C3G: Symptoms, Types, Causes and Treatment

C3 glomerulopathy (C3G) is a rare but significant kidney disease driven by dysregulation of the complement system, particularly the alternative pathway. As our understanding of this disease has advanced, so too has our ability to recognize its varied presentations, underlying causes, and emerging treatment possibilities. This article provides a comprehensive exploration of C3G—what it is, how it manifests, why it occurs, and the latest in its management—grounded in up-to-date scientific research.

Symptoms of C3G

C3G does not present the same way in every patient. Its symptoms can range from subtle changes in urine tests to severe kidney dysfunction. Recognizing the full spectrum of C3G symptoms is critical for early diagnosis and effective management.

Symptom	Description	Onset	Sources
Proteinuria	Excess protein in urine	Early or late	4 5 9
Hematuria	Blood in urine (micro or macro)	Early or late	5 7 16
Edema	Swelling (often in legs/face)	With nephrotic syndrome	5 9
Renal impairment	Reduced kidney function	Variable	4 5 16
Hypertension	Elevated blood pressure	Variable	5 9
Nephrotic syndrome	Heavy proteinuria, low albumin, edema	Severe disease	5 9
Nephritic syndrome	Blood/protein in urine, high BP, kidney injury	Severe disease	5 9
Asymptomatic	Detected only by lab tests	Mild disease	5

Table 1: Key Symptoms

Understanding the Symptom Spectrum

C3G can be a clinical chameleon. Some individuals are entirely asymptomatic, and the diagnosis is made incidentally based on routine urine tests showing blood (hematuria) or protein (proteinuria) in the urine 5. Others may experience:

• Edema: Swelling, commonly in the legs or around the eyes, usually due to protein loss in the urine.
• Hypertension: High blood pressure, which can develop as kidney function is impaired.
• Nephrotic Syndrome: Characterized by heavy proteinuria, low blood albumin, high cholesterol, and swelling 5 9.
• Nephritic Syndrome: Marked by blood in the urine, proteinuria, reduced kidney function, and hypertension 5 9.
• Progressive Renal Impairment: In more severe cases, kidney function declines, potentially leading to chronic kidney disease or end-stage renal disease (ESRD) 4 5 16.

Factors Influencing Symptom Severity

The clinical course of C3G is highly variable. Some patients may maintain stable kidney function for many years, while others progress rapidly to kidney failure 4 9. Children and adults can both be affected, and the symptoms may evolve over time.

Special Considerations

• Children vs. Adults: Children may present more frequently with nephrotic or nephritic syndromes, while adults often exhibit proteinuria and hematuria 5.
• Monoclonal Gammopathy: In older adults, C3G can be associated with abnormal monoclonal immunoglobulins, and may cause more severe kidney dysfunction 16.
• Recurrence After Transplantation: C3G frequently recurs in kidney transplants, sometimes leading to graft loss 10.

Recognizing the diverse manifestations of C3G is essential for timely intervention and for tailoring management strategies to individual needs.

Types of C3G

C3G is not a single disease but a spectrum. Understanding its subtypes helps clinicians determine prognosis and the best course of action for each patient.

Type	Key Features	Diagnostic Hallmark	Sources
C3GN	Glomerular C3 deposits, variable electron-dense deposits	Dominant C3 staining; less dense deposits	4 6 8 9
DDD	Dense Deposit Disease: ribbon-like, highly electron-dense deposits	Dense osmiophilic deposits in GBM	6 7 8 9
MIg-associated C3G	C3G with monoclonal immunoglobulin involvement	Presence of MIg; older age; C3 deposition	15 16

Table 2: C3G Types

C3 Glomerulonephritis (C3GN)

C3GN is defined by:

• Dominant C3 deposits in the glomeruli (filtration units of the kidney)
• Electron microscopy may reveal variable, segmental, or global electron-dense deposits, but not as dense or ribbon-like as in DDD 4 6 8 9.

Patients with C3GN can have a range of symptoms from mild hematuria/proteinuria to severe kidney dysfunction. The prognosis is variable, but recurrent disease after transplantation is common 10.

