C3 glomerulopathy (C3G) is a rare and complex kidney disease caused by dysregulation of the immune system’s complement pathway, which plays a critical role in protecting the body from infection. The disease primarily affects the glomeruli, which are clusters of tiny blood vessels in the kidneys that filter waste and excess fluid from the blood. Overactivation of the complement system can lead to kidney damage, and if left untreated, C3G can ultimately lead to kidney failure. In this article, we will discuss the etiology, frequency, pathophysiology, diagnosis, and treatment of C3 glomerulopathy and highlight its clinical complexity through case studies.
Synonyms: C3G, C3-predominant glomerulonephritis
What is C3 glomerulopathy?
C3 glomerulopathies are an umbrella term for a group of kidney diseases that are caused by dysfunction of the complement system, part of the immune response. The two main forms of C3 glomerulopathies are dense deposition disease (DDD) and C3 glomerulonephritis (C3GN). Both conditions share common characteristics, but they appear in different age groups. Dense deposits are more common in children, whereas C3 glomerulonephritis is usually diagnosed in the elderly. Although the age of onset differs, both conditions cause damage to the glomeruli, leading to inflammation, proteinuria (excess protein in the urine), hematuria (blood in the urine), high blood pressure, and progressive kidney dysfunction.
C3G is notorious for its high relapse rate, which significantly increases the risk of end-stage renal disease (ESRD), particularly in patients with dense deposit disease. The disease is also associated with a variety of other health complications, especially in older patients. Studies have found that C3G is closely associated with monoclonal gammaglobulinemia in individuals over 50 years of age, who are more likely to relapse after kidney transplantation.
Causes of C3 glomerulopathy
The underlying cause of C3 glomerulopathy is genetic mutations that disrupt the regulation of the complement system. The complement system is a group of proteins that work together to defend against foreign invaders such as bacteria and viruses, remove damaged cells and trigger 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 lead to overactivity of the complement system, leading to kidney damage. For example, mutations in the CFHR5 gene are associated with C3 glomerulopathy in Cypriot individuals. Other mutations, such as those in the C3 and CFH genes, have been found in different populations, although these mutations account for only a small proportion of all cases.
In addition to genetic mutations, certain genetic variations (called polymorphisms) are associated with an increased risk of C3 glomerulopathy. The presence of specific combinations of these genetic variations can make an individual more susceptible to the disease, although not everyone with these genetic variations will develop the disease.
Overactivation of the complement system can lead to damage to the glomeruli, the small blood vessels in the kidneys that filter blood waste. When the renal glomeruli are damaged, they can no longer perform their important role, leading to kidney dysfunction. In addition to kidney damage, this overactive complement response has been linked to other health problems, such as acquired partial lipodystrophy (a disease involving abnormal fat distribution) and retinal drusen (a hallmark of eye disease). accumulation.
Frequency of C3 glomerular lesions
C3 glomerulopathies are extremely rare, with an estimated incidence of 1 to 2 cases per million people worldwide. Interestingly, it is equally common in men and women, although it primarily affects people with a specific genetic predisposition. Because of its rarity, many healthcare professionals may not recognize C3 glomerulopathy immediately, which may delay diagnosis and treatment.
Pathophysiology of C3 glomerular lesions
In most cases of C3 glomerulopathy, the disease is caused by the presence of autoantibodies, specifically C3 nephritic factor (C3NeF). These autoantibodies bind to C3 convertase (C3bBb), a key protein complex in the alternative complement pathway, and prevent it from being regulated by the body’s normal control mechanisms. This disruption leads to continued activation of the complement system, which leads to excessive deposition of C3 in the glomerulus, further damaging the kidneys.
Although most cases of C3 glomerulopathy are caused by autoantibodies, a small proportion (approximately 10-15%) are associated with mutations in complement proteins such as C3, factor B, factor H, and factor I. It can help to differentiate between these two causes by identifying the presence or absence of C3 nephritic factor.
