Bradley Dixon, MD

Panelists discuss how the complexity of diagnosing C3 glomerulopathy (C3G), the need for long-term treatment options, and the importance of addressing unmet needs, including the psychological impact on patients and families, highlights the challenges and future directions in improving care for these individuals.

Treating the Whole Patient: Addressing the Broader Unmet Needs in C3G Management

Video content above is prompted by the following: 

Discussion on C3G Treatment and Challenges

The conversation highlighted various aspects of managing C3G, with an emphasis on treatment options, diagnosis, and unmet needs in patient care.

Diagnosing C3G can be complicated due to the need to differentiate between acquired and genetic forms of the disease.

Current treatment options focus on long-term therapy, but the uncertainty of how long treatment should continue remains a challenge.

C3G patients, especially young adults, face significant psychological challenges due to the uncertainty surrounding their disease and its impact on their future, such as career development, education, and family support.

Mental health and psychosocial support are critical. This includes addressing not just the disease itself but the broader emotional and social impacts of living with a chronic condition.

The pediatric population presents a key unmet need. Current studies (e.g., the VALIANT and APPEAR C3G studies) focus on patients aged 12 and older, but younger children with C3G (ages 7-9 years) also need treatment and safety data.

There is a need for the development of pediatric-friendly formulations of medications, such as liquid forms for those unable to swallow pills.

Early diagnosis is crucial. Physicians should strive to identify C3G in the general population earlier to prevent the progression to chronic kidney disease (CKD) and improve patient outcomes.

The ultimate goal is to prevent patients from needing dialysis by catching the disease early.

Future Directions and Precision Medicine:

While there has been significant progress in treatment options for C3G, the next phase of research should focus on identifying which patients will benefit most from specific therapies.

Precision medicine approaches will be critical in advancing the care for C3G and other glomerular diseases.

The discussion concluded with optimism about ongoing research and the potential to dramatically improve the outcomes for C3G patients through early intervention and personalized treatment strategies.

Videos

Panelists discuss how patient history, vaccination status, and risk of infection influence the decision to administer complement inhibitors, with some expressing caution in high-risk cases, particularly in pediatric populations with prior infections or low immunoglobulin levels.

Balancing Complement Inhibition and Infection Risk in C3G Treatment

Summary for Physicians on Use of Complement Inhibitors in High-Risk Patients:

Patients with nephrotic syndrome who experience significant protein loss, leading to very low IgG levels, are at an increased risk for infections. These patients may not be ideal candidates for complement inhibitors due to concerns about their ability to fight bacterial infections, particularly encapsulated organisms.

Early trial data, particularly from studies like 

, suggest that while complement inhibitors are used in posttransplant patients on immunosuppressive therapy, they did not significantly increase the risk of infections, especially when vaccinated and managed with prophylactic antibiotics.

Vaccination and prophylactic antibiotics (e.g., penicillin or macrolides) are essential to reduce infection risks when using complement inhibitors. It’s important to assess local infection resistance patterns (e.g., penicillin resistance rates) before initiating therapy.

Clinical trials, such as the APEX trial, excluded patients with a history of recurrent invasive infections caused by encapsulated organisms. However, in clinical practice, the timing of infections, vaccination status, and use of prophylactic antibiotics are important factors to consider.

A patient who has had a meningococcal infection but was not vaccinated may still be a candidate for complement inhibitor therapy if vaccinations are administered and prophylactic antibiotics are used.

In real-world settings, physicians may proceed with complement inhibitors in high-risk patients, provided that adequate precautions are taken, including vaccination, use of prophylactic antibiotics, and consultation with infectious disease specialists when necessary. This approach has been successful in managing patients safely over extended periods.

It’s crucial to address concerns from parents or caregivers, particularly in pediatric populations. Parents need reassurance regarding the safety of long-term use of complement inhibitors, especially in the context of infection risks.

Panelists discuss how future clinical trials for C3 glomerulopathy (C3G) and other rare kidney diseases must evolve to accommodate emerging therapies targeting the complement system, improve inclusivity across patient populations, utilize molecular and genetic data, and reassess end point criteria to overcome challenges in patient recruitment and demonstrate treatment efficacy.

