Shikha Wadhwani, MD, MS

Kidney Compass: New 2-Year APPLAUSE-IgAN Data for Iptacopan at WCN 2026

The treatment landscape for IgA nephropathy (IgAN) continues to evolve at a rapid pace, and new data presented at the World Congress of Nephrology (WCN) in Yokohama, Japan, suggest a potential shift in how clinicians approach disease modification in high-risk patients. In this episode of 

, hosts Shikha Wadhwani, MD, MS, and Brendon Neuen, MBBS, PhD, spoke with Vlado Perkovic, MBBS, PhD, about newly presented 2-year eGFR slope data from the phase 3 APPLAUSE-IgAN trial evaluating iptacopan.

Perkovic explained that the trial built on previously published findings in the 

 showing a 38% reduction in proteinuria at 9 months, but emphasized that the key question remained whether this would translate into long-term kidney protection. As he noted during the discussion, the study enrolled a particularly high-risk population, with median proteinuria around 1.7 g/g and rapid progression in the placebo arm—where eGFR declined by more than 6 mL/min/1.73 m² per year. Both hosts highlighted how this rate of decline reinforced the urgency for new therapies.

According to Perkovic, treatment with iptacopan slowed that decline to just over 3 mL/min/1.73 m² annually, representing an approximately 50% reduction compared with placebo and a treatment effect that exceeded initial expectations. Wadhwani and Neuen both pointed to this magnitude of benefit as especially compelling, particularly given that the trial was powered for a much smaller difference. Perkovic further noted that the key secondary composite endpoint, 30% eGFR decline or kidney failure, was reduced by 43%, which the hosts emphasized as evidence that the slope findings are likely to translate into meaningful clinical outcomes.

Safety was another focal point of the conversation. Perkovic noted that adverse events, serious adverse events, and discontinuations were comparable between groups, with no deaths reported. While he acknowledged a numerical increase in infections with iptacopan, he emphasized that all cases were manageable and resolved with treatment, and there was no concerning signal for severe or encapsulated infections.

The discussion then shifted to how iptacopan might fit into an increasingly complex treatment paradigm. Wadhwani raised the question of where complement inhibition would sit alongside existing therapies and evolving guideline recommendations, prompting Perkovic to stress that foundational treatments such as renin-angiotensin system inhibitors and SGLT2 inhibitors remain essential. However, he noted that patients receiving SGLT2 inhibitors in the trial still derived clear additional benefit, supporting the idea of combination therapy.

Neuen also highlighted the importance of understanding eGFR slope dynamics, asking whether acute versus chronic effects might influence interpretation of treatment benefit. In response, Perkovic explained that, unlike some other therapies, iptacopan did not appear to have an acute hemodynamic effect on eGFR, resulting in a more linear and interpretable slope over time, a point both hosts noted could simplify comparisons across agents.

Looking ahead, all three speakers emphasized the likelihood that combination approaches will be necessary, particularly for patients with high baseline proteinuria. As Perkovic pointed out during the exchange, achieving guideline-recommended targets may require multiple therapies with complementary mechanisms. Wadhwani further stressed the importance of earlier diagnosis and intervention, while Perkovic suggested that evolving data may prompt clinicians to reconsider biopsy thresholds and treatment timing.

Editors’ Note: Relevant disclosures for 

 include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for

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

include Boehringer Ingelheim,AbbVie, Inc., Bristol-Myers Squibb, servier, Astellas Pharma US, Merck, Janssen Pharmaceuticals, GSK, and others.

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Vlado Perkovic, MBBS, PhD, discusses APPLAUSE-IgAN data showing iptacopan reduced eGFR decline and lowered kidney event risk in IgA nephropathy.

Kidney Compass: ASSIST Trial Shows Atrasentan Benefit on Top of SGLT2 Inhibitors

As the treatment landscape for IgA nephropathy grows increasingly complex, new data presented at the World Congress of Nephrology 2026 in Yokohama, Japan, are beginning to clarify how emerging therapies may work together. 

, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, sat down with Hiddo Heerspink, PhD, PharmD, to discuss the phase 2 ASSIST trial, which evaluated the efficacy and safety of atrasentan in combination with SGLT2 inhibitors.

Throughout the discussion, Heerspink emphasized that the trial was intentionally designed to address a rapidly evolving standard of care. As he explained, growing evidence supporting SGLT2 inhibitors in chronic kidney disease, specifically in IgA nephropathy, prompted the need to understand whether additional therapies like atrasentan could provide incremental benefit when layered on top. Neuen and Wadhwani both highlighted this rationale, framing the study as a forward-looking effort to anticipate real-world combination therapy.

