Chee Kay Cheung, MBCHB, MRCP, PhD

Dr. Wadhwani asks Dr. Cheung for the rationale behind targeting the BAFF/APRIL axis. Dr. Cheung explains that both cytokines come from activated dendritic and myeloid cells in the mucosal microenvironment, where B-cell priming takes place, and that they drive production of pathogenic galactose-deficient IgA1. BAFF supports maturation of immature B cells and class switching to IgA-producing cells. APRIL also supports class switching and acts on later-stage cells, including survival of the plasma cells that make antibody. Unlike rituximab, these agents do not broadly deplete peripheral B cells.

Targeting BAFF and APRIL in IgAN: Mechanisms and VISIONARY eGFR Data

Dr. Cheung then separates two approaches. Monoclonal antibodies, including approved sibeprenlimab and one still in trials, selectively block APRIL, which signals through BCMA on late-stage B cells. Fusion proteins such as atacicept combine a receptor with the Fc portion of IgG and suppress B-cell signaling more broadly. Dr. Wadhwani notes that Kidney Week featured a record three IgAN late-breakers in one plenary session, all on this class.

Dr. Geara reviews the VISIONARY trial of selective APRIL inhibition. Proteinuria fell about 50 percent with sibeprenlimab versus a 2.1 percent increase on placebo at nine months, and the effect was sustained through 24 months. Mean eGFR change at 24 months was 1.3 mL/min versus a loss of 7.9 with placebo. He stresses how poorly the placebo group fared, underscoring the need for therapy.

Dr. Wadhwani calls the result remarkable. Earlier phase 3 trials separated treatment from placebo but still showed negative slopes. Here the annualized slope was positive at 0.3 mL/min per year, against a placebo decline above 4, which she says gives patients and clinicians real hope.

Our next episode, "Dual BAFF/APRIL Inhibition in IgAN: ORIGIN 3 Data and Open Questions," turns to the ORIGIN 3 results for dual inhibition and what the panel still wants to learn about durability.

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Cytokines produced in mucosal tissue drive pathogenic IgA, which makes BAFF and APRIL logical targets. VISIONARY data on selective APRIL inhibition showed a positive eGFR slope, a first in a phase 3 IgAN trial.

Dr. Geara explains that the major change in the 2025 KDIGO guidelines is simultaneous treatment of the IgA pathway and supportive care. In his clinic, patients now start targeted therapy and supportive care together from the outset. The guidelines also give him leverage with insurers and reassure patients that they receive the current standard of care. Choosing an agent from each pathway is harder, and he emphasizes an individual approach based on risk factors, demographic profile, and each drug's adverse effects.

2025 KDIGO Guidelines in IgAN: Treatment Selection and Overcoming Inertia

Dr. Cheung names access as the key barrier, then points to familiarity with immune-targeting therapies and the need to educate patients and colleagues about monitoring. Treatment inertia persists in the UK, partly from a perception that IgAN progresses slowly. Registry data from the UK, US, Europe, and Asia show otherwise, and Dr. Cheung urges earlier diagnosis. Dr. Wadhwani adds that time of diagnosis is not time of onset, and many patients have already lost half their kidney function.

For selection, Dr. Geara says all six approved agents reduce proteinuria and separate from placebo on eGFR, though the degree differs. He credits sibeprenlimab and atacicept with the most durable eGFR stability, sparsentan with strong proteinuria effects, and targeted-release budesonide with less suppression. Complement inhibitors act quickly on inflammation.

He favors an APRIL or BAFF/APRIL agent for maintenance. For a highly inflammatory presentation, he might start a complement inhibitor and transition later. Dr. Wadhwani adds that patient preferences matter, including willingness to inject, accept immunosuppression, or take steroids again. Dr. Wadhwani agrees that the expanding menu of options is a welcome challenge, but one that demands an individualized conversation with each patient.

The next episode in this series, "Targeting BAFF and APRIL in IgAN: Mechanisms and VISIONARY eGFR Data," features Dr. Cheung explaining the rationale for B-cell modulation, followed by Dr. Geara's read of the VISIONARY results.

The 2025 KDIGO guidelines endorse treating both the IgA pathway and supportive care from the start. Dr. Geara and Dr. Cheung discuss treatment inertia, early diagnosis, and matching each agent to patient risk and preferences.

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.

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.

Chee Kay Cheung, MBCHB, MRCP, PhD

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