Sayna Norouzi, MD, is an assistant professor of medicine and clinical nephrologist at Loma Linda University Medical Center

Sayna Norouzi, MD

New Therapeutic Options Raise More Questions for IgA Nephropathy Treatment, With Sayna Norouzi, MD

Evidence shows a continually and rapidly expanding therapeutic landscape for patients with IgA nephropathy (IgAN). Due to the heterogeneity of the disease, clinicians remain undecided about how to approach these options with the IgAN’s complex, individualized presentation.

“It's getting more and more complicated with having more options out there, and we still have ongoing clinical trials, and we recruit for these trials as well. We have to keep in mind that we don't have a cure for IgAN yet, and we're not done with this field,” Norouzi siad. “I think the next step for a lot of our colleagues who are not spending a lot of time with IgAN patients would be a referral to a glomerular disease clinic or center of excellence.”

At WCN, a plethora of data supporting positive progress in IgAN was presented. In a

, Norouzi highlighted the emergence of targeted agents, including targeted-release budesonide, endothelin receptor antagonists like sparsentan and atrasentan, complement inhibitors such as iptacopan, and newer APRIL-targeting therapies. Together, these agents provide clinicians with multiple avenues to reduce proteinuria and preserve kidney function.

“When I go back from every conference that I attend to my clinic, my patients are excited. Sometimes I share with them that I'm going to a conference, and they know when I come back, I'm going to have more data, and they might have more options for their disease. And it's not just about IgAN. We're getting more options for C3G, lupus nephritis,” she concluded. “It's an exciting time to be a nephrologist.”

Norouzi reports relevant disclosures with Calliditas, Travere, Apellis and others.

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Norouzi discussed the remaining challenges that come with having evolving treatment options and a robust patient population in IgAN.

Rethinking When and How to Treat IgA Nephropathy, With Sayna Norouzi, MD

The treatment landscape for IgA nephropathy is undergoing a profound transformation, driven by updated clinical guidelines, earlier diagnosis, and a rapidly expanding therapeutic arsenal. Where management was once largely reactive, the field is now moving toward earlier, more aggressive, and more targeted intervention aimed at altering disease trajectory.

 at World Congress of Nephrology in Yokohama, Japan, Sayna Norouzi, MD, a clinical nephrologist and associate professor of medicine at Loma Linda University Medical Center, said one of the most significant shifts between the 2021 and 2025 guidelines is the redefinition of high-risk disease.

Previously, proteinuria thresholds of around 1 gram per day were used to guide treatment escalation. Now, patients with proteinuria ≥0.5 g/day are considered at risk, representing a major change in how clinicians identify and manage disease severity. This lower threshold underscores a growing recognition that IgA nephropathy is not a benign condition and can lead to kidney failure if not addressed early.

“The sooner you diagnose these patients, [the sooner] you're going to be able to treat them, and with effective treatment of IgA nephropathy, you might be able to delay dialysis or transplant or complications in general, for your patients,” she said.

The updated guidelines also emphasize more ambitious treatment goals, with a target proteinuria level ideally < 0.3 g/day. Norouzi explains that this shift reflects mounting evidence linking lower proteinuria to improved long-term outcomes, including delayed progression to dialysis or transplant. As a result, clinicians are now encouraged to pursue tighter disease control from the outset.

Another key evolution lies in treatment strategy. Historically, care began with supportive measures like blood pressure control, lifestyle modification, and initiation of RAAS blockade, with additional therapies introduced only after inadequate response. In contrast, the 2025 guidance promotes a more proactive, simultaneous approach, and while supportive care remains foundational, clinicians are now urged to initiate therapies targeting the underlying pathophysiology earlier in the disease course rather than waiting for treatment failure.

This paradigm shift is enabled by a growing list of therapeutic options. Norouzi highlights the emergence of targeted agents, including targeted-release budesonide, endothelin receptor antagonists like sparsentan and atrasentan, complement inhibitors such as iptacopan, and newer APRIL-targeting therapies. Together, these agents provide clinicians with multiple avenues to reduce proteinuria and preserve kidney function.

Despite this progress, she says important questions remain. Norouzi notes that clinical trials provide only a limited snapshot of efficacy and safety, often over relatively short durations. As these therapies enter real-world practice, she says clinicians will need to better understand long-term tolerability, optimal sequencing, and effectiveness in more heterogeneous patient populations.