To efficiently generate these data, Heerspink noted that the investigators used a randomized, placebo-controlled crossover design, allowing each patient to serve as their own control. As Neuen pointed out during the conversation, this approach improves statistical efficiency and reduces the required sample size. The study enrolled 51 patients, each receiving atrasentan and placebo sequentially on top of background SGLT2 inhibition, with both short-term (12-week) and longer-term (24-week) treatment periods incorporated into the design.

Wadhwani underscored another key distinction raised by Heerspink: the inclusion of patients with lower levels of proteinuria, starting at 0.5 g/day. According to Heerspink, this decision, made before the latest guideline updates, allowed the trial to explore efficacy in a broader, earlier-stage population than many prior phase 3 studies. Both hosts noted how this aligns with a growing emphasis on earlier diagnosis and intervention in IgA nephropathy.

In presenting the results, Heerspink stated that atrasentan reduced proteinuria by approximately 25% compared with placebo when added to SGLT2 inhibitors, with effects apparent by 12 weeks and sustained through 24 weeks. He further emphasized that the drug did not produce an acute decline in eGFR, challenging longstanding assumptions about endothelin receptor antagonists, and that its effects on blood pressure were modest.

Safety was a central focus of the discussion. Heerspink highlighted concerns around fluid retention with this class of agents but noted that, in ASSIST, these risks were minimal when atrasentan was combined with SGLT2 inhibitors. Both Neuen and Wadhwani pointed to the reassuring safety signals, including stable body weight and no clinically meaningful changes in biomarkers, reinforcing Heerspink’s conclusion that the combination appears both safe and well tolerated.

Looking beyond the trial, the conversation turned to broader implications for clinical practice and research design. Wadhwani raised the potential for crossover studies to help individualize therapy, prompting Heerspink to suggest that such designs could offer insight into patient-specific responses. However, he cautioned that variability in proteinuria measurements must be carefully considered when interpreting individual-level changes.

Heerspink additionally challenged the conventional sequencing of therapies. As he explained during the episode, the order in which drugs are developed should not dictate how they are used in practice. Instead, he advocated for a more pathophysiology-driven approach, tailoring treatment selection and sequencing to disease mechanisms and stage rather than defaulting to historical standards of care.

 include AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Chinook Therapeutics Inc., Gilead Sciences, Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Travere Therapeutics, and others. Relevant disclosures for 

 include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for 

include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics.

Hiddo Heerspink, MD, PhD, highlights ASSIST trial data showing atrasentan reduced proteinuria by 25% on top of SGLT2 inhibitors in IgA nephropathy.

Kidney Compass: Phase 3 Data on Telitacicept in IgA Nephropathy at ASN Kidney Week 2025

New phase 3 data released by Vor Bio underscore the potential of telitacicept, a dual BLyS/APRIL inhibitor, as a disease-modifying therapy for 

, particularly for patients at high risk of progression.

Kidney Compass: Navigating Clinical Trials

, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS sit down with study investigators Jicheng Lv, MD, PhD, and Hong Zhang, MD, PhD, professors of internal medicine at Peking University First Hospital, following their presentation at the 

American Society of Nephrology (ASN) Kidney Week 2025

Telitacicept is a recombinant fusion protein designed to neutralize BLyS and APRIL, upstream drivers of B-cell survival and immunoglobulin class switching, including production of galactose-deficient IgA1, the pathogenic hallmark of IgAN. The 39-week multicenter, randomized, double-blind trial evaluated the agent’s impact on proteinuria, B-cell activity, immunoglobulin levels, and kidney function.

In stage A, adults were randomly assigned 1:1 to telitacicept 240 mg subcutaneous weekly or placebo, in addition to background supportive care. The primary endpoint, which was defined as change in 24-hour urine protein-to-creatinine ratio (UPCR), was met with a −58.9% reduction in the telitacicept arm compared with −8.8% with placebo (

 < .0001). Week-39 data were consistent, with the treatment group showing a 55% 24-hour UPCR reduction.

Clinically meaningful thresholds associated with improved long-term renal outcomes were achieved at substantially higher rates with telitacicept:

24h-UPCR <0.8 g/g: 61% vs 19.5% (placebo)

Investigators highlighted kidney function remained stable across secondary endpoints. Mean eGFR change at week 39 was essentially unchanged with telitacicept (−0.010 mL/min/1.73 m²) compared with a modest decline in the placebo group (−0.77 mL/min/1.73 m²). Investigators also observed a lower risk of ≥30% eGFR decline (27%) with telitacicept versus placebo.

