Abdallah Geara, MD, is an Associate Professor of Clinical Medicine at the University of Pennsylvania.

Abdallah Geara, MD

Dr. Wadhwani asks Dr. Cheung how each available drug class targets a different point in the multi-hit pathogenesis of IgAN, and how that thinking guides where each therapy belongs. Dr. Cheung begins with drugs that reduce production of pathogenic IgA and immune complexes. Targeted-release budesonide was the first approved. It is designed to release its maximum dose in the terminal ileum, where Peyer's patches prime the B cells that make pathogenic IgA. Much of it is metabolized in the liver, limiting systemic exposure.

IgAN Pathogenesis: How Each Drug Class Targets the Multi-Hit Pathway

Next come APRIL and BAFF inhibitors, which act on B-cell maturation and class switching to IgA-producing cells, as well as the plasma cells and plasmablasts that secrete antibody. Dr. Cheung notes lots of data on this class at Kidney Week. Agents still in development include anti-CD38 therapies that target plasma cells, along with approaches that aim to degrade galactose-deficient IgA1 and IgA itself.

Complement inhibitors act mainly on glomerular inflammation, although some data suggest effects on tubulointerstitial inflammation and fibrosis. They work at different levels of the cascade. More proximal agents, including an antisense oligonucleotide in a clinical trial, contrast with terminal pathway blockers. On the other side of the algorithm are kidney-protective drugs that manage the general response to nephron loss. These include familiar agents used across chronic kidney disease and newer options that may add anti-inflammatory effects.

Dr. Wadhwani calls this a good problem to have compared with six to ten years ago, when clinicians had mainly RAS inhibitors and corticosteroids. She notes that some regions still rely on lower-dose corticosteroids, while the new armamentarium offers greater efficacy and a better safety profile.

In "2025 KDIGO Guidelines in IgAN: Treatment Selection and Overcoming Inertia," the panel will turn to the 2025 KDIGO framework and how Dr. Geara and Dr. Cheung choose among six targeted therapies.

Videos

IgAN arises through a multi-hit process, and each therapeutic class acts at a different step. Dr. Cheung maps mucosal B-cell priming, plasma cells, complement, and kidney-protective therapies onto the pathway.

Dr. Wadhwani asks Dr. Geara whether optimized supportive care can be sufficient. Dr. Geara explains that earlier guidelines treated supportive care first and added IgA-directed therapy later, but current guidelines recommend addressing both at the same time. Supportive care remains important, and its umbrella keeps growing. Still, he stresses that IgAN is an inflammatory disease, so few patients should rely on supportive care alone. Only a patient with well-documented stability over several years might qualify.

IgAN Treatment Escalation: Beyond Supportive Care and Access Barriers

Dr. Cheung agrees that most patients benefit from added targeted therapy, with supportive care continued in the background, because these classes have shown better eGFR preservation. Dr. Cheung and Dr. Wadhwani highlight residual proteinuria as a concern for both renal and cardiovascular risk. Dr. Cheung says the KDIGO targets once seemed unrealistic but now look well within reach. The approach is to start effective therapy early, monitor frequently, and switch when response is insufficient. Dr. Wadhwani adds that data shown at Kidney Week suggest even the eGFR target is achievable.

On real-world challenges, Dr. Geara describes six approved therapies in the United States but uneven access, since most require insurance approval and are expensive. He adds that proteinuria and eGFR have shortcomings for assessing activity and response, and neither tells clinicians which drug to give or for how long. Dr. Wadhwani notes that no approved agent was compared head to head, populations differed, and baseline SGLT2 inhibitor use varied. Approval does not guarantee access.

Up next, in "IgAN Pathogenesis: How Each Drug Class Targets the Multi-Hit Pathway," Dr. Cheung maps each therapeutic class onto the points in the pathway where IgAN disease activity arises.

Guidelines now call for treating the immune driver of disease and providing supportive care at the same time. The panel considers how ambitious targets have become realistic, and why access still limits what clinicians can offer.

Welcome back to another HCPLive Peer Exchange series. In "IgAN Progression Risk: Proteinuria, eGFR Decline, and the Role of Hematuria," moderator Shikha Wadhwani, MD, MS, FASN is joined by Chee Kay Cheung, MBChB, MRCP, PhD, FHEA and Abdallah S. Geara, MD to open the series on IgA nephropathy.  Dr. Wadhwani welcomes viewers, introduces the panel, and previews the discussion before asking Dr. Geara how much risk of kidney failure remains despite recent therapeutic advances. Dr. Geara describes IgAN as a progressive chronic kidney disease that leads to dialysis in the majority of patients. He notes that the disease affects every race and ethnicity, although patients of East Asian ancestry tend to present younger with more progressive disease. Age at onset and eGFR at presentation are additional risk markers. Dr. Cheung adds that proteinuria and eGFR decline are the two key variables, with proteinuria standing out as the main modifiable risk factor. Dr. Cheung cites the recent KDIGO guidance, which targets proteinuria below 0.5 grams per day and an eGFR decline under 1 mL/min per year, matching physiologic aging.  Dr. Wadhwani recalls that a goal of less than 1 gram per day once seemed sufficient, and that registry data, including the UK RADAR registry, have changed that thinking. Dr. Cheung explains that proteinuria can be measured accurately in clinic, whereas eGFR trajectory needs many data points over a longer period, so early proteinuria response guides judgment about a new treatment. The panel then debates hematuria. Dr. Cheung considers proteinuria and eGFR decline far better validated, notes that isolated hematuria with stable function carries a good outlook, and observes that therapies can now reduce hematuria. Dr. Geara agrees that hematuria is not uniform across patients. He treats its disappearance on targeted therapy, and its return after stopping, as a sign of recurring inflammation, interpreted patient by patient.  The next episode in this series, "IgAN Treatment Escalation: Beyond Supportive Care and Access Barriers," features the panel weighing when supportive care alone falls short and what ambitious goals now look like.

