How C3 Inhibitors Work How C3 Inhibitors Work The complement system is part of your immune system and is an essential component of your defense against infections. It consists of a group of proteins that are normally in an inactive state. Complement proteins are activated in response to some type of stimulus. For example, when you’re exposed to an infectious bacteria, these proteins will “turn on” in a chain reaction, or cascade. This contributes to your overall immune response to fight off the infection. But if complement activation is excessive, it can cause problems such as tissue damage.e60dc2a1-f33c-4a05-9b50-8e3e8e597629b961a2c8-42e9-42b6-941f-380e40d3ee52 The complement system becomes dysfunctional in both IC-MPGN and C3G. This results in a buildup of deposits in the kidneys’ filtering system, called the glomeruli. C3G causes complement proteins to break down, including one called C3. The protein fragments accumulate in the kidneys, leading to inflammation and damage to the glomeruli. In IC-MPGN, deposits of C3 accumulate in the glomeruli along with other protein fragments and antibodies. Together, they form “immune complexes” that damage the kidneys.e60dc2a1-f33c-4a05-9b50-8e3e8e597629a878b674-82a6-4fe2-84a7-d6e725e76b92 It remains unclear what causes the complement system to malfunction. In C3G, it’s believed that the complement system is triggered by genetic changes or antibodies that target and attack your own body’s healthy cells and tissue (autoantibodies). In IC-MPGN, complement system dysfunction is often associated with other health conditions, including autoimmune diseases like rheumatoid arthritis, certain cancer types, and chronic infections.e60dc2a1-f33c-4a05-9b50-8e3e8e59762956cf270e-e7ca-43db-92fb-5e085a8860dde60dc2a1-f33c-4a05-9b50-8e3e8e5976291685b02b-7f62-4249-87e7-23ef8c0e9c8b Complement inhibitors represent a new era for treating these diseases. Other treatments for C3G and IC-MPGN are supportive, and aimed at delaying disease progression and reducing damage to the kidneys. This includes drugs to control hypertension (high blood pressure) , steroids to reduce inflammation, and medications that suppress or calm the immune system (mycophenolate mofetil and rituximab).e60dc2a1-f33c-4a05-9b50-8e3e8e5976291014d339-9f4b-4f35-9c72-94c7d4c862fc Complement inhibitors, on the other hand, actually target the complement system, and reduce the damage caused by C3 deposits in the kidney filters. Two drugs have been approved to date, and others are currently being studied in clinical trials:e60dc2a1-f33c-4a05-9b50-8e3e8e5976296a72a158-a143-4684-a4dc-9e255be4e495 Iptacopan (Fabhalta) was approved by the FDA in March 2025 to treat C3G. It’s an oral medication that blocks one signaling pathway in the complement system, which prevents the breakdown of some C3 and disrupts the rest of the chain reaction. The clinical trial that led to its approval showed that iptacopan reduced proteinuria at both 6 and 12 months (35 and 37 percent, respectively). It also helped stabilize eGFR decline.e60dc2a1-f33c-4a05-9b50-8e3e8e597629ee6dccd4-f2d6-463e-ae68-4763373a9e8f Pegcetacoplan (Empaveli) was approved July 2025 for both C3G and IC-MPGN. It’s a twice-weekly injection that blocks all three signaling pathways in the complement system, preventing the breakdown of additional C3. FDA approval was based on a clinical trial in which patients taking pegcetacoplan saw a 68 percent reduction in proteinuria at 26 weeks compared with a placebo.e60dc2a1-f33c-4a05-9b50-8e3e8e5976294b874b4a-661e-4cde-b810-48665eacdbcb
Questions to Ask Your Nephrologist Am I a candidate for complement inhibitor therapy? How do they compare to the treatment I’m currently using? Will my insurance cover the cost? Are there any clinical trials of complement inhibitors that I could join? What risks are associated with these therapies?
Proteinuria (uPCR) and Kidney Health Proteinuria and Kidney Health The presence of protein in urine, or proteinuria , is usually a sign that your kidneys aren’t working properly. Your kidneys filter waste products from your blood and send them out of your body in urine. At the same time, they keep what your body needs, such as protein. While a small amount of protein in your urine is nothing to be alarmed over, high amounts are often a marker of kidney disease. One of the key symptoms of C3G and IC-MPGN is proteinuria.e60dc2a1-f33c-4a05-9b50-8e3e8e5976290d947bf1-77b7-4035-86df-e0c0e612b6ff A tool used to diagnose C3G and IC-MPGN is the urine protein creatinine ratio (uPCR) test. Creatinine is a waste product that comes from muscles. It’s eventually filtered out by your kidneys and excreted in urine. The uPCR compares levels of protein in your urine with levels of creatinine to estimate how much protein is lost over a period of time. A test result higher than the normal range may indicate kidney disease.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e7f12364-dff5-46c2-a9a7-d2463b6ecb22 “Protein in the urine actively drives progressive kidney injury through multiple pathways that cause direct injury to the kidney tubules, kidney inflammation and fibrosis, and irreversible kidney scarring,” says Emilia Maria C. Cadiz, DO , a pediatric nephrologist at Phoenix Children’s Hospital. “Increased protein in the urine overwhelms the kidney tubule’s normal capacity to reabsorb protein and leads to accumulation in the kidney tubule cells. This will trigger pathways that result in overall damage to the kidney tissue.” Dr. Cadiz explains that once kidney cells are injured by protein overload and inflammation, they may self-destruct in a process called apoptosis. Another outcome is that the injured cells will transform into other types of cells, replacing normal kidney tissue with scar tissue. The severity of kidney damage is measured by the estimated glomerular filtration rate (eGFR). The eGFR is a blood test that measures how well your kidneys are filtering out waste from your blood.e60dc2a1-f33c-4a05-9b50-8e3e8e59762901ef694e-3c24-428f-aecd-ce6084c0522f “Protein in the urine directly causes damage to kidney tissue,” says Cadiz. “Lowering protein levels in the urine is imperative to treating kidney disease and this directly translates into protecting the kidneys by preserving kidney tissue.”
