Do Medium Cut-Off Dialyzers Offer Any Clinical Benefit or Should We Focus on Hemodiafiltration?

In this issue of JASN, a study is presented that addresses the question of whether the use of Theranova, a medium cut-off (MCO) dialyzer, is associated with a better preservation of residual kidney function as compared with standard high-flux hemodialysis in the treatment of kidney failure.¹ Over 12 months, the Theranova group demonstrated a significantly smaller decrease in GFR than the high-flux group (least squares mean difference of change [95% confidence interval]: −1.4 [−2.4 to −0.5] ml/min per 1.73 m²). Theranova maintained greater 24-hour urine volume until 9 months, not at 12 months, compared with the high-flux dialyzer. The differences in urinary output were around 160–180 ml/d at 6 and 9 months, without a difference at 12 months. One may argue that these differences are small. However, patients on dialysis will probably say that every drop of urinary output counts. So, any difference could be interpreted as clinically relevant. The authors also report that there was some suggestion that inflammatory markers related to kidney injury are lower during the use of MCO dialyzers. This is an interesting idea as a possible explanation for their clinical findings.

What are MCO membranes? Given these findings, it seems worthwhile to briefly discuss what MCO dialyzers actually are, what sort of information on these membranes is available, and what the place in everyday clinical practice could be. They are built upon high-flux dialyzer technology, featuring larger pores to enhance middle molecule clearance (up to 45 kDa) while minimizing albumin loss.² In addition, MCO fibers have a narrower intraluminal diameter or prolonged length, facilitating convective clearance through enhanced internal filtration–back-filtration. This convective clearance is uncontrollable, unmeasurable, and unpredictable in clinical practice, while being considered a key contributor to solute clearance. In high-flux hemodialysis, convective volumes are estimated to be several liters per treatment. A MCO dialyzer delivers approximately 7.1–12.7 L convective volumes during 4-hour experimental sessions, depending on filter size and blood flow rates (Q_B).³ To the best of our knowledge, this is the only study that gives an idea of the magnitude of the convective volume. This convective volume is passively compensated by a backshift of dialysate fluid into the bloodstream.

What Else Do We Know about MCO Dialyzers?

Various meta-analyses and review articles conclude that they offer a superior clearance profile of uremic toxins when compared with regular high-flux dialyzers. The published evidence on the effects of MCO hemodialysis as compared with standard hemodialysis on clinical outcomes, such as mortality and hospitalization, is still evolving. Some studies have addressed certain aspects of quality of life, such as intensity of pruritus or of restless legs and overall symptom burden. However, the grade for the current evidence base suffer from methodological challenges, such as small sample sizes and short follow-up durations, data from observational and retrospective studies with lack of randomization, potential confounding, and selection bias. At this time, no firm conclusions can be drawn regarding the effectiveness of MCO hemodialysis on clinical and quality-of-life outcomes.

What Is the Position of MCO Dialyzers as Compared with High-Dose Hemodiafiltration?

If we accept for a moment that MCO dialyzers offer an intermediate step from high-flux hemodialysis toward hemodiafiltration (HDF), then the present study can serve as a rationale to find out what the effect is of high-dose HDF on residual kidney function. The hypothesis could be that HDF offers a more pronounced effect than is reported in this paper. So far, this has not been properly investigated. Such a study would add to the discussion why HDF is associated with improved clinical outcome.

When looking for a better treatment than present-day high-flux hemodialysis, MCO dialyzers and high-dose HDF need to be compared and the most effective should be chosen. In general, one might say that a treatment is effective when it does what it is supposed to do. The two well-accepted efficacy parameters in the treatment of patients with kidney failure are survival and patient-reported outcomes. When comparing MCO dialyzers with high-dose HDF, there seems to be a huge difference in the level of evidence. Multiple studies show superiority of high-dose HDF.⁴ A recent meta-analysis based on individual data of trials showed improved outcomes on both all-cause and cardiovascular mortality and also suggests a lower infection-related mortality.⁵ This evidence is now supported by multiple so-called real-world analyses.⁶ No such data of similar size and/or quality exist on MCO dialyzers.