IgAN Progression Risk: Proteinuria, eGFR Decline, and the Role of Hematuria

Welcome back to another HCPLive Peer Exchange series. In "IgAN Progression Risk: Proteinuria, eGFR Decline, and the Role of Hematuria," moderator Shikha Wadhwani, MD, MS, FASN is joined by Chee Kay Cheung, MBChB, MRCP, PhD, FHEA and Abdallah S. Geara, MD to open the series on IgA nephropathy.

Dr. Wadhwani welcomes viewers, introduces the panel, and previews the discussion before asking Dr. Geara how much risk of kidney failure remains despite recent therapeutic advances. Dr. Geara describes IgAN as a progressive chronic kidney disease that leads to dialysis in the majority of patients. He notes that the disease affects every race and ethnicity, although patients of East Asian ancestry tend to present younger with more progressive disease. Age at onset and eGFR at presentation are additional risk markers. Dr. Cheung adds that proteinuria and eGFR decline are the two key variables, with proteinuria standing out as the main modifiable risk factor. Dr. Cheung cites the recent KDIGO guidance, which targets proteinuria below 0.5 grams per day and an eGFR decline under 1 mL/min per year, matching physiologic aging.

Dr. Wadhwani recalls that a goal of less than 1 gram per day once seemed sufficient, and that registry data, including the UK RADAR registry, have changed that thinking. Dr. Cheung explains that proteinuria can be measured accurately in clinic, whereas eGFR trajectory needs many data points over a longer period, so early proteinuria response guides judgment about a new treatment. The panel then debates hematuria. Dr. Cheung considers proteinuria and eGFR decline far better validated, notes that isolated hematuria with stable function carries a good outlook, and observes that therapies can now reduce hematuria. Dr. Geara agrees that hematuria is not uniform across patients. He treats its disappearance on targeted therapy, and its return after stopping, as a sign of recurring inflammation, interpreted patient by patient.

"IgAN Treatment Escalation: Beyond Supportive Care and Access Barriers,"

features the panel weighing when supportive care alone falls short and what ambitious goals now look like.

Despite new therapies, IgAN still progresses to kidney failure in most patients. The panel reviews who is at greatest risk, which targets matter, and how hematuria fits alongside proteinuria and eGFR.

is rapidly transitioning into what clinicians described as a “mechanism-first era,” as emerging targeted therapies reshape how nephrologists approach diagnosis, risk stratification, and long-term disease management.

To commemorate IgAN Awareness Day on May 14, 2026, 

 spoke with nephrologists about key evolving concepts in IgAN, including earlier diagnosis, dynamic treatment sequencing, and unresolved questions around biomarkers and remission.

Corey Cavanaugh, DO — Cleveland Clinic nephrologist

Abdallah Geara, MD — Associate Professor of Clinical Medicine, University of Pennsylvania

Edgar Lerma, MD — Clinical Professor of Medicine, University of Illinois Chicago

“We now are in what we call a mechanism-first era,” said Edgar Lerma, MD. “We’re not in a sequencing-consensus era anymore in IgAN.”

Earlier Diagnosis Remains a Major Missed Opportunity

Despite therapeutic advances, clinicians emphasized that earlier recognition of IgAN remains one of the most important unmet needs in practice.

“The early diagnosis is, I think, the most critical,” said Corey Cavanaugh, DO. “That does not necessarily involve a new drug. It doesn’t even involve necessarily a new lab test.”

Instead, clinicians pointed to missed opportunities in routine care, particularly among younger patients presenting with microscopic hematuria, hypertension, or subtle urinary abnormalities.

“We know that 75% of patients with IgA nephropathy, when they’re biopsied, already have established CKD stage 3,” Geara said. “So early diagnosis is something we still need to work on.”

Experts also highlighted the lack of standardized screening approaches, including limited use of urinalysis in routine preventive care.

“If we can get sooner access and just basic things like urinalysis, blood pressure checks, creatinine checks in young people, we can identify a lot of this very early,” Cavanaugh added.

