Sayna Norouzi, 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

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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

The Evolving IgAN Treatment Landscape and Advances in FSGS, with Sayna Norouzi, MD

focal segmental glomerulosclerosis (FSGS)

 and their nephrologists have faced a frustrating reality: the absence of FDA-approved therapies. Instead, treatment largely relied on supportive measures, non-specific immunosuppression, and off-label approaches, with limited ability to alter the long-term risk of kidney failure.

Now, the landscape is beginning to shift, with recent FDA approvals and promising developments ushering in a new era of hope for patients and providers managing these glomerular diseases.

, Sayna Norouzi, MD, an assistant professor of medicine, clinical nephrologist, and founder and director of the glomerular disease and polycystic kidney disease clinics at Loma Linda University Medical Center, explains how for many years, providers were diagnosing patients with IgAN but had limited options to offer them in the way of treatment.

“We never had an FDA-approved medication out there to say ‘Hey, let's sit down and let's talk about your options,’ or to talk with patients about what medications we could start them on today that could hopefully prevent dialysis in the future,” Norouzi said. “Then, all of a sudden, we started receiving a lot of good news about the IgA nephropathy landscape.”

Specifically, she cites the FDA approvals of delayed budesonide (Tarpeyo), sparsentan (Filspari), and iptacopan (Fabhalta), describing the impact the availability of these medications has had on patient care and the emergence of conversations about combination therapy in light of now having multiple treatment options to offer patients. Additionally, she points to the need for further research on the long-term impacts of these medications.

Although FSGS does not yet have any FDA-approved therapies, Norouzi expresses optimism that one might be on the way following Travere Therapeutics’ submission of a supplemental New Drug Application for sparsentan.

“I think every nephrologist out there can agree with me that sometimes, at some point with treatment of FSGS, we aren’t sure what else we can do,” Norouzi explained.” We are trying different medications and they are not responding, and you see that they still have protein in the urine, and as long as you have protein in the urine, you're going to be at risk of losing your kidney function and ending up on dialysis at some point.”

She goes on to describe how the prospect of having an FDA-approved treatment to offer patients with FSGS brings her a lot of hope.

“It's such an exciting time to be a nephrologist and to be an expert on glomerular disease,” Norouzi said. “Hearing about the newly FDA-approved medications, all the clinical trials that are ongoing, and possibilities for the future and for my patients, it makes my job more interesting these days and I feel like I'm happier as a nephrologist because we have more options.”

Editors’ note: Norouzi has relevant disclosures with Calliditas, Novartis, Otsuka, and Boehringer Ingelheim.

Brooks A. Travere Therapeutics Submits sNDA for Sparsentan (Filspari) in FSGS. HCPLive. March 17, 2025. Accessed April 28, 2025. 

https://www.hcplive.com/view/travere-therapeutics-submits-snda-sparsentan-filspari-fsgs

Norouzi discusses recent advancements in IgAN therapeutics and looks ahead to a potential first FDA-approved FSGS treatment.

What’s New and What’s Next in Glomerular Disease Care, with Sayna Norouzi, MD

The first quarter of 2025 saw significant advancements in 

, especially for glomerular diseases, whose treatment landscape is rapidly evolving and has already seen several therapeutic milestones so far this year.

“I feel like our field is exploding,” Sayna Norouzi, MD, an assistant professor of medicine, clinical nephrologist, and founder and director of the glomerular disease and polycystic kidney disease clinics at Loma Linda University Medical Center, said to 

. “We had so many newly FDA-approved medications last year and we have 2 new medications that got approved for glomerular diseases this year as well.”

Specifically, Norouzi references the FDA approvals of atrasentan (Vanrafia) for 

 She describes how for many years, treatment options for these patients were limited. Now, when she diagnoses someone with a glomerular disease, she has options to discuss with them.

“I think the future is really bright for our patients and the nephrology community,” Norouzi said. “Nothing makes me happier when I hear about another new option for my patients.”

For many patients living with glomerular diseases, Norouzi describes how finding community, support, or even reliable information can be both challenging and isolating. Unlike more common conditions such as hypertension or diabetes—where patients can often turn to friends, family, or a well-established online community—those with rare kidney diseases often rely solely on their nephrologist for guidance and updates, especially as it pertains to the treatment options available to them.

Looking ahead, Norouzi highlights several pipeline developments she believes hold the most promise to shape the rest of 2025. For C3G, she points to pegcetacoplan, a complement inhibitor evaluated in the VALIANT trial, as another potential key player in this space.

In IgAN, she says the next wave of treatments may come from B-cell modulators, APRIL inhibitors, and dual APRIL/BAFF inhibitors, with several of these agents already showing significant reductions in proteinuria in clinical trials. Additionally, she calls attention to several complement inhibitors being studied in IgAN, suggesting this class may also hold potential for reshaping the IgAN treatment landscape.

“There are so many other mechanisms of action and other medications in ongoing clinical trials that are in earlier stages,” Norouzi said. “Hopefully in the next few years, we're going to see good results from these clinical trials, which can translate into more options for our patients in the near future.”

Campbell P. Atrasentan (Vanrafia) Receives Accelerated Approval in IgA Nephropathy. HCPLive. April 2, 2025. Accessed April 25, 2025. 

https://www.hcplive.com/view/atrasentan-vanrafia-receives-accelerated-approval-in-igan

Campbell P. FDA Approves Oral Iptacopan (Fabhalta) as First C3 Glomerulopathy Therapy. HCPLive. March 20, 2025. Accessed April 25, 2025. 

https://www.hcplive.com/view/fda-approves-oral-iptacopan-fabhalta-as-first-c3-glomerulopathy-therapy

Brooks A. FDA Accepts Pegcetacoplan (Empaveli) sNDA for C3G, IC-MPGN. HCPLive. April 1, 2025. Accessed April 25, 2025. 

https://www.hcplive.com/view/fda-accepts-pegcetacoplan-empaveli-snda-c3g-ic-mpgn

Norouzi reflects on significant advances in glomerular disease from Q1 and looks ahead to what the rest of 2025 may have to offer.

Sayna Norouzi, MD

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