1 Patry, C., Webb, N. J. A., Feißt, M., et al. (2024). Kidney Transplantation in Children and Adolescents With C3 Glomerulopathy or Immune Complex Membranoproliferative Glomerulonephritis: A Real-World Study Within the CERTAIN Research Network. Pediatric Nephrology, 39(12), 3569–3580.
2 Latropoulos, P., Noris, M., Mele, C., et al. (2016). Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Molecular Immunology, 71, 131–142.
3 Bomback, A. S., Santoriello, D., Avasare, R. S., et al. (2018). C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney International, 93(4), 977–985.
4 National Kidney Foundation. (2025). Immune Complex Membranoproliferative Glomerulonephritis (IC- MPGN). Retrieved from https://www.kidney.org/kidney-topics/immune-complex-membranoproliferative-glomerulonephritis-ic mpgn
5 Noris, M., & Remuzzi, G. (2024). C3G and Ig-MPGN—treatment standard. Nephrology, Dialysis,Transplantation, 39(2), 202–214.
6 Dąbrowska-Bender, M., Dykowska, G., Żuk, W., Milewska, M., & Staniszewska, A. (2018). The impact on quality of life of dialysis patients with renal insufficiency. Patient Preference and Adherence, 12, 577–583.
Understanding the Complement System
Your immune system is your body’s natural defence network. It works quietly in the background every day, helping to protect you from infections and clearing away damaged cells. For people living with ultra-rare kidney conditions such as Complement 3 Glomerulopathy (C3G) or primary Immune Complex Mediated Membranoproliferative Glomerulonephritis (IC-MPGN), one part of this system – the complement system – can behave a little differently.
Instead of switching on and off as needed, the complement system can stay more active than intended. Whilst over protecting the body, it mistakenly harms the kidneys, leading to inflammation and damage. Learning how the complement system works can make it easier to understand your diagnosis.
What is the Complement System?
The complement system is made up of proteins that circulate in your blood and tissues. Most of these proteins are produced by the liver and work together in a carefully organised sequence – often described as a “cascade.” This helps the immune system remove harmful germs, trigger a mild inflammatory response to attract protective cells, and clear away debris or damaged tissue.1
There are three main pathways that can start this cascade:2
- Classical: Starts when antibodies attach to something the immune system wants to remove
- Lectin: Begins when certain proteins recognise specific patterns found on germs
- Alternative: This pathway is gently active all the time, helping the body stay alert and respond quickly whenneeded
All three pathways meet at a key point involving a protein called C3. C3 is at the core when it comes to C3G and primary IC-MPGN. When C3 is activated, it splits into smaller pieces (C3a and C3b) that help drive the immune response forward.
In a healthy immune response, balance between activation and regulation of the complement system protects the body, helping to fight infection while avoiding damage to healthy tissues. When this balance is disrupted, complement activity can harm instead of help.3
Keeping the System in Balance
As the complement system does its work, the body has built-in “brakes” to keep everything balanced. Special regulatory proteins help switch the system off once its job is done.
In a healthy immune response, this balance between activation and regulation protects the body while avoiding damage to healthy tissues.
When the Complement System Becomes Unbalanced
In conditions such as C3G and primary IC-MPGN, this balance can shift. The complement system becomes disrupted and can stay active for longer than intended, particularly within the kidneys.
This can happen in a few different ways:
- Increased C3 Activity4
In C3G and primary IC-MPGN, the process that controls C3 activation doesn’t work as efficiently. This can lead to higher levels of C3b fragments circulating in the blood and settling in kidney tissue.
- Antibodies that keep the system “switched on”5
Some people make antibodies, such as C3 nephritic factors (C3NeFs), that prevent the complement system from switching itself off. This allows activity to continue longer than it should.
- Changes in regulatory proteins2
Some people have changes – either inherited or acquired- that affect regulatory proteins making it harder for the body to keep complement activity under control.
- Build-up in the kidneys2
Over time, complement proteins can collect in the kidney’s tiny filtering units called glomeruli. This can attract immune cells and cause inflammation, gradually affecting how well the kidneys work.
Why This Matters for You and Your Loved One
Knowing that the complement system is central to conditions such as C3G and primary ICMPGN can help in several ways:
- Making sense of your diagnosis: Sometimes kidney problems can’t be fully explained by common causes such as infections or autoimmune diseases. Learning that over-activity of the complement system is involved provides a clearer picture of what is happening inside your kidneys. To learn more about the diagnosis of a rare kidney condition, check out our article, your diagnosis and care journey.
- Understanding care and monitoring: Your healthcare team will monitor complement levels in your blood, such as C3, and related regulatory proteins. Find out more here.
- Recognising why experiences differ: Since the balance between activation and regulation of the complement system varies from person to person—depending on genetics, antibodies, and other factors—people may progress at different rates or respond differently to care.8
- Finding hope in research: Scientists are learning more about how to control complement over-activity, with new complement-modulating care being developed to manage the disease more precisely. While research is ongoing, it is encouraging to know that progress is being made.9
This sense of hope in research is something Fabrizio, a caregiver, has experienced firsthand:
I know that at the beginning there was nothing, nothing was known but we are not really reaching in the dark now, especially in the recent years. Research has made great strides, really giant steps.
Possible care approaches are also coming that once just weren’t there. So, my message is; evolution is really important, it is making great strides and mine is a message of absolute optimism
Although there is not yet a complete cure, many people live active and fulfilling lives with careful monitoring, supportive care and good attention to kidney health.
Next Steps
If you would like to explore more about complement biology or learn more about C3G and primary IC-MPGN in general, you may find the following resources helpful:
- International Society of Nephrology: Narrated animation on complement system dysregulation and its impact on the kidney.
- The Central Role of C3: Narrated animation on the role of the C3 protein in C3G and primary IC-MPG
- CompCure: A resource dedicated to complement disorders.
- NephCure: Information, individual stories and advocacy around C3G and related kidney diseases (e.g. the C3G fact sheet).
- World Kidney Day: Global kidney health awareness and education.
You may also want to explore local or national kidney organisations or charities in your country for further information and support.
The Kidney Disease Glossary and FAQ pages that accompany this site are another useful resource. They provide clear explanations of terms, and include answers to common questions about the complement system and kidney disease.