Patricia de Sequera, MD, PhD, chief of nephrology at University Hospital Infanta Leonor in Madrid

Patricia de Sequera, MD, PhD

 using medium cut-off membranes demonstrated comparable mortality and 

 outcomes to online hemodiafiltration (OL-HDF) in patients receiving hemodialysis, according to findings from the MOTheR trial presented at the 63rd European Renal Association (ERA) Congress.

While OL-HDF is an established dialysis modality and considered standard of care in some countries, including Spain where the MOTheR trial was conducted, conventional hemodialysis remains the predominant standard of care in many other regions.

OL-HDF has demonstrated survival benefits compared with conventional hemodialysis, but implementation requires additional infrastructure, including ultrapure water systems, online substitution fluid generation, and the ability to achieve adequate convective volumes.

HDx uses medium cut-off membranes designed to improve clearance of larger-middle molecules while being delivered on standard hemodialysis platforms. In the randomized MOTheR trial, which included 533 incident hemodialysis patients in Spain followed for up to 36 months, HDx was non-inferior to OL-HDF for a composite endpoint of all-cause mortality and cardiovascular events.

Interim findings from the real-world CONCORDIA study further supported these results, showing no statistically significant difference in all-cause mortality between patients treated with HDx and those receiving HDF after adjustment for demographic, clinical, and laboratory factors.

Q&A: HCPLive spoke with Patricia de Sequera, MD, PhD, chief of nephrology at University Hospital Infanta Leonor in Madrid and lead investigator of the MOTheR trial, about how clinicians should interpret non-inferiority findings, which patients may benefit most from HDx, and what questions remain before broader adoption.

HCPLive: The MOTheR and CONCORDIA studies demonstrated the non-inferiority of HDx compared with OL-HDF in terms of mortality and cardiovascular outcomes. How should nephrologists interpret non-inferiority in the context of selecting the appropriate therapy for each patient?

 Non-inferiority does not imply equivalence, and clinicians should avoid that interpretation. What MOTheR demonstrates, and what CONCORDIA corroborates, is that HDx does not significantly increase the risk of death or major cardiovascular events compared with OL-HDF.

The incidence rate ratio in our trial was 0.87, numerically favorable to HDx, although we designed the study to evaluate non-inferiority, not superiority.

From my perspective, the most important thing for nephrologists and patients is that we have another highly efficient dialysis therapy with a safety profile and cardiovascular and mortality rates very similar to OL-HDF. HDx is an option for patients who cannot undergo OL-HDF for either clinical or infrastructural reasons.

For individual clinical decisions, the message is this: if a patient cannot receive optimal OL-HDF, whether due to vascular access limitations, low blood flows, or center infrastructure limitations, HDx is a clinically validated alternative with a comparable safety and efficacy profile over a median follow-up of nearly 2 years. Nephrologists should stop considering HDx as a last resort and start viewing it as a legitimate option in appropriate settings.

That said, non-inferiority trials define a threshold, not a recommendation. The margin we pre-established was an IRR of 1.25, and we stayed within it. This is reassuring, but it does not tell us whether specific subgroups might benefit differently from one modality than the other, which requires further investigation.

HCPLive: Are there specific patient populations, based on clinical profile, comorbidities, or disease stage, for whom HDx may be preferentially indicated over OL-HDF, or vice versa?

 Our trial did not aim to answer this question, but we will perform subgroup analyses and determine whether we have sufficient statistical power to draw conclusions. Therefore, any response presented here should be considered hypothesis-generating rather than evidence-based.

That said, several patient profiles emerge from clinical reasoning and the biological basis of both modalities.

HDx may be particularly suitable for patients with poor vascular access, where achieving the high blood flows necessary for optimal convective volumes in OL-HDF is simply not feasible. In these patients, OL-HDF often fails to deliver its theoretical benefit, whereas HDx achieves solute removal through membrane design rather than convective volume, making it less dependent on hemodynamic performance.

Conversely, for patients who can reliably achieve convective volumes greater than 23 liters per session, as demonstrated in the CONVINCE and ESHOL studies, a biological argument remains in favor of OL-HDF given the dose-response relationship between convection and the survival benefit.

In our trial, the mean convective volume in the OL-HDF group was 25.8 ± 4.8 liters, a high-performance result that not all centers in clinical practice can replicate.

The truth is that we still lack the necessary data to formulate definitive recommendations for each population. This will undoubtedly be one of the most important issues.

HCPLive: A key differentiator of HDx is that it can be delivered without additional infrastructure or specialized training. What are the practical implications of this for dialysis centers, particularly those in community or resource-limited settings?

 This is where I believe the impact of MOTheR extends well beyond what the primary endpoint conveys.

