Brendon Neuen, MBBS, PhD

Kidney Compass: REMODEL Trial Provides Mechanistic Rationale for Semaglutide in CKD

At the World Congress of Nephrology 2026 in Yokohama, Japan, growing attention is being paid not just to whether therapies improve outcomes in chronic kidney disease, but how they work at a mechanistic level. In this episode of 

, host Brendon Neuen, MBBS, PhD, spoke with David Cherney, MD, PhD, about the REMODEL trial, a mechanistic study designed to better understand the kidney-protective effects of semaglutide in patients with type 2 diabetes and chronic kidney disease.

As Cherney explained during the discussion, REMODEL was conceived as a companion to the landmark FLOW trial, which demonstrated significant reductions in cardiorenal outcomes with semaglutide. While FLOW established clinical efficacy, Cherney emphasized that REMODEL was designed to answer a different question: why these benefits occur. Both he and Neuen highlighted that prior analyses suggested the observed kidney protection could not be fully explained by traditional risk factor improvements such as glycemic control, weight loss, or blood pressure reduction.

To address this, Cherney described how REMODEL incorporated a range of advanced imaging and biomarker-based endpoints. The primary outcome focused on MRI-derived measures of kidney oxygenation, while secondary endpoints included albuminuria, kidney function, and a suite of mechanistic markers such as fibrosis, intrarenal fat, and inflammatory pathways. A subset of participants also underwent paired kidney biopsies, allowing for direct assessment of cellular and molecular changes within the kidney.

According to Cherney, the trial did not demonstrate an effect on kidney oxygenation, but did reveal several other important mechanistic signals. He noted that semaglutide led to a reduction in perirenal and hilar fat, a finding that Neuen highlighted as particularly intriguing given emerging hypotheses around the role of local adiposity in kidney injury. Cherney also pointed to improvements in markers of fibrosis and inflammation, including changes in endothelial cell biology and reductions in inflammatory cell populations, suggesting a direct intrarenal effect.

The conversation explored these findings in greater depth, with Neuen raising the possibility that perirenal fat may contribute to kidney injury through both mechanical and inflammatory mechanisms. In response, Cherney outlined multiple potential pathways, including physical compression of renal structures and the metabolic activity of adipose tissue driving cytokine-mediated injury. Both emphasized that these hypotheses warrant further investigation but may represent an underappreciated contributor to disease progression.

Clinically, Cherney reported that semaglutide reduced albuminuria by approximately 40%, reinforcing its potential as a kidney-protective therapy. He also presented subgroup analyses from the REMODEL trial showing consistent effects regardless of baseline use of SGLT2 inhibitors. Neuen noted that this finding aligns with broader evidence suggesting additive and complementary mechanisms between these drug classes, supporting their combined use in high-risk patients.

Looking ahead, both speakers emphasized the broader implications of these findings. Cherney suggested that the mechanisms observed in REMODEL, particularly those related to inflammation and endothelial dysfunction, are likely not specific to diabetes and may extend to non-diabetic kidney disease. He also stressed the importance of reframing semaglutide as a kidney-directed therapy, independent of its effects on glucose or weight, a point Neuen reinforced as critical for both clinicians and patients.

Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for Cherney include Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Abbvie, Janssen, AMGEN, Bayer, , Gilead, CSL-Behring, Otsuka, Novartis, GSK, and others.

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David Cherney, MD, PhD, discusses REMODEL trial insights into how semaglutide reduces albuminuria and impacts kidney fat and fibrosis pathways.

Kidney Compass: IV Iron and Functional Outcomes in Kidney Transplant Recipients

Iron deficiency is increasingly recognized as a clinically meaningful yet underexplored contributor to morbidity in kidney disease, extending beyond its traditional association with anemia. In populations such as kidney transplant recipients, where graft function may be stable, many patients continue to experience impaired physical function, reduced quality of life, and lingering fatigue.

As evidence from other fields, particularly cardiology, has begun to demonstrate the benefits of intravenous iron on functional outcomes independent of hemoglobin, questions are emerging about whether similar strategies could improve how patients with kidney disease feel and function, not just how they measure on laboratory parameters.

In this episode of Kidney Compass recorded on-site at World Congress of Nephrology in Yokohama, Japan, hosts Shikha Wadhwani, MD, MS, and Brendon Neuen, MBBS, PhD, spoke with Martin de Borst, MD, PhD, about his investigator-initiated randomized trial of intravenous iron in kidney transplant recipients.

Throughout the conversation, de Borst emphasized that the study was motivated by a gap between clinical perception and patient experience. While kidney transplant recipients are often thought to do well, he noted that a subset of patients continue to experience reduced exercise capacity, approximately 20% lower than healthy individuals on average. At the same time, iron deficiency remains common in this population, affecting roughly 1 in 5 patients.

Drawing on prior observational work, de Borst explained that iron deficiency had been associated with worse outcomes across multiple domains, including physical function, quality of life, and cognitive performance, raising the question of whether these relationships were causal.

Neuen reinforced that iron’s biological role extends well beyond erythropoiesis, highlighting its importance in mitochondrial function and muscle performance, while Wadhwani underscored the novelty of focusing on functional endpoints rather than traditional kidney metrics. As de Borst described, the trial was designed with a primary endpoint of the 6-minute walk test, selected for its practicality and reproducibility in a multicenter setting, alongside a broad range of secondary outcomes including neurocognitive testing, quality of life assessments, and cardiac imaging.

The study enrolled 148 stable kidney transplant recipients with iron deficiency, irrespective of hemoglobin levels, and randomized them to receive intravenous ferric carboxymaltose or placebo over a 24-week period. According to de Borst, the results showed modest improvements in exercise capacity. Of note, these improvements were observed in both the treatment and placebo groups, with no significant difference between them. He further noted that secondary outcomes, including cognitive function, cardiac parameters, and quality of life, were similarly neutral.

Despite these findings, de Borst pointed out that biochemical markers of iron status improved substantially in the treatment arm, indicating that while iron stores were corrected, this did not translate into measurable clinical benefit in this population. He also highlighted a small, unexpected signal suggesting a potential improvement in kidney function, though he cautioned that this finding requires further investigation.

The discussion then turned to how these results should be interpreted. Neuen raised the possibility of a ceiling effect, noting that patients in the trial were relatively high functioning at baseline, which may have limited the ability to detect meaningful improvements. De Borst agreed, explaining that while participants had some impairment compared with predicted values, they were not as severely affected as populations in which intravenous iron has shown benefit, such as heart failure.

Looking back, de Borst reflected that selecting a more symptomatic population or one with greater baseline functional limitation may have yielded different results. Both hosts emphasized that this highlights the challenges of trial design in relatively stable transplant populations and the importance of aligning endpoints with patient characteristics.

The conversation expanded beyond the trial itself to broader implications for the field. Neuen stressed that unlike cardiology, where intravenous iron has demonstrated benefits on functional outcomes, nephrology has remained largely focused on hemoglobin-based endpoints. He and de Borst both suggested that this paradigm may need to shift, particularly in non-dialysis chronic kidney disease populations where symptom burden is high and data on patient-centered outcomes remain limited.

Wadhwani echoed this perspective, noting the growing need to better understand how therapies impact how patients feel and function, not just traditional laboratory measures.

Editors’ note: Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. De Borst reports no relevant disclosures.

Martin de Borst, MD, PhD, discusses IV iron use in transplant recipients through an RCT focused on exercise capacity, function, and quality of life.

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.

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.

Brendon Neuen, MBBS, PhD

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