pathways is a cluster of proteins called a membrane attack complex, which kills a targeted cell by “punching holes” in the cell membrane. The level of this substance in your blood, called your serum membrane attack complex (sMAC) level, can be high in C3G.
This level might be measured as part of a broader testing panel, but, according to Marc Richards, MD, a nephrologist and the director of the Florida Kidney Physicians Glomerulonephritis Center of Excellence in Boca Raton, sMAC testing takes a specialized lab and it’s unclear what it means for the severity of the disease.