Can We Avoid Dialysis? Long-Term Prognosis Long-Term Prognosis While many things influence the prognosis of C3G and IC-MPGN, a large percentage of patients will be unable to stop disease progression, and even after a transplant, the disease can recur and damage the new kidney.e60dc2a1-f33c-4a05-9b50-8e3e8e59762901165999-4008-47aa-bed0-5c4edb3c307a Unlike other treatments, complement inhibitors are designed to block the overactivation of the complement system. Rather than only managing symptoms, these agents can potentially modify the course of the disease. But these therapies are still very new, and it’s impossible to know if they represent a cure. “It is too early to tell, as pegcetacoplan is only approved by the FDA to reduce proteinuria,” says Dr. Richards. “True data on preservation of GFR will be known after two years of data is accrued. However, the VALIANT trial did show benefits in patients who were rebiopsied, as 74 percent noted a reduction in C3 at week 26 compared with just 12 percent of the patients in the placebo arm. This could suggest long term benefits with pegcetacoplan.” Rossana Malatesta Muncher, MD , a pediatric nephrologist and an assistant professor at Baylor College of Medicine in Houston, notes that proteinuria is well documented to correlate with kidney failure progression regardless of the cause of kidney disease. “In C3G, proteinuria is caused by the disease process and later by chronic changes in the kidneys,” she says. “Pegcetacoplan has been shown to significantly decrease this proteinuria. Otherwise, I think it’s too soon to tell if this therapy will be curative or a long-term stabilization strategy.” Cadiz says complement inhibitors “represent the start of something very exciting” in C3G and IC-MPGN treatment. “So although not a ‘cure’ per se, since stopping the medication may result in increased proteinuria and the generation of the toxic environment leading to inflammation and kidney scarring, these therapies allow us to offer something to patients that has been proven to lower protein levels in the urine,” she says. “Hopefully we can prevent further progression of kidney disease to [kidney failure], requiring dialysis and transplant.”
C3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare and progressive kidney diseases that often lead to kidney failure. Both involve overactivity in the part of your immune system called the complement system, which leads to inflammation and damage to the kidneys’ ability to filter the blood.e60dc2a1-f33c-4a05-9b50-8e3e8e5976295c62f791-d6f6-4b3a-93f9-da3221338a5a Although many things can affect your individual prognosis, about half of all patients will reach kidney failure within 10 years of their diagnosis and need dialysis or a kidney transplant. Even after a transplant, the risk of disease recurrence is high.e60dc2a1-f33c-4a05-9b50-8e3e8e597629ace43cf1-d0f5-47dd-9ff8-f46bdc754846 “There is no true standard of care because until recently, there were no approved agents for these conditions,” says Marc Richards, MD , a nephrologist and the director of the Florida Kidney Physicians Glomerulonephritis Center of Excellence in Boca Raton. “In C3G, options ranged from conservative therapy to attempts at immunosuppression with mycophenolate, steroids, or monoclonal antibodies such as eculizumab. Typically, treatment of IC-MPGN focused on managing the underlying condition that caused this disease.” A new class of drugs known as complement inhibitors, or complement-targeting therapies, is now emerging. These drugs target the root cause of the conditions by inhibiting or calming the overactive complement system. Two drugs have received approval by the U.S. Food and Drug Administration (FDA) and others are being studied in clinical trials.e60dc2a1-f33c-4a05-9b50-8e3e8e5976292cdebb2a-6102-4848-ac09-b1ad632a4e00 These new treatments have the potential to rewrite the long-term prognosis for these rare diseases.
Resources We Trust Cleveland Clinic: Complement 3 Glomerulopathy (C3G)Mayo Clinic: If You’ve Been Diagnosed With C3G, Here’s What to Know About Tracking Your SymptomsEuropean Rare Kidney Disease Reference Network: C3 Glomerulonephritis & IC-MPGNNational Organization for Rare Diseases: C3 GlomerulopathyNational Kidney Foundation: 6 New Kidney Disease Medications Approved in 2025
The Takeaway Complement-targeting therapies could change the long-term prognosis of C3G and IC-MPGN. Unlike other therapies used to treat these conditions, complement inhibitors target the root cause by inhibiting or calming the overactive complement system. Instead of managing symptoms only, complement inhibitors have the potential to modify the course of the disease. It’s important to be proactive in monitoring your health and progress, and keep track of trends in your lab results.
Monitor Your Progress and Advocate for Care Monitoring Your Progress It’s important to take a proactive role in monitoring your health and progress, especially since C3G and IC-MPGN can be “silent” conditions. This means that you may not have any obvious symptoms even if your kidney function is declining. Here’s what you can do.e60dc2a1-f33c-4a05-9b50-8e3e8e597629806f1a2f-8128-4b6e-95b8-90c651b769d2e60dc2a1-f33c-4a05-9b50-8e3e8e5976291d21669f-6bef-4396-be24-a40a3e5d179a Monitor key metrics. This includes your blood pressure, weight (weight gain may be due to fluid buildup), and urine output. Track lab tests. Watch for trends in the results of your routine lab tests, including eGFR (checks how well kidneys are removing waste) and uPCR (checks protein levels). Note your symptoms. Pay attention to how you feel and discuss any new symptoms with your doctor. Monitor medication side effects. All medications have potential side effects; write down anything you’re experiencing to discuss with your doctor.
C3G/IC-MPGN Progression: Can New C3 Inhibitors Stop the Path to Dialysis?
