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.