Last updated:
3/2/2026
Years published: 2005, 2010, 2013, 2015, 2018, 2023, 2026
NORD gratefully acknowledges Richard JH Smith, MD, Director – Molecular Otolaryngology and Renal Research Laboratories, Director – Iowa Institute of Human Genetics, Sterba Hearing Research Professor, Vice Chair – Department of Otolaryngology – Head & Neck Surgery, Professor – Otolaryngology, Internal Medicine, Pediatrics, Molecular Physiology & Biophysics, Anatomy & Cell Biology at the University of Iowa and Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for their assistance in the preparation of this report.
C3 glomerulopathy (C3G) is a rare form of kidney disease defined by abnormal deposition of the complement protein C3 within the glomeruli, the microscopic filtering units of the kidney. The complement system is part of the body’s innate immune defense, and in C3G it becomes inappropriately activated and insufficiently regulated, leading to chronic injury of the glomeruli. People with C3G commonly present with blood in the urine (hematuria), excess protein in the urine (proteinuria), swelling of the face or legs caused by fluid retention (edema), high blood pressure, and a gradual or sometimes rapid decline in kidney function. These findings reflect damage to the glomerular basement membrane, the specialized structure that normally allows waste products to pass into the urine while retaining blood cells and proteins.
C3G includes two conditions that were previously considered separate diseases: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).
DDD and C3GN cause similar symptoms, including blood in the urine (hematuria), foamy or cloudy urine from excess protein or white blood cells, swelling of the legs or other body parts (edema), high blood pressure, reduced urine output, and general fatigue or decreased alertness. In addition to affecting the kidneys, DDD can also involve the eyes. Some people develop deposits called drusen in a layer of the eye known as Bruch’s membrane, which is similar in structure to the kidney’s filtering membrane. This similarity likely explains why deposits form in both places. It is less clear how often this eye involvement occurs in C3GN or how clinically important it is.
Both DDD and C3GN are identified on kidney biopsy by a buildup of a protein called C3, an important component of the immune system’s complement pathway. This C3 buildup is seen using a laboratory technique called immunofluorescence, which uses special dyes and light to highlight specific proteins within kidney tissue. The main difference between the two lies in how the C3 deposits look under electron microscopy, a high-resolution imaging method that allows doctors to see structures at a very fine, ultrastructural level. In DDD, the deposits appear extremely compact and dark, often described as “sausage-like,” and are located within the glomerular basement membrane, the thin filtering layer of the kidney. In C3GN, the deposits are less dense, fluffier, and more irregularly distributed, accumulating in the mesangium, which provides structural support to the glomerulus, and along the walls of the tiny blood vessels that make up the glomerular capillaries.
C3G is caused by poor control of the alternative complement pathway, a part of the immune system that becomes overactive. Overactivity can result from inherited genetic changes, acquired autoantibodies that keep the pathway switched on, or both. Ongoing complement activation leads to buildup of C3 fragments in the glomeruli, causing inflammation, scarring, and progressive loss of kidney function. About half of the affected people develop kidney failure within ten years, often requiring dialysis or transplantation, and the disease frequently recurs after transplant because the underlying immune abnormality affects the whole body.
Diagnosis relies on kidney biopsy, supported by laboratory findings such as low blood C3 levels due to ongoing complement consumption. Increasingly, detailed complement testing and genetic analysis are used to better define the disease. There are four components to a thorough complement evaluation, functional activity, biomarker assays, antibody tests, and genetic analysis, that are informative to patient care. The interpretation of results is remarkable for significant biomarker associations with complement activity, renal function, and pathology, the complexity of which necessitates measuring multiple complement proteins and their breakdown fragments.
Treatment for C3G focuses on supportive care to protect kidney function and, when appropriate, specific targeted therapy with Iptacopan (Fabhalta) or Pegcetacoplan (Empaveli). These two drugs block activity of the alternative complement pathway, reduce protein in the urine, and prevent or even reverse disease progression in most patients if irreparable damage to the kidneys has not yet occurred. If irreparable kidney damage has been done and is severe, dialysis or kidney transplantation is required.
