What Is Complement, and How Can It Affect Kidney Function?

Medically reviewed by Walead Latif, D.O.
Written by Emily Wagner, M.S.
Posted on April 3, 2023

  • The complement system is a part of your immune system that helps protect your body against bacteria and viruses.
  • Although it’s normally helpful, the complement system can become overactivated, causing inflammation that damages the kidneys.
  • Four different complement-mediated diseases can affect your kidney function.

Your immune system protects your body against bacteria, viruses, and other foreign invaders to keep you healthy. The complement system plays an important role in supporting — or complementing — the rest of your immune system’s normal functions. However, when the complement system becomes overactivated, it can cause inflammation, leading to kidney damage and disease.

Your kidneys are made of delicate structures that help constantly filter waste and water out of your blood. When these structures become damaged by inflammation related to the complement system, one of several kidney diseases can develop. This article describes the complement system and how it can affect your kidneys.

What Is the Complement System?

A complex part of your immune system, the complement system is made up of around 50 proteins that work together to protect your body from invaders. The complement system belongs to your innate immune system, the first line of defense activated during infections.

There are three pathways for complement activation — classical, alternative, and lectin. When one of these pathways is triggered, it’s often referred to as a complement cascade. As different proteins switch on, they set off other reactions like dominoes falling, quickly creating more inflammation to activate the immune system.

The classical pathway is activated when an antibody — an immunoglobulin (Ig) — attaches to a protein or antigen (a substance that prompts the immune response) from a bacteria or virus. Complement proteins attach to two specific types of antibodies, IgG and IgM, which then turn on other proteins.

The alternative complement pathway becomes activated when supporting proteins called complement factors (factor B, factor D, factor H, and factor I) recognize fats, proteins, or carbohydrates on the surface of foreign invaders.

Finally, the lectin pathway — also known as the mannose-binding lectin (MBL) pathway — gets activated when specialized proteins known as lectins attach to mannose, a type of sugar found on the surface of bacteria and viruses.

In the end, each pathway splits the complement factor protein C3 with a specialized enzyme known as C3 convertase. C3 breaks into two components, C3a and C3b. C3a creates inflammation to bring in other immune cells. C3b turns on other complement proteins to produce the membrane attack complex (MAC), which punches holes into bacterial cells so that they burst.

Complement System and the Kidneys

Each kidney contains about a million tiny structures called nephrons, which consist of a tubule and a filter called a glomerulus. Blood vessels in the glomerulus allow water and waste to exit the body in urine, while nutrients like proteins — but no waste products — are absorbed into blood. (Adobe Stock)

Your kidneys filter your blood to remove waste products and extra fluid from your body to excrete in your urine. Each kidney contains around 1 million nephrons, each of which is made of a tubule and glomerulus (filter). The glomeruli are collections of tiny, delicate blood vessels that allow water and waste to flow out while blood cells and proteins stay behind.

Complement proteins can interact with other parts of the immune system, leading to inflammation that can damage organs — and the kidneys are especially vulnerable. Glomeruli in the kidneys also have receptors that bind to the C3a protein, which can produce even more inflammation.

When the complement system causes too much inflammation, the glomeruli can’t filter blood as well, and waste and toxins build up in your bloodstream. This is known as glomerular disease. Kidney dysfunction can also reduce the amount of urine your body makes and cause proteinuria (excess protein in urine).

Complement-Mediated Kidney Diseases

Complement-mediated kidney diseases develop for several reasons. Some conditions are caused by autoimmune diseases that create inflammation and damage healthy tissues, while others are related to genes passed down through families.

In many people, genetic mutations prevent proper regulation of the complement system, especially in the alternative pathway. This pathway is always active at low levels, and mutations in the complement regulatory proteins can make the inflammation uncontrollable.

Complement 3 Glomerulopathy

A kidney disease called complement 3 glomerulopathy (C3G) is caused by the overactivation and breakdown of the C3 protein. The protein fragments can get stuck in the kidneys’ glomeruli, causing inflammation and damage. Specifically, C3G is caused by gene mutations in complement regulatory proteins. The effect is like driving a car without brakes — C3 continues to be activated, creating more and more inflammation. The lack of control leads to C3G, reducing renal function — the kidneys can’t filter blood as well.

Symptoms of C3G include:

  • Edema (swelling in the ankles, feet, and hands from fluid buildup)
  • Fatigue
  • Foamy urine caused by proteinuria
  • Hematuria, or blood in urine

There are two types of C3G — C3 glomerulonephritis and dense deposit disease. Each damages the kidney in a different way, and they look different under a microscope. Your doctor may take a small piece of your kidney tissue, called a biopsy, to make a diagnosis.

Immunoglobulin A Nephropathy

Antibodies act as flags that tag foreign invaders, letting your immune system know what to attack. IgA antibodies are the first line of defense against invaders in your lungs, nose, and digestive tract. However, these antibodies can also cause kidney damage.

People with IgA nephropathy tend to have some IgA antibodies with less than a normal amount of galactose, a type of sugar. The immune system recognizes these antibodies as foreign invaders and attacks them. New antibodies attach to the galactose-lacking IgA antibodies, forming clumps known as immune complexes. These clumps are too big to be filtered by the tiny blood vessels in the kidneys, so they become stuck in the glomeruli.