“We need more data on these medications, on the safety, on how they are going to work over time. The clinical trials are looking at a limited amount of time. They follow patients for 9 months for the initial outcome data, and then they follow patients for 2 years,” Norouzi said. “Once the medication is FDA approved and it's on the market, that's when we are going to have more information and see in real life if patients are tolerating the medications. We're going to hear more about the side effects, how to monitor these patients over time, and if they are responding well to the medications as well.”

Brooks A. KDIGO Releases Updated IgA Nephropathy, IgA Vasculitis Clinical Practice Guideline. HCPLive. September 18, 2025. Accessed March 28, 2026. 

https://www.hcplive.com/view/kdigo-releases-updated-iga-nephropathy-iga-vasculitis-clinical-practice-guideline

Campbell P. Iptacopan Receives Accelerated Approval for Reducing Proteinuria in IgA Nephropathy. August 7, 2024. Accessed April 1, 2026. 

https://www.hcplive.com/view/iptacopan-receives-accelerated-approval-for-reducing-proteinuria-in-iga-nephropathy

Campbell P. Atrasentan (Vanrafia) Receives Accelerated Approval in IgA Nephropathy. April 2, 2025. Accessed April 1, 2026. 

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

New IgAN guidelines emphasize earlier diagnosis, lower proteinuria targets, and combination therapy to delay kidney failure and improve long-term outcomes.

Complement Inhibitors Reshape Treatment Landscape for C3 Glomerulopathy, With Sayna Norouzi

As complement-targeted therapies have entered the treatment landscape for 

, investigators suggest these agents hold the potential to modify the disease and may ultimately shift kidney failure from an expected outcome to a more “remote prospect” for patients.

“For years and years, we didn’t have any FDA-approved medications for these patients,” said Sayna Norouzi, MD, clinical nephrologist and associate professor of medicine at Loma Linda University Medical Center. “Now we have two newly approved options, and it feels really good when a patient comes in, and we can actually discuss treatments and make a shared decision about what might work best for them.”

The first complement therapeutic used for C3G was eculizumab, a monoclonal antibody against C5, and is currently used off-label in native and transplanted kidneys. According to the report, evidence suggested ecuizumab is most effective when initiated before evidence of terminal pathway activation and before significant sclerotic changes develop.

Other complement inhibitors have been evaluated but have not demonstrated meaningful clinical benefit in C3G.

Avacopan, an oral small-molecule C5a receptor antagonist, did not show a significant improvement in the primary endpoint—the percentage change in the histologic index of disease activity from baseline to week 26—in the phase 2 ACCOLADE trial.

Similarly, danicopan, a factor D inhibitor evaluated in the phase 2 ACH471-204 trial, produced only partial inhibition of the alternative complement pathway. Investigators reported the therapy did not reach systemic concentrations sufficient for sustained pathway blockade, resulting in limited clinical response.

More recently, complement-targeted therapies have achieved regulatory approval for C3G. The 

approved iptacopan (Fabhalta) based on data from APPEAR-C3G. The primary efficacy endpoint evaluated the percent change in proteinuria, measured by urine protein-to-creatinine ratio (UPCR) from a 24-hour urine collection, after 6 months of treatment. At 6 months, treatment with iptacopan resulted in a 35% reduction from baseline in 24-hour UPCR compared with placebo.

Another complement-targeted therapeutic that entered the treatment landscape for C3G in 2025 was pegcetacoplan, a peptide-based inhibitor of C3 and C3b, which the FDA approved in July. In an 

, pegcetacoplan maintained a 70% reduction in proteinuria over 52 weeks in adolescents with C3G and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), with many patients achieving remission (≤0.5 g/g) or normalization (≤0.2 g/g).

Norouzi also emphasized the importance of monitoring safety risks associated with complement inhibition.

“Any medication that works on the complement system can increase the chance of encapsulated infections, including meningococcal infections. They’re rare, but if they happen, they can be deadly, so vaccination and careful monitoring are really important for these patients.”

Editor’s Note: Norouzi reports relevant disclosures with Calliditas, Travere, Apellis and others.