Dense Deposit Disease (DDD)

DDD is a distinct, more severe form of C3G:

• Diagnostic hallmark: On electron microscopy, there are characteristic ribbon-like, extremely electron-dense deposits within the glomerular basement membrane (GBM) 6 7 8 9.
• Clinical course: Tends to be more aggressive, often progressing to kidney failure. Recurrence after transplant is also frequent, and graft loss is common 10.

Monoclonal Immunoglobulin (MIg)-Associated C3G

A subset of C3G cases, especially in older adults, involve abnormal monoclonal immunoglobulins:

• MIg-associated C3G: These cases show C3-dominant deposits but also evidence of monoclonal Ig, such as in patients with multiple myeloma or other B-cell disorders 15 16.
• Distinct features: This form may require specialized treatment directed at the underlying B-cell clone.

Diagnostic Approach

• Immunofluorescence: All C3G types show dominant C3 staining; only minimal or absent immunoglobulin deposition 4 6 7 8 9.
• Electron Microscopy: Differentiates between C3GN and DDD based on the pattern and density of deposits 6 8 9.

Overlapping and Evolving Classification

C3G subtypes may overlap or evolve over time as new molecular and genetic information emerges. Some cases previously classified as membranoproliferative glomerulonephritis (MPGN) are now recognized as C3G based on immunopathologic features 7 9 11.

Causes of C3G

The root cause of C3G lies in the dysregulation of the alternative complement pathway—a crucial part of the body’s immune defense. However, the reasons for this dysregulation can be diverse.

Cause/Mechanism	Description	Key Details/Examples	Sources
Genetic Mutations	Mutations in complement regulatory genes	CFH, CFI, CFB, CFHR1–5, C3, etc.	4 11 12 13
Autoantibodies	Stabilize complement convertase, drive overactivation	C3 nephritic factor, C4 nephritic factor	4 6 11 14
Monoclonal Immunoglobulins	MIg interferes with complement regulation	Seen in older adults, associated with B-cell disorders	15 16
Unknown/Idiopathic	No identifiable cause	Up to 20–30% of cases	4 9 11

Table 3: Causes and Pathogenesis

Genetic Mutations

A significant proportion of C3G cases are linked to hereditary mutations that affect the regulation of the alternative complement pathway. These include:

• Complement Factor H (CFH), CFI, CFB, CFHR1–5, and C3 genes 4 11 12.
• Mutations can disrupt normal regulation, leading to uncontrolled activation of complement and deposition of C3 breakdown products in the kidney.
• Novel mutations in genes like THBD (thrombomodulin) are also implicated in rare cases 11.

Pathogenic Mechanisms

• Some mutations cause abnormal oligomerization of regulatory proteins (e.g., CFHR1/CFHR5), which enhances complement activation 12 13.
• These genetic changes can be inherited or arise spontaneously.

Autoantibodies

Autoantibodies, particularly C3 nephritic factor (C3NeF), are found in up to 80% of patients:

• C3NeF: Stabilizes the C3 convertase enzyme, prolonging its activity and leading to continuous C3 activation and breakdown 4 6 11 14.
• C4 nephritic factor (C4NeF): Stabilizes classical pathway convertase; less common but contributes to complement dysregulation in some cases 14.
• Patients may also harbor other complement-directed autoantibodies (e.g., anti-C1q, anti-C3) 14.

Monoclonal Immunoglobulins (MIg)

In older adults, C3G can be triggered by monoclonal immunoglobulins (paraproteins):

• MIg can interfere with complement regulation, often in the context of B-cell disorders like multiple myeloma or monoclonal gammopathy of renal significance 15 16.
• This form necessitates evaluation and treatment of the underlying hematologic disease.

Other/Idiopathic Cases

In some cases, no clear genetic, autoimmune, or MIg-related cause is identified, highlighting the need for ongoing research 4 9 11.

Pathophysiology in Brief

• Central Role of Alternative Pathway: Loss of regulation leads to C3 cleavage and deposition of C3 breakdown products (especially C3dg, iC3b) in the glomeruli 6 8.
• Inflammation and Injury: The resulting complement activation damages glomerular cells and structure, leading to the clinical manifestations of C3G 4 6.

Treatment of C3G

Managing C3G is challenging due to its rarity, variability, and the incomplete understanding of its pathogenesis. Recent advances are opening new possibilities, but there is still no universally accepted or FDA-approved therapy.