OL-HDF requires ultrapure water production systems, online preparation of substitution fluid, high blood flow rates, reliable arteriovenous fistulas, and staff trained in managing convective sessions. These are not trivial requirements. In Spain alone, a significant proportion of patients receive dialysis in satellite or community units where achieving optimal OL-HDF dosing consistently is difficult. Globally, this constraint is far more pronounced.

HDx, by contrast, runs on standard dialysis platforms. No substitution fluid. No additional water treatment beyond what is already required for standard hemodialysis. No modifications to existing prescriptions. In practical terms, a center that today delivers conventional high-flux hemodialysis can transition to HDx with essentially no infrastructure investment, just a change in dialyzer.

The implication is significant: HDx could extend the benefits of advanced solute clearance to millions of patients who are currently receiving standard hemodialysis simply because their center cannot support OL-HDF. That is not a minor consideration; it is a fundamental equity argument for broader access to this technology.

HCPLive: What are the most important limitations of the current data, and what questions remain to be answered before HDx can be more broadly adopted as a standard alternative to OL-HDF?

 I want to be direct about this because scientific credibility requires it.

The most significant limitation is that we lacked the power to establish non-inferiority for all-cause mortality as a standalone endpoint. The p-value for non-inferiority for mortality was 0.062, which falls below the conventional threshold. We designed the trial around a composite endpoint to achieve adequate statistical power within a feasible sample size, a methodologically sound and widely accepted approach in dialysis trials, but this means we cannot make definitive claims about mortality in isolation.

Secondly, the open-label design is a genuine limitation. Participants and investigators knew which treatment was being administered. This is essentially unavoidable in dialysis trials, but it may have influenced the assessment of secondary outcomes such as hospitalization rates.

Third, the COVID-19 pandemic significantly disrupted recruitment and follow-up, extending the trial from the planned 24 to 36 months and potentially affecting event rates in ways that are difficult to fully explain.

HCPLive: The Spain resource utilization analysis suggested meaningful per-session cost savings with HDx. How much weight should healthcare providers give to economic data of this kind when making therapy decisions?

 Economic data should inform therapeutic decisions, but they should never guide them independently of clinical evidence.

In the case of HDx, the economic argument is relevant precisely because clinical evidence supports comparable outcomes; cost analysis does not need to compensate for inferior outcomes.

I did not participate in the study you are referring to, but I am familiar with it and find it interesting. The resource utilization data in Spain suggesting cost savings per session with HDx reflect a real structural difference: no replacement fluid is required, no additional water treatment is needed, and it is compatible with existing infrastructure.

However, the appropriate hierarchy is as follows: first, establish non-inferiority or clinical comparability, which MOTheR achieves. Second, assess safety, which is comparable between groups. Third, consider patient-specific factors, such as vascular access, center capabilities, and tolerability. Economic considerations come in fourth place, either as a tiebreaker or as a system-level argument for widespread implementation when multiple clinically comparable options exist.

What I advise against is using cost data to justify selecting HDx in patients for whom OL-HDF with high convective volumes is feasible and clinically preferable. The economic argument is stronger in contexts where the question is not “which is better?” but “how do we expand access to effective therapy?” and it is precisely here that the data from our trial and the economic analyses converge most strongly.

Editor’s note: de Sequera reports relevant disclosures with Amgen, Astellas, Astra Zeneca, Braun, Fresenius, Nipro, Otsuka, Vantive and Vifor Pharma.

de Sequera P, et al. MOTheR HDx study: A multicentre, open-label, prospective, randomized study to explore the morbidity and mortality in patients dialyzed with the Theranova dialyzer and HDx therapy in comparison to online hemodiafiltration. Presented at: European Renal Association Congress; June 3-6, 2026; Glasgow, Scotland.

Pecoits-Filho R, et al. The CONCORDIA study: All-cause mortality with Theranova dialyzer compared with hemodiafiltration using DOPPS as an external real-world comparator. Presented at: European Renal Association Congress; June 3-6, 2026; Glasgow, Scotland.

Articles

Expanded hemodialysis using medium cut-off membranes achieved non-inferior outcomes versus online hemodiafiltration for a composite of all-cause mortality and cardiovascular events in 533 incident Spanish hemodialysis patients followed up to 36 months. Real-world interim data similarly showed no adjusted mortality difference versus HDF. HDx offers advanced middle-molecule clearance on standard HD platforms, avoiding OL-HDF requirements for ultrapure water, online substitution fluid, and consistently high convective volumes. Non-inferiority supports HDx as a validated alternative when OL-HDF is not optimally deliverable.

MOTheR trial data suggest expanded hemodialysis offers comparable outcomes to online hemodiafiltration for dialysis patients, Patricia de Sequera, MD, PhD explains. 