C3 glomerulopathy (C3G) is a rare and complex kidney disease caused by dysregulation of the immune system’s complement pathway, which plays a key role in protecting the body from infections. This disorder primarily affects the glomeruli. Glomeruli are collections of small blood vessels in the kidneys that are responsible for filtering waste and excess fluid from the bloodstream. Overactivation of the complement system can cause kidney damage, and if left untreated, C3G can eventually lead to kidney failure. This article explores the causes, frequency, pathophysiology, diagnosis, and management of C3 glomerulopathy, with case studies highlighting its clinical complexity.
Synonyms: C3G, C3 dominant glomerulonephritis
What is C3 glomerulopathy?
C3 glomerulopathies are a group of kidney diseases that result from dysfunction of the complement system, which is part of the immune response. The two main forms of C3 glomerulopathy are dense deposition disease (DDD) and C3 glomerulonephritis (C3GN). Both conditions have common features but occur at different age groups. C3 glomerulonephritis is usually diagnosed in older adults, while dense deposit disease is more common in children. Despite the difference in age of onset, both conditions cause glomerular damage and lead to inflammation, proteinuria (excess protein in the urine), hematuria (blood in the urine), hypertension (high blood pressure), and progressive Causes renal dysfunction.
C3G is known to have a high recurrence rate and significantly increases the risk of end-stage renal disease (ESRD), especially in patients with high-deposition disease. This disorder is also associated with a variety of other health complications, especially in older patients. Studies have shown that C3G is strongly associated with monoclonal gammaglobulinemia in people over 50 years of age and is more likely to recur after kidney transplantation.
Causes of C3 glomerulopathy
The root cause of C3 glomerulopathy lies in genetic mutations that disrupt the regulation of the complement system. The complement system is made up of a group of proteins that work together to defend against foreign invaders such as bacteria and viruses, remove damaged cells, and cause inflammation. When the complement system is functioning properly, it is carefully regulated to ensure that it targets harmful invaders without attacking healthy tissue.
In many cases of C3 glomerulopathy, genetic mutations in complement-related genes contribute to overactivity of the complement system, leading to kidney damage. For example, mutations in the CFHR5 gene are associated with C3 glomerulopathy in people from Cyprus. Other mutations, such as those in the C3 and CFH genes, have also been identified in various populations, but these mutations account for only a small percentage of all cases.
In addition to genetic mutations, certain genetic variations called polymorphisms are associated with an increased risk of developing C3 glomerulopathy. The presence of certain combinations of these genetic variations may make an individual more susceptible to this disease, but not everyone with these genetic variations will develop this condition.
When the complement system becomes overactive, it damages the glomeruli, the small blood vessels in the kidneys that filter waste products from the blood. When the glomeruli are damaged, they are no longer able to fulfill their important role, leading to kidney dysfunction. In addition to kidney damage, this excessive complement response can lead to other health problems, such as acquired partial lipodystrophy (a condition with abnormal fat distribution) and drusen buildup in the retina (a marker of eye disease). is also related.
Frequency of C3 glomerulopathy
C3 glomerulopathy is extremely rare, with an estimated prevalence of 1 to 2 per million people worldwide. Interestingly, it primarily affects people with certain genetic predispositions, but is equally common in both men and women. Because of its rarity, many medical professionals may not immediately recognize C3 glomerulopathy, potentially delaying diagnosis and treatment.
Pathophysiology of C3 glomerulopathy
In most cases of C3 glomerulopathy, the disease is caused by the presence of autoantibodies, particularly C3 nephritic factor (C3NeF). These autoantibodies bind to C3 convertase (C3bBb), a key protein complex in the alternative complement pathway, preventing control by the body’s normal regulatory mechanisms. This destruction leads to continued activation of the complement system and excessive deposition of C3 in the glomeruli, further damaging the kidneys.
The majority of cases of C3 glomerulopathy are caused by autoantibodies, but a smaller proportion (approximately 10-15%) are caused by mutations in complement proteins such as C3, factor 2, factor H, and factor I. related to. Laboratory tests can help distinguish between them. These two causes are identified by determining the presence or absence of the C3 nephritic factor.

Management of C3 glomerulopathy
Although there is currently no definitive treatment for C3 glomerulopathy, several therapeutic strategies are used to manage this disease and its complications. The goal of treatment is to control an overactive complement system, reduce inflammation, and slow the progression of kidney damage.
- Symptomatic treatment:Many patients with C3 glomerulopathy are treated with other nonspecific drugs commonly used for chronic kidney disease, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and lipid-lowering drugs. It is treated with therapy. These treatments help manage the high blood pressure, proteinuria, and lipid abnormalities associated with the disease.
