Sayna Norouzi @SaynaNorouzi – @saynanorouzi.bsky.social

Sayna Norouzi is an associate professor of Medicine and clinical nephrologist at Loma Linda University Medical Center and completed her fellowship at Baylor College of Medicine in Houston, TX. She is the founder and director of the glomerular diseases clinic at Loma Linda and serves as the director of the online GlomCon Glomerular Diseases fellowship program. She is also the founder and director of Polycystic Kidney Disease clinic. She has been recognized as the educator of the year for two consecutive years and is a member of the Alpha Omega Alpha medical honor society. Dr. Norouzi focuses on glomerular diseases and polycystic kidney diseases, actively participating in various research projects and clinical trials.

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Saloni Gupta

Saloni Gupta is a second-year Nephrology fellow at Loma Linda University Medical Center. She completed her Internal Medicine residency at Arrowhead Regional Medical Center, CA. She has served as chief Nephrology fellow at LLUMC and is a member of the Gold Humanism Honors Society. Dr. Gupta’s interests include home dialysis and cardiovascular-kidney-metabolic syndrome, with a focus on medical education and improving healthcare disparities.

The remaining competitors, our Left and Right Kidneys:

Team B-cell Modulators

Copyright: Ana Aguirre Perez/ Shutterstock

vs 

Team C3G Treatment

Copyright: Wollertz/ Shutterstock

If NephMadness has taught us anything, it’s that the kidneys love drama– but C3G brings a particular complement-fueled plot twist. Once considered an obscure corner of membranoproliferative glomerulonephritis, C3G has rebranded itself with molecular flair, reminding us that sometimes the most intriguing stories happen at the level of dysregulated proteins rather than under the light microscope. This is a disease where pathophysiology steals the spotlight, genetics whispers from backstage, and therapeutics are just starting to figure out their lives. 

As we know, C3G is a rare histopathologic pattern of disease rather than an individual disease entity, which is driven by activation of the alternate complement pathway; its incidence is approximately 0.2-2 cases per million people annually making diagnosis and treatment extremely difficult. Until now, treatment for C3G has consisted of immunosuppression such as steroids and mycophenolate mofetil, which are both nonspecific and untargeted. KDIGO guidelines recommended using these for at least six months in those with worsening renal function or proteinuria. Treatment with these agents has led to high recurrence/relapse rates as well as a class of patients being labeled as “non-responders.” Other agents include Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for blood pressure control and proteinuria reduction.  

Some off-label use has been demonstrated with terminal complement inhibitors like Eculizumab and Ravulizumab, which were administered as infusions however their efficacy and long-term benefits are still undetermined. While limited studies showed benefits in renal function stabilization and proteinuria reduction, recurrence after discontinuation occurred in several patients. Other patients showed limited response as well, and while it may help select C3G patients, these medications are not FDA approved, nor do they address the underlying cause of complement dysregulation in C3G.  

Enter Iptacopan and Pegcetacoplan, the recently FDA-approved and the long-awaited specialists who finally RSVP’d to the right pathway. By directly targeting the alternative complement cascade- C3G’s main troublemaker- these therapies shift us from damage control to disease interception. It’s not just a new treatment; it’s a total upgrade, where we’re no longer guessing- we’re aiming!  

Pegcetacoplan (PEG), a subcutaneous infusion, is a C3/C3b inhibitor which directly inhibits C3 overactivation by targeting the central components of the complement pathway, thus preventing deposition of C3 breakdown products into the glomeruli. Early phase 2 data demonstrated a 50-65% reduction in proteinuria, normalization of serum albumin levels, and a stable eGFR over 48 weeks. It also showed biochemical evidence of complement suppression. The phase 3, VALIANT trial supported these findings, showing ~67-68% proteinuria reduction versus placebo by 26 weeks in as early as 4 weeks, as well as histologic clearance of glomerular C3 deposits in most patients. One-year-follow-up data continued to show sustained proteinuria reduction, while up to one-third of patients achieved complete remission. This trial was especially captivating because it also included adolescents (≥12 yrs) and adults with native or post-transplant recurrent C3G or primary IC-MPGN; this is the first ever Phase 3 trial to investigate the use of this medication in such populations. VALIANT also included those previously on Mycophenolate and/or prednisone (less than or equal to 20 mg/day). Pegcetacoplan received its FDA approval for C3G use on July 28, 2025.  

Iptacopan, an oral, upstream complement inhibitor that targets factor B to selectively inhibit the alternative pathway, has also shown compelling results. Phase 2 studies demonstrated significant proteinuria reduction, improvements in complement biomarkers, and reductions in C3 deposition in the kidneys, noted on repeat biopsies. Phase 3 APPEAR-C3G data found ~35% placebo-adjusted reduction in proteinuria at 6 months, with effects that were sustained at 12 months. Improved eGFR slopes were also seen compared to prior decline, suggesting a potential delay in progression to kidney failure. Adults (age 18-60) with biopsy proven C3G were treated with twice daily tablets of Iptacopan versus placebo. Those with prior organ transplant were excluded from the trial. Participants in both trials received maximally tolerated supportive therapy including ACEi/ARBs, SGLT2 inhibitors and background immunosuppression was continued if already in use (Prednisone or MMF). Iptacopan received its FDA approval for C3G on March 20, 2025.  

With these types of targeted therapies, we have gone from shuddering at pathogenesis to actively intercepting it. This is the ultimate plot twist. And every nephrologist should care because C3G is the prototype for where the field is headed: mechanism-driven diagnosis, biomarker-guided care, and therapies that actually make pathophysiologic sense. Some key factors to keep in mind however, as with any new breakthrough, are the limitations and uncertainties that arise as well. For example, although patients now have daily oral tablet versus weekly injection alternatives, treatment duration for both remains unclear. Can we stop the medication, and if so, when is it safe to do so? This is a very important question and still requires further data. The trials also show histologic clearance of C3; however, we do not know how this correlates to disease activity and what it means for monitoring. Due to this, C3G is not only a hot topic for NephMadness, but also for the growing field of nephrology. Today, it’s “rare disease nephrology” however tomorrow, it’s the blueprint for everything else. Ignore C3G’s advancements, and you just might miss the future of how we treat glomerular diseases.  

C3G is proof that when we truly understand mechanisms, we can finally change outcomes. Team C3G Treatment should win NephMadness for one simple reason: it’s the ultimate glow-up story in nephrology. In the ever-evolving bracket of nephrology, this is one contender that’s not just playing the game- it’s rewriting the rules. 

Copyright: Wollertz/ Shutterstock

– Guest Post written by Sayna Norouzi and Saloni Gupta

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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