The current classification of C3G is the result of major advances in understanding the complement system and kidney disease over the past 20 years. DDD was long viewed as a distinct entity, but recognition that a broader group of people shared dominant C3 deposition and complement-mediated injury led to an international consensus in 2013 that introduced the umbrella term C3G. DDD and C3GN were formally grouped together under this diagnosis. C3G itself belongs to a larger category called C3-dominant glomerulopathies. This group includes other conditions that also show strong C3 staining on biopsy, such as monoclonal gammopathy–associated C3 disease (also known as MGRS or monoclonal gammopathy of renal significance) and some forms of post-infectious glomerulonephritis (PIGN) that can resemble C3G on biopsy, especially early in the disease course, but differ in cause, outcome, and treatment.
This reclassification has changed how doctors think about C3G. It is now understood primarily as a disease driven by problems in the complement system. This shift has shaped ongoing research and has helped guide the development of new treatments that target the complement pathway directly.
Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) cause similar signs and symptoms related to damage of the kidney’s filtering units. Common findings include:
In addition, people with C3G often have characteristic laboratory abnormalities. Because complement proteins become trapped in the kidneys, blood tests frequently show reduced levels of these proteins, especially C3. Low C3 levels are common in both DDD and C3GN. More detailed testing typically shows abnormalities in multiple complement proteins and is an important component of a thorough complement evaluation. Researchers are increasingly studying these patterns, known as complement biomarker profiling, to better understand disease activity, the specific “signature” associated with DDD and C3GN, and to help guide treatment decisions.
The immediate cause of the symptoms of C3G is the change in the filtering mechanism of the kidney. The damaged glomeruli (the filters) permit protein and red and white blood cells to pass into the urine-containing space.
The most abundant protein in the blood stream is albumin. As albumin passes into the urine and is lost from the blood stream, hypoalbuminemia or ‘low albumin in the blood stream’ develops. One consequence of hypoalbuminemia is that water leaks out of the circulation and accumulates in the surrounding tissues. This process leads to edema or swelling. Because of gravity and hydrostatic pressure (water pressure), the effects of fluid leakage are most apparent in the feet and ankles, which become swollen. As kidney function further deteriorates and urine output decreases, sodium and water are retained, and the swelling becomes magnified. High blood pressure also develops.
The specific cause of C3G is lack of regulation of the complement system. The causes of complement dysregulation can be divided into genetic and acquired factors. Amongst the former are changes in many of the complement genes, and amongst the latter are specific antibodies called C3 nephritic factors (C3Nefs) and C5 nephritic factors (C5Nefs) that impair normal regulation of the complement system. It appears that people with DDD are more likely to have C3Nefs, while people with C3GN are more likely to have C5Nefs. Identifying drivers of complement dysregulation in C3G remains an active area of research because in about 30% of patients, a precise cause for the underlying complement dysregulation cannot be found.
C3G is a very rare disease. The incidence of C3G is estimated at 1-3 new cases per 1,000,000 people per year (in the United States, with a prevalence of approximately 5 per 1,000,000. Incidence refers to new cases occurring annually while prevalence refers to the total existing cases. The global incidence is similarly estimated at 1-2 new cases per million individuals per year.
C3G can only be definitively diagnosed with a kidney biopsy. This procedure involves removing a small sample of kidney tissue, which is then examined using specialized laboratory techniques. In people suspected of having C3G based on their symptoms and laboratory findings, the biopsy must show a large amount of the complement protein C3 within the glomeruli, the kidney’s filtering units. This finding is essential for the diagnosis, and if prominent C3 deposition is not present, C3G can be ruled out.
