Review

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Expanded hemodialysis: a new concept of renal
replacement therapy
Jonny Jonny ‍ ‍, Maria Teressa ‍ ‍

Division of Nephrology, ABSTRACT

Department of Internal Expanded hemodialysis (HDx) is an innovation that can WHAT IS ALREADY KNOWN ON THIS TOPIC
Medicine, Gatot Soebroto ⇒ Conventional hemodialysis lacks the ability
Army Hospital, Jakarta, increase the effectiveness of hemodialysis. The dialysis
Indonesia process is expected to promote more uremic toxins to provide adequate removal of uremic
removal without causing significant hypoalbuminemia toxins over a broad molecular weight range.
Correspondence to using the medium cut-­off (MCO) membrane or ⇒ Retention of wide spectrum of uremic
Dr Maria Teressa, Division also known as the high retention onset membrane. toxins induces adverse biologic effects and
of Nephrology, Department Compared with conventional membranes such as various complications.
of Internal Medicine, Gatot
those of low-­flux hemodialysis, high-­flux hemodialysis,
Soebroto Army Hospital, WHAT THIS STUDY ADDS
Jakarta 10410, Indonesia; and hemodiafiltration, the MCO membrane in HDx is
​dr.​mariateressa@​gmail.​com considered to be the closest to the physiology of the ⇒ The medium cut-­off (MCO) membrane has
glomerular membrane. Several studies have shown the the potential to remove medium to large
Accepted 18 May 2022
use of the MCO membrane in HDx provides clinical molecular weight toxins.
benefits and better outcome although further studies ⇒ Routine use of MCO dialyzers is safe and
are needed to assess the long-­term effect and greater does not cause a significant decline in
impact for dialysis patients. serum albumin levels.
⇒ The MCO membrane with its expanded
hemodialysis (HDx) method has the
potential for better removal of toxins and
INTRODUCTION chronic inflammatory factors compared
Hemodialysis (HD) technology continues to with conventional hemodialysis.
develop until now, but these developments some- HOW THIS STUDY MIGHT AFFECT
times achieve unsatisfactory results. One of the RESEARCH, PRACTICE OR POLICY
unmet needs in HD is the maximum removal of
⇒ HDx can be an option for dialysis patients
uremic toxin. Currently, the synthetic membrane
in HD is not able to remove large uremic toxins,
who do not achieve maximum results after
as is done by the glomerular membrane of the
conventional hemodialysis.
kidney. As a result, dialysis patients in their plasma
have high moderate to large molecule uremic
toxins.1 Despite technological advances in recent cost, limitations in infrastructure, and the lack of
years, HD is still being a burden for patients with resources in each dialysis unit.3
chronic kidney disease (CKD). To increase uremic toxin removal and membrane
Currently, HD patients can undergo low-­flux permeability, in recent years, membrane technolo-
HD (LF-­HD), high-­flux HD (HF-­HD), or hemo- gies that have similar efficacy but minimal impact
diafiltration (HDF). The difference between the on albumin loss have been developed. The medium
three techniques lies in the permeability of the cut-­off (MCO) membrane or also known as the
dialysis membrane to remove toxins with different high retention onset (HRO) membrane, which is
molecular weights.2 LF-­HD is conventional HD, now considered as expanded HD (HDx), has led
having a membrane that is permeable only to toxins to new hope for the condition and quality of life
with low molecular weight (<1 kD). The HF-­HD of HD patients.4 Thus, this review aims to explore
features a high-­flux synthetic membrane which is the molecular removal of the dialysis process using
more biocompatible for removing medium-­sized the HDx method and its relevance to the clinical
to large-­sized molecules, whereas HDF treatment benefit for HD patients.
© American Federation for combines diffusive and convective transport with
Medical Research 2022. a high-­flux membrane.2 3 Nonetheless, removing DIALYSIS MEMBRANE EVOLUTION: MCO
Re-­use permitted under
CC BY-­NC. No commercial medium to large molecules using HF-­ HD and MEMBRANE
re-­use. Published by BMJ. HDF modes still has limitations. The evolution of The development of a highly selective and
HF-­HD, also known as protein-­leaking membrane permeable membrane represents a good oppor-
To cite: Jonny J,
(PLM), or super-­flux or high cut-­off (HCO), can tunity for effective and high-­quality dialysis.