- complement inhibition: A promising area of ​​treatment for C3 glomerulopathy is complement inhibition. Drugs that block the complement system, such as terminal pathway blockers, reduce complement activation and may help slow disease progression. Although complement inhibition has shown some success in certain patients, it is not universally effective.
- Dialysis and kidney transplant:For patients who develop end-stage renal disease (ESRD) due to C3 glomerulopathy, treatment options are limited to dialysis or kidney transplantation. Unfortunately, C3 glomerulopathy tends to recur in nearly all kidney transplants, often leading to graft failure in 50-90% of transplant recipients.
- plasma replacement therapy: In patients with mutations in the CFH gene, plasma replacement therapy may help control complement activation and slow the progression of kidney failure.
- surveillance:Regular monitoring of renal function is essential for patients with C3 glomerulopathy, especially those at risk of progressing to ESRD. A nephrologist familiar with C3G should perform complement pathway evaluation and routine eye exams twice a year to monitor for associated retinal problems.
Diagnosis of C3 glomerulopathy
Diagnosis of C3 glomerulopathy requires a combination of clinical suspicion, laboratory tests, and renal biopsy. The key diagnostic feature of C3G is the presence of low levels of the complement component C3 in the blood, known as hypocomplementemia.
- kidney biopsy:The gold standard for diagnosing C3 glomerulopathy is a kidney biopsy, which allows a pathologist to examine kidney tissue under a microscope and assess the extent of glomerular damage. Biopsy is also helpful in differentiating C3 glomerulonephritis from hyperplasia. Immunofluorescence (IF) microscopy reveals bright staining of C3, which is characteristic of C3 glomerulopathy.
- Electron microscope (EM): EM is important to distinguish between C3GN and DDD. This is because the two conditions have different patterns of glomerular deposition. C3GN usually shows light nodular deposits on the glomerular basement membrane, whereas DDD shows dense ribbon-like deposits on the glomerular basement membrane.
- Molecular genetic testing: Genetic testing can help identify pathogenic mutations in complement-related genes. This will help confirm the diagnosis, determine the cause of the disease, and determine treatment.

Case study: C3 glomerulopathy after renal transplantation
A 78-year-old man with chronic kidney disease recently underwent a kidney transplant. Initially, his renal function improved, but during a follow-up visit, his renal function began to deteriorate rapidly. The patient was treated with methylprednisolone for suspected acute rejection, but no improvement was seen. Renal biopsy revealed predominant C3 deposits and a diagnosis of C3 glomerulonephritis (C3GN) was made. Despite receiving eculizumab, a complement inhibitor, there was no clinical improvement and the patient underwent hemodialysis. This case highlights the challenges of C3G management, especially when it relapses after kidney transplantation.
Heredity and genetic considerations
Most cases of C3 glomerulopathy occur sporadically. That is, it is not inherited from family members. However, some families have more than one member affected by the disease, and there may be a link between C3 glomerulopathy and an autoimmune disease in which the immune system attacks the body’s tissues. The exact relationship between C3G and autoimmune diseases is still under investigation.
conclusion
C3 glomerulopathy is a rare but serious kidney disease caused by overactivation of the complement system. Although there is no cure, early diagnosis and management are critical to slowing disease progression and improving patient outcomes. Physicians should consider C3G in patients with unexplained renal dysfunction, especially those with a history of autoimmune disease or kidney transplantation. Continued research into complement inhibition and genetic testing is expected to provide new treatment options in the future.
References
- Miller, L. E., and Stevens, C. D. (2021). Clinical immunology and serology: a laboratory perspective. FA Davis Company.
- Ponticelli, C., Calatroni, M., and Moroni, G. (2023). C3 glomerulopathy: dense deposition disease and C3 glomerulonephritis. Frontiers in Medicine, 10. https://doi.org/10.3389/fmed.2023.1289812
- Luis-Fuentes, M. C., Cava-Molina, M., Polo-Moyano, A., Palomares-Bayo, M., Galindo-Sacristan, P., and de Gracia-Guindo, C. (2023).
- A 78-year-old man with chronic kidney disease and monoclonal gammaglobulinopathy developed C3 glomerulopathy after transplantation – recurrent or new? Case report and literature review. American Journal of Case Reports, 24. https://doi.org/10.12659/ajcr.939726
- Smith, RJH, Appel, GB, Blom, AM. Others. C3 Glomerulopathy — Understand a rare complement-dependent kidney disease. nat rev nephrol 15129–143 (2019). https://doi.org/10.1038/s41581-018-0107-2