Therapy Type	Examples/Agents	Indications/Notes	Sources
Supportive	ACE inhibitors, ARBs, blood pressure control, diuretics	All patients, foundation of care	4 5 7 9
Immunosuppressive	Corticosteroids + mycophenolate mofetil	First-line for active/progressive disease	4 5
Anti-complement	Eculizumab (anti-C5), iptacopan (factor B inhibitor)	For refractory/rapidly progressive cases; clinical trials	4 5 17 19
MIg-targeted therapy	Chemotherapy for B-cell clone	For MIg-associated C3G	15 16
Transplantation	Kidney transplant	Risk of recurrence is high	10
Clinical trials	Novel complement inhibitors	Enrollment encouraged	17 19

Table 4: Treatment Approaches

Supportive Therapy

Every patient with C3G should receive optimal supportive care:

• Blood pressure control: Using ACE inhibitors or ARBs to minimize proteinuria and slow progression.
• Diuretics: Manage edema.
• General nephroprotection: Avoid nephrotoxic medications and maintain cardiovascular health 4 5 7 9.

Immunosuppressive Therapy

For those with active or progressive disease, immunosuppressive regimens are often used:

• Corticosteroids combined with mycophenolate mofetil: Have shown improved renal outcomes compared to other immunosuppressive strategies 4 5.
• The response is variable, and not all patients benefit, emphasizing the need for individualized approaches.

Complement-Targeted Therapy

With the recognition that C3G is a complement-mediated disease, several targeted therapies are under investigation:

• Eculizumab: A monoclonal antibody that blocks C5, part of the terminal complement pathway. Used in severe or refractory disease, but responses are heterogeneous—effective in some, not in others 4 5 19. Its use is mainly reserved for rapidly progressive forms 4 5.
• Iptacopan: A selective factor B inhibitor, blocks activation of the alternative pathway upstream of C5. Early trials show promise in reducing proteinuria and C3 deposition; ongoing clinical studies are evaluating its efficacy 17.
• Other agents: Multiple other complement inhibitors are being studied in clinical trials. Enrollment in trials is encouraged when available 17 19.

Monoclonal Immunoglobulin-Targeted Therapy

For MIg-associated C3G:

• Chemotherapy targeting the B-cell clone: Such as bortezomib-based regimens, improves renal outcomes if a hematologic response is achieved 15 16.
• Non-targeted immunosuppression is less effective in this subgroup.

Kidney Transplantation

• Transplantation is an option for ESRD, but recurrence of C3G in the allograft is common, especially in DDD, and can lead to graft loss 10.
• Complement abnormalities often persist despite transplantation.

Future Directions

• Personalized medicine: Genetic and complement biomarker profiling may help predict who will respond to which therapies 4 6 11 19.
• Clinical trials: With several new agents in development, participation in trials is important for advancing care 17 19.

Conclusion

C3 glomerulopathy is a complex and evolving disease. Early recognition, accurate classification, and understanding the underlying mechanisms are crucial for optimal management. While supportive care remains the cornerstone, new therapies targeting the complement system offer hope for better outcomes.

Key Takeaways:

• C3G presents with a wide range of symptoms: from asymptomatic proteinuria/hematuria to nephritic/nephrotic syndrome and kidney failure 5 9 16.
• Two main types: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), with a subset associated with monoclonal immunoglobulins 4 6 7 8 9 15 16.
• Caused by: genetic mutations, autoantibodies, or monoclonal immunoglobulins leading to dysregulation of the alternative complement pathway 4 6 11 12 13 14 15 16.
• Treatment is multifaceted:
  • Supportive care for all
  • Immunosuppression for active disease
  • Complement inhibitors (e.g., eculizumab, iptacopan) for select cases
  • MIg-targeted therapy for those with monoclonal gammopathy
  • Transplantation is possible but recurrence is frequent 4 5 10 15 16 17 19
• Research is ongoing: Participation in clinical trials is encouraged as new, targeted therapies are developed 17 19.

C3G remains a challenging but increasingly understood disease. Advances in genetic and molecular diagnostics, along with complement-targeted therapies, are paving the way for more personalized and effective management strategies.