The biopsy sample is analyzed using immunofluorescence, a method that highlights specific proteins in the tissue, and electron microscopy, a high-resolution imaging technique that allows doctors to see the structure of the deposits in detail. These studies show that the deposits contain C3 and its breakdown products, along with other proteins from the complement system, which helps explain how the disease causes kidney injury and allows further classification as DDD or C3GN.
Increasingly, when DDD or C3GN are diagnosed, a thorough complement evaluation is ordered. This evaluation measures complement function, complement protein levels in the blood, the presence of antibodies like C3Nefs and C5Nefs, and screens for genetic mutations in complement genes. The results are informative to patient care and can provide clinicians with insight into what is happening at the level of the complement system in their patients.
Treatment for C3G has advanced significantly and includes supportive measures and therapies that directly target the complement system.
Supportive care remains essential for all people with this condition and focuses on protecting kidney function by tightly controlling blood pressure and reducing protein loss in the urine.
Medications such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are commonly used for this purpose and help reduce stress on the kidney’s filtering units. If blood lipid levels are elevated, lipid-lowering medications are recommended to reduce cardiovascular risk and may also help slow progression of kidney disease. SGLT2 inhibitors are also increasingly being integrated into supportive care to slow renal progression. These medications decrease protein loss in the urine by reducing intraglomerular blood pressure.
There are now two targeted complement therapies approved for C3G.
Iptacopan (brand name Fabhalta) is an oral medication that blocks factor B, a key protein in the alternative complement pathway. The alternative pathway is one arm of the complement system, which is part of the body’s immune defense. In early 2025, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved iptacopan for adults with C3G to reduce proteinuria, meaning excess protein in the urine, a sign of kidney damage. In clinical trials, iptacopan was shown to reduce proteinuria by 37% after one year of use. Many patients also experienced stabilization of kidney function during the one-year study period.
Pegcetacoplan (brand name Empaveli) is another complement-targeted medication. It works by blocking C3, a central protein in the complement system that is involved in all complement pathways. In July 2025, the FDA approved pegcetacoplan for adults and adolescents aged 12 years and older with C3G. In clinical trials, a majority of treated patients achieved a reduction in proteinuria of more than 50%.
Although both medications target the complement system, they act at different points in the pathway. As a result, each produces distinct changes in complement biomarkers, which are blood test measurements that reflect complement activity. Careful monitoring of these biomarkers can help physicians evaluate how effectively treatment is controlling complement activation.
Before targeted complement therapies became available, immunosuppressive treatment was commonly used. This included mycophenolate mofetil (MMF) and corticosteroids, which reduce immune system activity more broadly rather than specifically targeting the complement pathway. In several studies and clinical experiences, MMF combined with corticosteroids showed encouraging results in some patients, particularly those with C3GN, with reductions in proteinuria and stabilization of kidney function. Rituximab, a medication that reduces certain immune cells called B cells, has also been used in selected cases. Eculizumab, in contrast, blocks the terminal part of the complement pathway. Overall, responses to these treatments have been variable, and not all patients experience sustained benefit.
If C3G progresses to kidney failure, dialysis or kidney transplantation becomes necessary. Dialysis is a treatment that filters waste products from the blood when the kidneys can no longer do so. Kidney transplantation can restore kidney function, but C3G often recurs, meaning it returns in the transplanted kidney. For this reason, close and ongoing monitoring is essential after transplantation. If C3G does recur, treatment with targeted complement inhibitors such as iptacopan or pegcetacoplan should be started to help control the disease and protect the transplanted kidney.
Many investigational anti-complement therapies are currently in clinical trials in Europe and North America. In the USA, all clinical trials receiving U.S. Government funding and some trials supported by private industry are posted on www.clinicaltrials.gov.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about this condition and clinical trials available at the University of Iowa, contact:
Richard JH Smith, MD
Director of the Molecular Otolaryngology and Renal Research Laboratories
University of Iowa
[email protected]
JOURNAL ARTICLES
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