Editor's Note: LV reports relevant disclosures with Chinook Therapeutics, KBP Bioscience, and others. Zhang reports no relevant disclosures

Lv, J, Liu LJ, Wang W, et al. Efficacy and Safety of Telitacicept in Patients with IgAN: Results from Stage A of a Phase 3 Clinical Study. 

Journal of the American Society of Nephrology

Telitacicept Achieved Primary Endpoint in Phase 3 Clinical Study for IgA Nephropathy | Vor Bio. Vor Bio. Published 2025. https://ir.vorbio.com/news-releases/news-release-details/telitacicept-achieved-primary-endpoint-phase-3-clinical-study-0

Dual BLyS/APRIL inhibition with telitacicept cut proteinuria and maintained kidney function in adults with IgA nephropathy.

Welcome to Kidney Compass: Navigating Clinical Trials!

Kidney Compass: SMART-C at ASN Kidney Week 2025

, Brendon Neuen, MBBS, PhD, doubles as a host and special guest as he offers host Shikha Wadhwani, MD, MS, a deep dive into the latest data from the the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) at the 

the large-scale meta-analyses provide comprehensive evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently reduce the risk of 

 progression, kidney failure, and related adverse outcomes across all levels of kidney function and albuminuria, regardless of diabetes status.

In the first analysis, the SMART-C team evaluated 70,361 participants from 10 randomized, placebo-controlled trials of SGLT2 inhibitors. Participants had a mean (SD) age of 64.8 (SD, 8.7) years, and 35.0% were female. During a median follow-up of 3 years, 2314 participants (3.3%) experienced CKD progression and 988 (1.4%) reached kidney failure.

SGLT2 inhibitors reduced the risk of CKD progression by 38% (25.4 vs 40.3 events per 1000 patient-years; hazard ratio [HR], 0.62 [95% CI, 0.57–0.68]), with consistent efficacy across eGFR categories:

≥60 mL/min/1.73 m²: HR, 0.61 (95% CI, 0.52–0.71)

45 to <60 mL/min/1.73 m²: HR, 0.57 (95% CI, 0.47–0.70)

30 to <45 mL/min/1.73 m²: HR, 0.64 (95% CI, 0.54–0.75)

<30 mL/min/1.73 m²: HR, 0.71 (95% CI, 0.60–0.83); 

Similar protection was observed across urinary albumin-to-creatinine ratio (UACR) levels, with HRs of 0.58 (95% CI, 0.44–0.76) for ≤30 mg/g, 0.74 (95% CI, 0.57–0.96) for 30–300 mg/g, and 0.57 (95% CI, 0.52–0.64) for >300 mg/g (

 for trend = .49). SGLT2 inhibitors also attenuated annual eGFR decline across all subgroups, including those without diabetes.

A complementary meta-analysis of 58,816 participants, including 48,946 with diabetes and 9870 without diabetes, across 8 clinical trials confirmed the broad efficacy and safety of SGLT2 inhibitors. Treatment significantly reduced kidney disease progression (HR, 0.65 [95% CI, 0.60–0.70] in diabetes; HR, 0.74 [95% CI, 0.63–0.85] without diabetes), acute kidney injury (HR, 0.77 [95% CI, 0.69–0.87] and HR, 0.72 [95% CI, 0.56–0.92]), all-cause hospitalization (HR, 0.90 [95% CI, 0.87–0.92] and HR, 0.89 [95% CI, 0.83–0.95]), and all-cause death (HR, 0.86 [95% CI, 0.80–0.91] and HR, 0.91 [95% CI, 0.78–1.05]).

Check out this interview with presenting investigator Natalie Staplin, PhD, for more on the 8-trial meta-analysis!

The magnitude of benefit was consistent across albuminuria strata (UACR ≥ 200 mg/g vs <200 mg/g), although absolute risk reductions were greater in those with higher baseline albuminuria.

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

Neuen BL, Fletcher RA, Anker SD, et al. SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis. 

 Published online November 07, 2025. doi:

Staplin N, Roddick AJ, Neuen BL, et al. Effects of Sodium Glucose Cotransporter 2 Inhibitors by Diabetes Status and Level of Albuminuria: A Meta-Analysis. 

Discover groundbreaking insights on SGLT2 inhibitors and their impact on kidney health, cardiovascular outcomes, and patient care at ASN Kidney Week.

Shikha Wadhwani, MD, MS

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