Treatment of C3 glomerulopathy
Currently, there is no clear cure for C3 glomerulopathy, but a variety of treatment strategies are available to manage the disease and its complications. The goals of treatment are to control the overactive complement system, reduce inflammation, and slow the progression of kidney damage.
- Symptom treatment: Many patients with C3 glomerulopathy receive other nonspecific therapies commonly used for chronic kidney disease, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and lipid-lowering drugs. These treatments help control disease-related hypertension, proteinuria, and dyslipidemia.
- complement inhibition:A promising therapeutic area for C3 glomerulopathies is complement inhibition. Drugs that block the complement system, such as terminal pathway blockers, may help reduce complement activation and slow disease progression. Although complement inhibition has had some success in some 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 recurs in nearly all kidney transplants, often resulting in graft failure in 50-90% of transplant recipients.
- plasma replacement therapy: For patients with CFH gene mutations, plasma replacement therapy may help control complement activation and slow the progression of renal failure.
- monitor: Regular monitoring of renal function is critical in patients with C3 glomerulopathy, especially those at risk of progression to ESRD. A nephrologist familiar with C3G should evaluate the complement pathway every two years and perform regular eye exams to monitor for associated retinal problems.
Diagnosis of C3 glomerular lesions
Diagnosis of C3 glomerulopathy requires a combination of clinical suspicion, laboratory testing, and renal biopsy. A 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, where a pathologist can examine kidney tissue under a microscope and assess the extent of glomerular damage. Biopsy can also help differentiate between C3 glomerulonephritis and dense deposit disease. Immunofluorescence (IF) microscopy shows bright staining of C3, a hallmark of C3 glomerulopathy.
- Electron Microscopy (EM): EM is critical to distinguish C3GN from DDD because these two conditions have different glomerular deposition patterns. C3GN typically shows light, hump-like deposits, whereas DDD shows dense, band-like deposits in the glomerular basement membrane.
- Molecular genetic testing: Genetic testing can help identify pathogenic variants in complement-related genes. This may help confirm the diagnosis, determine the cause of the disease, and guide treatment decisions.
Case study: C3 glomerulopathy after renal transplantation
A 78-year-old man with chronic kidney disease recently received a kidney transplant. Initially, his kidney function improved, but during follow-up, his kidney function began to deteriorate rapidly. Treatment with methylprednisolone for suspected acute rejection did not improve the condition. Kidney sections showed predominantly C3 deposition, leading to the diagnosis of C3 glomerulonephritis (C3GN). Despite treatment with the complement inhibitor eculizumab, clinical symptoms did not improve and the patient underwent hemodialysis. This case highlights the challenges of managing C3G, particularly when it recurs after kidney transplantation.
Genetics and genetic factors
Most cases of C3 glomerulopathy are sporadic, meaning they are not inherited from family members. However, some families have multiple members with the disease, and there may be a link between C3 glomerulopathy and autoimmune diseases, which involve the immune system attacking body tissue. The exact relationship between C3G and autoimmune diseases is still under investigation.
in 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 treatment 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. Ongoing research into complement inhibition and genetic testing is expected to provide new treatment options in the future.
refer to
- Miller, LE, and Stevens, CD (2021). Clinical immunology and serology: a laboratory perspective. FA Davis Company.
- Ponticelli, C., Calatroni, M., & Moroni, G. (2023). C3 glomerulopathy: dense deposits and C3 glomerulonephritis. Medical Frontiers, 10.
- Ruiz-Fuentes, MC, Caba-Molina, M., Polo-Moyano, A., Palomares-Bayo, M., Galindo-Sacristan, P., & De Gracia-Guindo, C. (2023).
- A 78-year-old man with chronic kidney disease and monoclonal gammopathy develops C3 glomerulopathy after transplantation—relapse or de novo? Case report and literature review. American Journal of Case Reports, 24.
- Smith, RJH, Appel, GB, Blom, AM et al. C3 glomerulopathy—Learn about a rare complement-driven kidney disease. nephrotic sodium 15129–143 (2019).