C3 proteins from the complement system are also found in the kidneys of those with IgA nephropathy. Research shows that the MBL pathway may be activated when complement proteins attach to certain sugars on IgA antibodies found in immune complexes. Studies have also shown that the more C3 there is in the kidneys, the more severe IgA nephropathy is.

Membranous Nephropathy

The glomeruli in your kidneys are made of two layers of cells — podocytes and endothelial cells — with a layer called the glomerular basement membrane (GBM) in between. These layers help filter waste and water out of your blood. When inflammation damages the GBM, a condition known as membranous nephropathy develops.

Doctors and researchers have found that membranous nephropathy is primarily an autoimmune disease. Most people with this condition have autoantibodies that recognize a protein on the surface of podocytes as foreign. This response creates inflammation that damages the podocytes and GBM, and protein leaks into the urine.

Research shows that the complement system is also activated in membranous nephropathy, and C3 proteins are often found in the glomeruli. The greater the deposit of C3, the more inflammation there is to cause severe disease.

Signs and symptoms of membranous nephropathy are similar to other complement-related kidney diseases. Together, these features are known as nephrotic syndrome, and they include:

  • Edema
  • Fatigue
  • Foamy urine from proteinuria
  • Increased cholesterol levels
  • Hypertension (high blood pressure)

Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disease that results in kidney damage. Specifically, aHUS is caused by mutations in genes that make regulatory complement proteins in the alternative pathway. Without these proteins, the complement system is continuously activated, and the resulting inflammation damages the kidneys.

This syndrome is a type of disease known as thrombotic microangiopathy, which causes tiny blood clots that keep blood from reaching your organs, especially your kidneys. Without proper oxygen and nutrients, the kidneys can be even more damaged.

The three main signs of aHUS include:

  • Kidney injury or disease
  • Thrombocytopenia (too few platelets — cell fragments that help blood clot)
  • Hemolytic anemia (low red blood cell count)

Talk to Your Doctor About Complement and Kidney Disease

If you’re concerned that the complement system is affecting your kidneys, talk to your doctor or nephrologist (a kidney specialist). They may run tests that measure your C3 levels to see if you have an overactivated complement system.

Your doctor can then develop a treatment plan to reduce inflammation and help prevent further tissue injury to your kidneys. If your complement-mediated kidney disease progresses to chronic kidney disease or end-stage renal disease (kidney disease), you may need dialysis or a kidney transplant. Your doctor can help you better understand your options.

Talk With Others Who Understand

At MyKidneyDiseaseCenter, the site for people with kidney disease and their loved ones, people come together to gain a new understanding of different kidney diseases and share their stories with others who understand life with kidney disease.

Are you living with a complement-mediated kidney disease? Have you discussed concerns about the symptoms with your doctor? Share your experiences in the comments below.

References
  1. Complement System — Cleveland Clinic
  2. Your Kidneys & How They Work — National Institute of Diabetes and Digestive and Kidney Diseases
  3. The Complement System and Innate Immunity — Immunobiology: The Immune System in Health and Disease. 5th Edition
  4. Complement System — British Society for Immunology
  5. The Alternative Complement Pathway Revisited — Journal of Cellular and Molecular Medicine
  6. The Role of Mannose-Binding Lectin in Health and Disease — Molecular Immunology
  7. Complement Membrane Attack Complex — The American Journal of Pathology
  8. Overview of Complement Activation and Regulation — Seminars in Nephrology
  9. The Complement C3a and C3a Receptor Pathway in Kidney Diseases — Frontiers in Immunology
  10. Glomerular Diseases — Cleveland Clinic
  11. IgA Nephropathy — National Institute of Diabetes and Digestive and Kidney Diseases
  12. Complement and the Kidney: An Overview — Advances in Chronic Kidney Disease
  13. Complement 3 Glomerulopathy (C3G) — National Kidney Foundation
  14. C3 Glomerulopathy — MedlinePlus
  15. Biochemistry, Immunoglobulin A — StatPearls
  16. Complement Activation in IgA Nephropathy — Seminars in Immunopathology
  17. Membranous Nephropathy — Cleveland Clinic
  18. The Role of the Complement System in Primary Membranous Nephropathy: A Narrative Review in the Era of New Therapeutic Targets — Frontiers in Immunology
  19. Atypical Hemolytic Uremic Syndrome — NORD
  20. aHUS (Atypical Hemolytic Uremic Syndrome) — American Kidney Fund
  21. C3 Complement Blood Test — Cleveland Clinic
  22. End-Stage Renal Disease — Mayo Clinic

Posted on April 3, 2023

Janice3

I have type 2 diabetes with an A1C of 5.9% and have chronic kidney disease type 2 . Type 2 I've read doesn't have symptoms. I've lost 33 lbs from 224lbs and goal is to reach 160. What signs should I notice with chronic kidney?

posted July 26, 2023
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Walead Latif, D.O. is a board-certified nephrologist and an assistant clinical professor at Rutgers New Jersey Medical School. Learn more about him here
Emily Wagner, M.S. holds a Master of Science in biomedical sciences with a focus in pharmacology. She is passionate about immunology, cancer biology, and molecular biology. Learn more about her here

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