Do complement pathways cause kidney injuries in patients with lupus nephritis?

In lupus nephritis, the immune system attacks the kidneys, causing inflammation and damage. One key player in this process is the complement system — a group of proteins that help fight infection but can also cause harm when overactivated. Research shows that complement pathways are directly involved in kidney injury in lupus nephritis. When immune complexes (antibodies bound to targets) build up in the kidneys, they trigger complement activation, which leads to inflammation and tissue damage ⁹¹⁰. This answer explains how complement pathways contribute to kidney injury and what this means for treatment.

What the research says

The complement system has three main activation pathways: classical, lectin, and alternative. In lupus nephritis, the classical pathway is activated when autoantibodies (antibodies that attack the body's own tissues) bind to antigens and form immune complexes that deposit in the kidneys ⁹¹⁰. This activation leads to the recruitment of inflammatory cells and direct damage to kidney cells. The alternative pathway also plays a role, amplifying the complement response and worsening injury ⁴. A 2023 review notes that complement-mediated microvascular injury is a key step in kidney damage after immune complex deposition ¹⁰.

Studies in mice show that reducing complement activation can protect the kidneys. For example, metformin treatment in lupus-prone mice decreased complement C3 deposition in the glomeruli (the kidney's filtering units) and improved kidney function ¹¹. This suggests that blocking complement activation may be a useful treatment strategy. A 2017 review highlights that complement activation is one of several pathogenic pathways in lupus nephritis, including aberrant apoptosis and autoantibody production ⁹.

New treatments are being developed that target complement pathways. A mini review discusses how targeting both extracellular and intracellular complement components holds promise for treating complement-driven kidney diseases, including lupus nephritis ⁴. Additionally, a phase 3 trial is testing cenerimod, a drug that may affect immune pathways, for active lupus nephritis ⁸. While cenerimod's exact mechanism is not fully described in the source, it represents the ongoing effort to find better therapies for this condition.

What to ask your doctor

• Could complement-targeted therapies be an option for my lupus nephritis?
• What do my complement levels (like C3 and C4) tell you about my disease activity?
• Are there any clinical trials for new complement inhibitors that I might be eligible for?
• How does complement activation affect my kidney function and long-term outlook?
• Should I be monitored for complement-related complications, such as thrombotic microangiopathy?