Bradley Dixon, MD

Panelists discuss how educating physicians and patients about C3 glomerulopathy (C3G) presents unique challenges due to its rarity, complexity, and the critical role of renal pathologists in diagnosis while emphasizing the growing importance of understanding the complement system as new targeted therapies emerge.

Strength in Numbers: Raising Awareness of C3G and Other Rare Diseases

Video content above is prompted by the following: 

C3G is an ultra-rare, complex kidney disease characterized by predominant C3 deposition in the glomeruli due to dysregulation of the alternative complement pathway. C3G serves as an umbrella term that includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).

C3G patients are typically complex and challenging to diagnose

Clinical presentation is often nonspecific and variable

Renal pathology is crucial for diagnosis, requiring specialized expertise

Hypocomplementemia is not universally present (normal complement levels don’t rule out C3G)

Can be difficult to distinguish from post-infectious glomerulonephritis, particularly in pediatric populations

: Essential for diagnosis; collaboration with experienced renal pathologists is critical

Monoclonal gammopathies (particularly in patients aged >50 years)

Genetic testing for complement pathway mutations

Autoantibody testing (C3 nephritic factor, anti-factor H)

Increasing recognition of complement’s role in glomerular diseases

Training on appropriate workup for suspected C3G

Familiarity with the complement system, particularly the alternative pathway

Awareness that C3G can present differently in pediatric vs adult populations

New complement-targeting therapies offer promising treatment options

Understanding the underlying mechanism is essential for appropriate therapy selection

Different management strategies may be needed for pediatric vs adult patients

Implications for kidney transplantation and potential living donors

Patients with ongoing proteinuria, active urinary sediment, or persistent symptoms should be evaluated for C3G even after initial diagnosis of another condition

Long-term monitoring is essential as the disease can progress slowly

Patients and families often become the experts on their condition

Primary care physicians may need education from specialists to provide appropriate care

Clear explanations of complement dysregulation help patients understand their disease and treatment options

Videos

Panelists discuss how eculizumab initially provides short-term benefits for patients with C3 glomerulopathy (C3G) through C5a inhibition and anti-inflammatory effects but often loses efficacy over time as the disease progresses due to inadequate control at the C3 convertase level, suggesting newer complement-targeting therapies may offer better long-term management than C5 blockade.

Managing C3G: Comparing Conservative and Emerging Targeted Treatment Strategies

Current Treatment Landscape and Eculizumab Efficacy

Patients with C3G treated with eculizumab often show an initial response followed by breakthrough disease progression after 1 to 2 years of therapy. This pattern occurs because:

Eculizumab targets C5, blocking both C5a (an anaphylatoxin) and C5b

The early response primarily stems from reduced inflammation through C5a inhibition

Long-term disease control fails because eculizumab does not address the underlying dysregulation at the C3 convertase level

Italian study data demonstrates the transient benefit pattern:

Initial proteinuria reduction and albumin improvement

Over time, proteinuria increases to above baseline

Albumin levels eventually drop below baseline

Avacopan (C5a receptor antagonist) has been evaluated:

Similar mechanistic limitations to eculizumab (targeting downstream of C3)

Clinical trials (ACCOLADE study) failed to demonstrate adequate disease control

The situation parallels breakthrough hemolysis in paroxysmal nocturnal hemoglobinuria (PNH):

Both conditions highlight the importance of targeting the appropriate level of the complement cascade

In PNH, C3-targeting drugs have proven superior to C5-targeting drugs

For progressive C3G with high risk of kidney failure:

C5 blockade appears insufficient for long-term disease control

C3-targeting therapies may offer more effective disease modification

Transition from current eculizumab treatment to newer, upstream complement inhibitors will likely be necessary

Panelists discuss how treatment approaches for C3 glomerulopathy (C3G) have evolved from nonspecific immunosuppression to targeted complement inhibition, with the recent FDA approval of iptacopan marking a significant advancement in disease management.

Personalizing C3G Treatment: Insights From Experienced Clinicians

All C3G patients require nonimmunosuppressive background therapy:

Renin-angiotensin-aldosterone system blockers (essential)

Potential additions: glucagon-like peptide-1 agonists and mineralocorticoid receptor antagonists

Most C3G patients will progress despite conservative background therapy

Management approaches have evolved significantly over the past 15 years

Various nonspecific immunosuppressive regimens have been tried

Mycophenolate-based regimens with steroids (similar to lupus nephritis treatment) showed the most consistent benefit

Most effective in patients with nephritic factors (60%-70% chance of significant proteinuria reduction)

Limitation: Re-biopsies show continued accumulation of chronicity despite treatment

Limitations of B-Cell–Directed Therapies

Despite C3G having autoimmune characteristics, B-cell–targeting agents have proven ineffective

Nephritic factors may not always be pathogenic

Nephritic factors might only initiate the disease process, with complement dysregulation continuing independently afterward

New Era of Complement-Targeting Therapies

First complement-targeting drug (Iptacopan) received FDA approval for C3G

At least 1 other similar agent is expected to receive approval soon

These targeted therapies address the underlying disease mechanism rather than just symptoms

Even in patients with nephritic factors, complement-targeting therapy is now preferred over antibody-depleting approaches

Treatment paradigm has shifted from nonspecific immunosuppression to targeted complement inhibition

Physicians should consider these newer options as they become available for C3G management

Panelists discuss how delayed diagnosis and treatment of C3 glomerulopathy (C3G) leads to progressive kidney damage and poorer outcomes, with approximately 50% of patients developing end-stage kidney disease within 10-15 years despite available treatments.

The Cost of Diagnostic Delay of C3G Across Age Groups

Early Diagnosis and Treatment of C3G Patients

This summary addresses the importance of timely diagnosis and treatment for patients with C3G, based on a conversation between Sayna Norouzi, MD; Bradley Dixon, MD; and Andrew S. Bomback, MD, MPH.

: C3G is characterized by slow but relentless progression toward chronic kidney disease, with approximately 50% of patients developing end-stage kidney disease within 10 to 15 years after diagnosis, despite available treatments.

: The glomerular inflammation caused by C3G leads to destructive fibrotic reactions, resulting in glomerulosclerosis. This progresses to hyperfiltration of remaining nephrons, causing accelerated nephron loss and ultimately kidney failure.

: Even when diagnosed promptly, historically available treatment tools have been limited in their effectiveness for C3G patients.

Dense Deposit Disease vs C3 Glomerulonephritis

: While European cohorts suggested dense deposit disease progresses faster than C3G, a New York cohort of over 100 patients showed both subtypes progressing at the same rate.

: Many patients with C3 glomerulonephritis are diagnosed late when significant chronicity is already present on biopsies. This delay in diagnosis likely contributes to worse outcomes and faster progression to kidney failure.

These findings emphasize the critical importance of early diagnosis and intervention in C3G to potentially slow disease progression and improve long-term kidney outcomes.

Panelists discuss how C3 glomerulopathy (C3G) is triggered by factors like infections or pregnancy that activate the alternative pathway in genetically predisposed individuals, presenting with diverse clinical manifestations that often overlap with other glomerular diseases, making diagnosis challenging without kidney biopsy.

Bradley Dixon, MD

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