Exploring therapeutic strategies for C3 Glomerulopathy (C3G)

Exploring therapeutic strategies for C3 Glomerulopathy (C3G)

C3 Glomerulopathy (C3G) Treatments Developing to Intervene Proteins Involved in Disease Activity

C3G, a rare kidney condition affecting around two to three individuals per million, is characterized by a buildup of protein deposits in the kidney's filtering tissues. Over time, this leads to impaired kidney function and, potentially, kidney failure. As no cure exists for C3G, treatment primarily focuses on supporting kidney function and suppressing the immune system.

Emerging therapies aim to target the proteins responsible for disease activity, deviating from existing approaches that primarily manage symptoms.

C3G develops due to an overactive immune system and changes in genes responsible for managing the complement system. An imbalance in these genes leads to excess C3 protein, which, in turn, leads to protein deposits in the kidney affecting the glomeruli—blood vessels responsible for filtering waste from the blood. The consequent damage to the glomeruli hinders the kidneys' ability to filter toxins effectively.

Apart from genetic changes, most individuals with C3G also carry antibodies that impair the complement system's regular function. Although experts believe there are genetic links between family members with the condition, they don't consider the genetic changes in C3G to be strictly inherited.

Current treatments for C3G cannot reverse or prevent the condition; their goal is to slow down kidney damage. Clinical guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) organization suggest supportive interventions to help slow and prevent kidney damage. As kidney function declines, the guidelines recommend immunosuppressive therapies.

ACE inhibitors and ARBs, medications typically used to lower blood pressure and prevent protein leakage, can also help manage C3G. Immunosuppressive medications, such as mycophenolate mofetil (MMF) and glucocorticoids, may also be prescribed once an individual has experienced declining kidney function for at least six months.

Complement inhibitors are considered a treatment option to slow down kidney damage. These medications stop complement system activity, potentially offering broader inhibition than terminal complement inhibitors. A doctor may suggest these medications to treat C3G if immunosuppressant medications are ineffective.

Individuals with C3G might benefit from specific dietary changes, such as reducing sodium, potassium, and phosphorus intake, while maintaining a balanced protein and healthy fat consumption. Fluid intake should also be carefully managed. Some individuals prefer working with a dietitian to create a diet plan that supports kidney health while ensuring adequate nutrition.

Researchers are currently investigating several emerging treatments for C3G that target different parts of the complement system. These treatments aim to interrupt the series of events that lead to the activation or breakdown of C3 or other proteins, with the goal of preventing the damage C3G causes to the kidneys. Some promising therapies include iptacopan, pegcetacoplan, avacopan, and others currently in various stages of clinical trials.

In March 2025, the U.S. FDA approved iptacopan for treating proteinuria in C3G. Iptacopan, an oral complement inhibitor, binds complement factor B (CFB), inhibiting the activation of the alternative complement pathway at an upstream level. This action blocks both C3 and C5 convertases, central to the pathogenesis of C3G.

Pegcetacoplan, another proximal complement inhibitor, targets C3. Its broader inhibition could offer advantages over terminal complement inhibitors. Avacopan, a C5a receptor antagonist, has shownefficacy in maintaining remission in native kidney C3G in isolated reports, but results in recurrent C3G after transplantation have been mixed.

A key clinical study, the APPEAR-C3G Trial, is evaluating new treatments for C3G, with a focus on aligning with regulatory standards and patient-led treatment progress. The results of this trial could significantly influence future therapeutic protocols for C3G.

In summary, recent advancements in C3G treatment focus on oral and injectable complement inhibitors that act upstream in the complement cascade, such as iptacopan and pegcetacoplan. These agents offer new avenues for disease control and potentially lower the risk of recurrence, especially in transplant recipients. The recent FDA approval of iptacopan marks a significant milestone in C3G therapy.

1. The rare kidney condition C3 Glomerulopathy (C3G) reveals protein deposits in the kidney's filtering tissues due to impaired kidney function and potential kidney failure.
2. No cure exists for C3G, but treatments focus on supporting kidney function and suppressing the immune system.
3. Emerging therapies aim to target the proteins responsible for disease activity, deviating from existing symptom-management approaches.
4. C3G develops due to an overactive immune system and changes in genes responsible for managing the complement system.
5. Most individuals with C3G also carry antibodies that impair the complement system's regular function.
6. Even though genetic links are known between family members with the condition, genetic changes in C3G are not strictly inherited.
7. Current treatments for C3G cannot reverse or prevent the condition; they aim to slow down kidney damage.
8. Clinical guidelines suggest supportive interventions, including dietary changes like reducing sodium, potassium, and phosphorus intake.
9. Researchers are investigating several emerging treatments for C3G, focusing on interrupting the series of events that lead to protein activation or breakdown.
10. Some promising therapeutic approaches include iptacopan, pegcetacoplan, and avacopan, currently in various stages of clinical trials.
11. In March 2025, the U.S. FDA approved iptacopan for treating proteinuria in C3G.
12. Pegcetacoplan offers broader inhibition over terminal complement inhibitors, and avacopan has shown mixed results for recurrent C3G after transplantation.
13. The APPEAR-C3G Trial is evaluating new treatments for C3G, with a focus on aligning with regulatory standards and patient-led treatment progress.
14. The recent FDA approval of iptacopan signifies a significant milestone in C3G therapy, while oral and injectable complement inhibitors develop as promising new avenues for disease control.
15. The results of the APPEAR-C3G Trial could significantly influence future therapeutic protocols for C3G, contributing to advancements in health-and-wellness, fitness-and-exercise, and mental-health services for affected individuals.

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