Risk Stratification Becomes More Dynamic and Prognostic

Clinicians described a shift away from static staging toward trajectory-based risk assessment incorporating proteinuria, eGFR slope, histology, and treatment response.

“The old model is that you have IgAN and will monitor kidney function over time,” Lerma said. “The new model is what we call an evidence-driven stratification era.”

He added that treatment response itself is now increasingly prognostic.

“How the patient responds to therapy within 12 months is becoming part of their prognosis,” Lerma said.

Proteinuria remains a central marker in clinical decision-making, despite limitations.

“The most powerful prognostic clinical indicator is proteinuria,” Cavanaugh said. “Unfortunately, it’s not a true biomarker in the sense that it tells us exactly what IgA is doing.”

A key challenge, clinicians added, is disease heterogeneity.

Expanding Treatment Options Complicate Sequencing Decisions

The IgAN treatment landscape now includes RAAS blockade, SGLT2 inhibitors, endothelin receptor antagonists, corticosteroids, targeted-release budesonide, complement inhibitors, and APRIL-directed therapies.

“The cornerstone remains ACE or ARB RAAS inhibition,” Cavanaugh said. “But endothelin receptor antagonists are the new nephron-sparing therapy that is not immunosuppression.”

He noted these agents can reduce proteinuria by approximately 50%, describing this as clinically meaningful for long-term prognosis.

Still, clinicians acknowledged there is no consensus on sequencing.

“The major question is who gets what and when,” Cavanaugh said.

“My core belief right now is nobody knows the right answer,” another clinician added. “The tools we have are inadequate to tell us exactly what to choose and when.”

Most clinicians, experts said, are still using a stepwise escalation approach rather than combination “stacking” of therapies.

Despite rapid innovation, adoption of newer therapies has been slower than expected.

Lerma outlined “five buckets” driving delayed uptake: regulatory burden, skepticism about surrogate endpoints like proteinuria, infrastructure challenges, disease heterogeneity, and physician familiarity.

“Most clinicians view reduction in proteinuria as positive,” Lerma said. “But whether it translates to preventing end-stage kidney disease still has some gray area.”

Additional barriers include prior authorization requirements, REMS programs, and monitoring demands.

“Adoption usually lags evidence by around 3 to 7 years in chronic kidney disease,” Lerma said.

APRIL Inhibition and the Future of Precision Nephrology

APRIL-targeted therapies are among the most closely watched emerging treatments, designed to reduce production of galactose-deficient IgA1 earlier in the disease pathway.

“These agents target upstream B-cell activation and reduce production of galactose-deficient IgA1,” Cavanaugh said.

Lerma added that APRIL inhibition may ultimately become a foundational therapy.

“In this moment, 2026, APRIL inhibition is not an add-on yet in standard practice, but it is a future backbone candidate,” he said.

Questions remain around dual APRIL–BAFF blockade and whether broader immunologic suppression improves outcomes or increases risk.

Despite therapeutic progress, clinicians emphasized that IgAN still lacks validated biomarkers for remission or precise response prediction.

“There’s still no definition of remission that we all agree on,” Cavanaugh said.

He added that improved therapies may ultimately force the field to define these endpoints more clearly.

“That’s the beauty of these therapies,” he said. “They force the issue of defining remission because we can actually achieve it.”

While IgAN remains incurable, clinicians expressed cautious optimism.

“There’s no cure,” Cavanaugh said. “But maybe we’re approaching that.”

Editor’s Note: Cavanaugh reports relevant disclosures with Otsuka Pharmaceutical Co, Novartis Pharmaceutical Corporation, Travere Therapeutics, and Vera Therapeutics. Abdallah reports relevant disclosures with Amgen, GlaxoSmithKline, Novartis, and others. Lerma reports disclosures with Amgen, Astra Zeneca, Calliditas, Novo Nordisk, Travere, Opko, and Otsuka

Cavanaugh C. Routine urinalysis in IgA nephropathy and young adults. 

 https://www.hcplive.com/view/routine-urinalysis-iga-nephropathy-young-adults-corey-cavanaugh

Geara A. Stratifying risk and optimizing therapy in IgA nephropathy. 

 https://www.hcplive.com/view/stratifying-risk-optimizing-therapy-iga-nephropathy-abdallah-geara-md

Articles

IgA nephropathy management is shifting to a mechanism-first paradigm as pathway-targeted agents expand beyond supportive care. Earlier recognition through urinalysis, blood pressure, and creatinine screening—particularly in young adults with microscopic hematuria—remains a major gap, with many first biopsied at CKD stage 3. Risk assessment is moving from static staging to trajectory-based prognostication using proteinuria, eGFR slope, histology, and 12‑month treatment response. Sequencing is unsettled amid more options and delayed adoption driven by regulatory, endpoint, infrastructure, and familiarity barriers. APRIL inhibition is a leading future backbone candidate.

On IgAN Awareness Day, clinicians highlight earlier diagnosis, dynamic risk stratification, and emerging targeted therapies reshaping care.