The Future of Clinical Trials on C3G: Lessons From the VALIANT and APPEAR Trials

Clinical Trials in C3G: Future Directions and Considerations for Physicians

As treatment strategies for C3G evolve, future clinical trials are expected to incorporate new complement-targeting therapies, while also adapting to the challenges of studying a rare and heterogeneous disease.

: Future trials aim to be more inclusive, enrolling both pediatric and adult populations, as well as transplant and non-transplant patients. Historically, pediatric inclusion has been limited, but this is now a priority to generate more comprehensive data.

: Leveraging rich genetic and molecular datasets will be critical. Trials will increasingly incorporate biomarkers and genetic phenotyping to identify patients more likely to benefit, relapse, or safely discontinue treatment.

: Integrating molecular and genetic data into trial design could enable more tailored therapies and improve our understanding of treatment responses and disease progression.

: Drawing on models like the chronic kidney disease clinical trials consortium, collaborative efforts and data pooling can help define robust clinical end points and advance biomarker research.

: A 6-month washout period for patients previously on complement inhibitors is likely to remain standard to prevent residual drug effects from confounding trial results.

Current trials (e.g., APPEAR) typically require ≥1 g/day proteinuria to ensure measurable treatment effects and to study more aggressive disease phenotypes.

While this helps demonstrate efficacy, it may limit recruitment. Lower thresholds (e.g., 500 mg/day) might be considered if accompanied by robust biomarkers.

 trial in transplant recipients pivoted from a proteinuria-based inclusion to histologic criteria, enabling successful recruitment and demonstrating histologic response despite minimal proteinuria.

Biomarkers hold promise for enabling less invasive end points in the future, akin to how 

 guide membranous nephropathy trials. However, validated biomarkers in C3G are not yet available for routine clinical or trial use.

: As therapies for C3G expand, trial designs must evolve to reflect real-world complexities. A personalized approach—guided by molecular insights and supported by collaborative research—will be essential to improve patient outcomes and ensure trial feasibility.

Panelists discuss how early protocol biopsies and proactive monitoring post-transplant can reveal subclinical recurrence of C3 glomerulopathy (C3G), prompting consideration of timely initiation of complement-targeting therapies to preserve graft function.

Managing Recurrent C3G for Patients Post Kidney Transplant


C3G is associated with a high rate of recurrence post-transplant, even in patients who exhibit stable clinical parameters (normal glomerular filtration rate, no proteinuria or hematuria). Histologic recurrence may be detectable early via immunofluorescence and EM, often preceding changes on light microscopy.


Data from Andrew S. Bomback, MD, MPH, and group suggest that performing 

protocol biopsies at 6-, 1-, and 24-months

 post-transplant reveals subclinical recurrence in most patients. These findings emphasize the progressive nature of C3G despite a lack of overt clinical signs.

early treatment with complement inhibitors

, such as iptacopan, may be beneficial—even in the absence of proteinuria or hematuria. The FDA label for iptacopan allows treatment initiation based solely on histologic diagnosis of C3G, independent of proteinuria thresholds.


In the absence of data from randomized controlled trials, clinicians are encouraged to consider:

Initiating complement inhibitors preemptively at or before transplant

 (analogous to atypical = hemolytic uremic syndrome management), or

Using the first protocol biopsy (typically at 6 months)

 to guide the start of therapy if histologic recurrence is present

Collaboration Between General Neurology and Transplant Teams:


As C3G and other glomerular diseases present complex post-transplant challenges, there is a growing need for 

closer collaboration between glomerular disease specialists and transplant nephrologists

Shared decision-making for high-risk patients

Joint planning for surveillance and treatment strategies

Raising awareness about the significance of subtle clinical signs and the utility of early biopsy


The field is evolving, and more studies comparing early vs delayed initiation of complement inhibitors are needed. Until then, clinicians are urged to 

adopt a proactive, not reactive, approach

 to surveillance and management of recurrent C3G in transplant recipients.

Bradley Dixon, MD

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