C3G and IC-MPGN: understanding the complement system

The immune system is a network of proteins, cells, tissues, organs, structures, and substances that fight disease and infection. It also plays a critical part in healing injuries. The immune system can be divided into two main subsystems, the innate immune system and the adaptive immune system.

The innate immune system can be thought of as a first-line defense. It acts against any foreign substances and/or pathogens that make their way into the body, such as bacteria, viruses, and harmful chemicals. The innate immune system also destroys abnormal cells—cells that are infected with viruses, cells that are damaged, and cells that have become cancerous.

The adaptive immune system can be thought of as specialized defense. This part of the immune system adapts or learns how to attack specific pathogens or foreign substances. It also stores this knowledge, which is why a person who becomes sick with a virus will have some immune protection against future infections with that same virus.

In other words, the innate immune system responds to all pathogens in the same way, while the adaptive immune system develops a specific response to a specific pathogen. Keep in mind that this is a simplified explanation of a very complicated system.

The complement system

While the immune system can be divided into its innate and adaptive components, these components are always working together, with different cells signaling and communicating with one another.

Part of this process involves the complement system. The complement system refers to several dozen different proteins that circulate in the body and activate when they encounter pathogens or infected cells. The activation of these cells triggers the activation of different parts of the immune system, including white blood cells, inflammatory proteins, and substances that destroy damaged and/or infected cells.

While the complement system is considered part of the innate immune system, it is also recognized as a bridge between the innate immune system and the adaptive immune system. Again, this is a simplified explanation.

Complement-mediated renal disease

While the complement system plays a critical role in protecting the body from disease, abnormal complement system activity can result in damage to healthy cells and tissues. Several immune mediated and autoimmune diseases are directly linked to abnormal activity within the complement system.

Complement-mediated kidney diseases are kidney diseases that occur when abnormal complement system activity causes damage to the kidneys. Two examples are C3G (complement 3 glomerulopathy) and IC-MPGN (immune complex membranoproliferative glomerulonephritis).

C3G

C3G occurs due to an overactive complement system, which causes the breakdown of a protein called C3. The fragments of this protein clump together to form deposits. These deposits clog the delicate filtering structures within the kidneys (called glomeruli). As the immune system attempts to break down these deposits, inflammation and damage to the kidney occur, and the kidneys begin to lose function. This leads to kidney failure in a significant percentage of cases.

IC-MPGN

The mechanisms of IC-MPGN are less well understood. The disorder involves a different type of deposit formation in the kidneys, a buildup of immune complexes.

Immune complexes are made up of immunoglobulin (also called antibodies) and antigens. Immunoglobulins are proteins that circulate in the body and attach to harmful substances (like viruses, infection-causing bacteria, or allergens). “Antigens” refers to these harmful substances. This process is essential to fighting off infections and illness.

Under normal circumstances, immune complexes are removed from the bloodstream by the immune system. When a person has IC-MPGN, immune complexes accumulate in the kidneys. This triggers an inflammatory response by the complement system, which causes damage to the kidneys and a loss of kidney function.

Again, the causes of IC-MPGN are not fully understood. This condition can occur as a result of another health condition, such as chronic infections or autoimmune diseases. This is known as secondary IC-MPGN. It can also occur for unknown or unidentifiable reasons, which is known as idiopathic IC-MPGN.

Like C3G, IC-MPGN leads to kidney failure in a significant percentage of cases. It's also worth mentioning that while C3G and IC-MPGN are distinct conditions, distinguishing between the two can be challenging, even with a kidney biopsy.

Complement inhibitors

Treatment options for kidney diseases like C3G and IC-MPGN are limited. Most treatments work by reducing symptoms of kidney disease, such as high blood pressure and proteinuria (protein in the urine). However, treatment options are improving. One new and emerging therapy is the use of complement inhibitors, drugs that suppress activity in the complement system.

As a person living with C3G, IC-MPGN, or another type of rare kidney disease, it’s worth learning more about new and emerging therapies and discussing these possibilities with your healthcare provider.