Mashayekhi M, Zuckerman JE, Barratt J, et al. C3 Glomerulopathy Diagnosis, Current Treatments, and Emerging Therapies. 

https://doi.org/10.1016/j.xkme.2026.101258

U.S. Food and Drug Administration. FDA approves first treatment for adults with complement 3 glomerulopathy, a rare kidney disease, to reduce proteinuria. U.S. Food and Drug Administration. Published 2025. 

https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-adults-complement-3-glomerulopathy-rare-kidney-disease-reduce

FDA-approved iptacopan and pegcetacoplan offer new complement-targeted therapies for C3 glomerulopathy.

Deep Diving into the Pathogenesis of C3 Glomerulopathy, With Sayna Norouzi

 is increasingly understood not as a single disease entity but as a histopathologic pattern of kidney injury driven by dysregulation of the alternative pathway of the complement system.

Although rare, new insights into complement dysregulation are reshaping its diagnostic and therapeutic framework, according to this recently published review.

“So I think the rarity of the disease is something that affects both sides,” said Sayna Norouzi, MD, clinical nephrologist and associate professor of medicine at Loma Linda University Medical Center. “A lot of physicians might not be comfortable treating C3G because they've never seen a patient before, and they don't feel comfortable starting treatment for these patients.”

With an estimated incidence of 0.2–2 cases per million people annually, C3G remains ultrarare and diagnostically challenging. Patients commonly present with proteinuria, hematuria, and progressive kidney function decline—features that overlap with other glomerular diseases. As a result, accurate diagnosis increasingly depends on understanding the underlying complement-mediated mechanism driving injury.

The complement system can be activated through 3 pathways: classical, lectin, and alternative. The classical pathway is triggered by antigen–antibody complexes, while the lectin pathway is activated by carbohydrate patterns on microbial surfaces. The alternative pathway is distinct in its ability to activate spontaneously through continuous low-level hydrolysis of C3, a process known as “C3 tick-over,” which generates C3a and C3b fragments.

Once initiated, the alternative pathway undergoes amplification through an enzymatic loop in which C3b binds factor B and is cleaved by factor D, forming the alternative pathway C3 convertase. This complex drives further C3 cleavage, creating a powerful amplification system. Under normal physiologic conditions, regulatory proteins, including complement factor H, complement factor I, and membrane cofactor protein (CD46), control this process by inactivating C3b and limiting C3 convertase activity to prevent host tissue injury.

Both genetic and acquired abnormalities contribute to dysregulation of the alternative pathway. Genetic variants have been identified in approximately 25%–40% of patients and affect complement components such as C3 and factor B, as well as regulatory proteins including factor H, factor I, complement factor H-related protein 5, and membrane cofactor protein. Acquired drivers, including autoantibodies stabilizing C3 convertase, may further amplify complement activation.

The downstream effect is uncontrolled alternative pathway activity, excessive C3 convertase formation, and dominant C3 deposition within the glomeruli, which has been described as the defining histopathologic feature of C3G.

According to investigators, the kidney appears particularly vulnerable to this dysregulation. The glomerular basement membrane lacks membrane-bound complement regulators and relies heavily on circulating regulators such as factor H for protection.

When this regulation fails, persistent complement activation generates proinflammatory mediators, including C3a and C5a, promotes opsonization through C3b, and culminates in the formation of the terminal membrane attack complex (C5b-9), ultimately driving glomerular cell injury and progressive renal dysfunction.

As understanding of these mechanisms deepens, clinicians are increasingly able to connect histopathology with molecular drivers of disease. For Norouzi and others in the field, this evolving insight represents more than scientific progress; it may help reduce diagnostic uncertainty and increase clinician confidence in managing a condition that, while rare, carries significant morbidity.

Editor's Note: Norouzi reports relevant disclosures with Calliditas, Travere, Apellis, and others.

Mashayekhi M, Zuckerman JE, Barratt J, et al. C3 Glomerulopathy Diagnosis, Current Treatments, and Emerging Therapies. Kidney Medicine. 2026;8(3):101258. doi:

Gashu Ayehu, Atari M, Hassanein M, Jhaveri KD. C3 Glomerulopathy. Nih.gov. Published November 5, 2024. 

https://www.ncbi.nlm.nih.gov/books/NBK609090/

Norouzi discusses a recent review where 11 clinicians described C3G pathology and diagnosis.  

Sayna Norouzi, MD

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