Shikha Wadhwani, MD, MS

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.

 in Denver, Colorado, cohosts Shikha Wadhwani, MD, MS, and Brendon Neuen, MBBS, PhD, welcomed Stephen Seliger, MD, of the University of Maryland School of Medicine, and Michel Chonchol, MD, of the University of Colorado Anschutz Medical Campus. The investigators discussed their pilot randomized trial of empagliflozin in autosomal dominant polycystic kidney disease (ADPKD), published simultaneously in the 

Journal of the American Society of Nephrology

Results showed the drug was safe and well tolerated, but an unexpected increase in kidney volume raised new questions for SGLT2 inhibitor research in this population.

Should SGLT2 Inhibitors Be Used in ADPKD? New Trial Data Explained

Why Test Empagliflozin in Rapidly Progressing ADPKD?

Seliger noted tolvaptan remains the only FDA-approved therapy to slow ADPKD progression in the US, but aquaretic adverse effects and a risk of liver injury limit its use. Chonchol added patients with ADPKD were excluded from the landmark SGLT2 inhibitor trials, leaving a gap the team set out to address.¹

Seliger explained risk in ADPKD is typically stratified by imaging using the Mayo classification, with classes 1C through 1E identifying rapid progressors. He clarified the FDA considers total kidney volume a likely surrogate end point, acceptable for accelerated approval only when accompanied by longer-term evidence of slower kidney function decline.

The investigators randomly assigned 50 adults aged 18 to 55 years with ADPKD at high risk of rapid progression, defined as Mayo imaging class 1C to 1E, to empagliflozin or placebo for 12 months.¹ Participants had an eGFR of 30 to 90 mL/min/1.73 m² and were not receiving tolvaptan. Seliger said concurrent tolvaptan was excluded because of concern about volume depletion.

Empagliflozin was started at 10 mg daily and increased to 25 mg after 1 month if tolerated.¹ The co-primary end points were safety and tolerability, with tolerability defined as taking the full dose at 12 months and reporting the ability to tolerate it lifelong. Chonchol explained the age cap was chosen to enrich for rapid progressors.

Did Empagliflozin Increase Kidney Volume in ADPKD?

All participants completed follow-up, and 96% in each group tolerated the full study drug dose at 12 months.¹ Adverse events were similar between groups, with 2 urinary tract infections and 1 genital infection in the empagliflozin group and 1 acute kidney injury event in the placebo group.

“The empagliflozin at 25 milligrams was very well tolerated,” Seliger said.

For the exploratory endpoints, height-adjusted total kidney volume increased by 10.5% per year with empagliflozin compared with 5.1% per year with placebo (

 = .001).¹ Empagliflozin produced the expected acute eGFR dip of 6.2 mL/min/1.73 m² at 1 month, but the chronic eGFR slope did not differ between groups, nor did aortic pulse wave velocity, copeptin, urinary KIM-1, or patient-reported outcomes.

Participants receiving empagliflozin were modestly more likely to be Mayo class 1E (32% vs 20%), though adjustment for imaging class did not materially change the kidney volume findings.

“At this point, it really does remain uncertain whether our finding of greater cyst enlargement and kidney volume enlargement over time is a true biologic finding or a chance finding,” Seliger said.

He noted some preclinical models suggest SGLT2 inhibitors can promote cyst growth, and future trials should weigh the possible safety signal. Although increased vasopressin release has been proposed as a mechanism, copeptin levels did not rise in the trial.¹ The team is now analyzing biomarkers of glucose metabolism and advanced imaging features of cyst growth.

Chonchol noted the 2025 KDIGO ADPKD guideline does not recommend SGLT2 inhibitors to slow disease progression.² He pointed to a German trial of 44 patients, including 10 receiving tolvaptan, expected to report in March, and a planned French trial of more than 400 patients. Neuen added the RENAL LIFECYCLE trial of dapagliflozin in advanced CKD permitted enrollment of patients with ADPKD.

 include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Disclosures for 

 include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Disclosures for 

 include Estuary, Vertex, Astra Zeneca, and Novartis. Disclosures for 

 include Estuary, Calico, Lonestar, and GindolaBIo.

Seliger SL, Gitomer B, You Z, et al. Empagliflozin therapy in autosomal dominant polycystic kidney disease: a feasibility randomized controlled trial. J Am Soc Nephrol. Published online October 24, 2026. doi:10.1681/ASN.0000001271

Torres VE, Ahn C, Barten TRM, et al. KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive summary. Kidney Int. 2025;107(2):234-254. doi:10.1016/j.kint.2024.07.010

Podcasts

Stephen Seliger, MD, and Michel Chonchol, MD, join Kidney Compass to discuss a pilot trial of empagliflozin in rapidly progressing ADPKD.

Shikha Wadhwani, MD, MS

Articles