The ongoing A Multicentre, Open-label, Prospective, Randomized Study to Explore the Morbimortality in Patients Dialyzed With the Theranova HDx in Comparison to On-Line-Hemodiafiltration (NCT03714386) trial is the first large-scale randomized controlled study to compare HDF or MCO hemodialysis, aiming to determine whether MCO hemodialysis is noninferior in reducing a combined end point of all-cause mortality and major ischemic events.⁷ Results are expected in the not-so-distant future.

It is also shown that high-dose HDF offers a benefit in relevant domains of quality of life, including cognitive function, physical function, and social participation,⁸ and that it is potentially cost effective.⁹ Again, no such data of similar size and/or quality exist on MCO dialyzers.

An important variable that may influence the choice in everyday clinical practice is that the efficacy of a treatment relates to the dosing of it. For high-dose HDF, this is now well established. Although 23 L convection volume per session is an often-used threshold to define high-dose HDF, it is important to realize that in fact a gradual relation between convection volume and all-cause mortality exists—the higher the dose, the bigger the effect.⁵ This relation needs to be confirmed, for instance, in large real-world datasets. In fact, HDF offers a treatment option in dialysis where dose directly relates to outcome. For MCO dialyzers, the situation is completely different. The mechanisms of enhanced clearance are unpredictable, uncontrollable, and unmeasurable. So, it is unclear whether metrics of dialysis dose relate to outcome. Therefore, it will not be possible to demonstrate a dose–effect relation. As a consequence, it will be impossible to establish whether a single treatment session was adequately dosed or not. In fact, the whole process is a total black box.

A sometimes heard downside of HDF is that it is more complex to deliver. Indeed, dialysis machines able to deliver HDF and some training of the dialysis staff on how to achieve high-dose HDF are necessary. Both trial and so-called real-world data indicate that delivering HDF year in, year out is possible in the majority of patients. In Europe and elsewhere in the world, there is more than 20 years of experience with high-dose HDF. For HDF, any larger high-flux dialyzer can be used. To what extent other dialyzer characteristics affect the efficacy of a HDF treatment session is poorly defined. For MCO dialyzers, the choice is limited to local availability of a specific brand, which will often be more expensive than standard high-flux dialyzers.

With a MCO dialyzer, up to 12 L of substitution fluid is infused into the patient, and with HDF, 23 L and more. Independent of what regulatory bodies have defined as quality standards, it is important to realize that both treatment modalities should be considered needing similar water quality, i.e., HDF level. The reasoning for that is simple. Applying different quality standards between 12 and 23 L simply does not make sense. In addition, the concern that HDF needs more water and energy might not be correct. In fact, although possibly considered counterintuitive, the opposite may be the case, i.e., lower volumes of water are necessary for a HDF session than for a standard hemodialysis session.¹⁰

In conclusion, this study addresses a relevant question, and the results can serve as a rationale to perform a similar study comparing high-dose HDF with standard hemodialysis. When aiming for an upgrade of present-day standard high-flux hemodialysis, one may consider MCO dialyzers and HDF. The choice of high-dose HDF is supported by solid evidence of superiority on clinical end points based on both trial and real-world data. Furthermore, trial data show beneficial effects on relevant domains of quality of life. Prescription variables of HDF are well defined, easy to handle, and clearly related to outcome. In fact, HDF offers a change in the basic principles of dialysis therapy, which for the first time in decades has turned out to be clinically meaningful. The MCO dialyzers offer a combination of higher high-flux hemodialysis and very low-dose HDF. So far, clinical studies offer limited argument for a switch from high-flux to MCO dialyzers. Furthermore, it is completely unknown how prescription variables can be used to dose the treatment. Indication for use is as yet undetermined and uncertain.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F256.

Funding

None.

Author Contributions

Conceptualization: Peter J. Blankestijn.

Writing – original draft: Peter J. Blankestijn.

Writing – review & editing: Peter J. Blankestijn.