Teressa M. J Investig Med
Epub ahead of print: enhance uremic toxin clearance compared with The MCO membrane can not only remove
[please include Day Month LF-­HD but often results in clinically significant large molecules with a molecular weight of up
Year]. doi:10.1136/jim- hypoalbuminemia. HDF has advantages over to 45,000 Da, which is similar in properties to
2022-002431 other modes, but it is still limited due to higher HCO membrane, but can also reduce excessive
Jonny J, Teressa M. J Investig Med 2022;0:1–4. doi:10.1136/jim-2022-002431 1
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J Investig Med: first published as 10.1136/jim-2022-002431 on 31 October 2022. Downloaded from http://jim.bmj.com/ on November 20, 2022 by guest. Protected by copyright.
albumin loss as in high-­flux membrane.5 With the devel-
opment of these membrane characteristics, the use of the
MCO membrane expands the spectrum of uremic toxins
clearance through HD, hence this new modality is now
known as HDx.4
MCO membranes have highly selective permeability
properties. Boschetti-­de-­Fierro et al conducted an in
vitro study regarding the membrane characteristics of
dextran filtration and found that the MCO membrane
has the most similar characteristics to the human kidney,
when compared with other modalities such as LF, HF,
HCO, and PLM membranes.6 The permeability character-
istics of membranes are described in sieving curve. The
sieving curve on the HF membrane describes a progressive
decrease in sieving value which is in line with the increase
in the molecular weight of the solute, until the point at
which 90% of the solute is retained in the filtration process Figure 1 Various sizes of uremic toxins and their clinical
(sieving=0.1). At this molecular weight, the membrane manifestations. CV, cardiovascular.
cut-­off value (molecular weight cut-­off/MWCO) is deter-
mined. Conversely, the molecular weight when 10% of
the solute is retained (sieving=0.9) shows the retention Figure 1 shows various molecular sizes and their retention
onset of the membrane (molecular weight retention onset/ effects in various clinical manifestations.
MWRO).7
The MWRO value can be used to differentiate membranes THE DEVELOPMENT OF HDX
based on the molecular cut-­off value. The MCO membrane Before MCO membrane is developed, HDF is widely used
has a cut-­off value similar to that of the HF membrane. In in the high-­flux dialysis method. Convective clearance (K)
the HF membrane, MWRO ranges in the 1200 Da (vitamin is the product of the ultrafiltration rate (Qf) and sieving (S)
B12), while MWRO for the MCO membrane ranges in for a particular molecule (K=Qf×S). When the value of S
the 12,000 Da (beta-­ 2 microglobulin (b2M)). MWCO is low, K must be increased by increasing Qf. This remains
of the MCO membrane is close to the value of the HF difficult because of limited equipment and higher cost. The
membrane, limiting the loss of albumin.8 For this reason, development of HDF, namely online HDF, has not been
the current MCO membrane is also referred to as the HRO widely used in many countries because it requires a complex
membrane.6 8 machine with several dialysate filtration steps.15
The term HDx is used to describe diffusion and convec-
tion methods in a hollow-­ fiber dialyzer using an MCO
MCO MEMBRANE MOLECULAR FILTRATION TARGET membrane.4 This can be done with an ordinary dialysis
Several improvements have been made to increase the machine, without the need for special devices or additional
removal of medium to large uremic toxins in the dialysis instruments. In the MCO dialyzer, the inner fiber diameter
process. Medium molecules are organic compounds that is reduced from 200 µm to 180 µm, allowing for an increase
have a molecular weight of more than 500 Da, which can in the wall shear rate and the blood rate per single fiber.
accumulate in patients with CKD and cause many compli- This results in less residue sticking to the blood membrane
cations. Middle molecule retention is associated with the and an increase in solute exchange.16 Another additional
development of cardiovascular disease, chronic inflamma- effect is an increase in end-­to-­end pressure with the impli-
tory disease, mineral and bone disorders, secondary immu- cation of increased cross-­filtration process along the fiber.17
nodeficiency, and amyloidosis.9 10 The combination of hydraulic permeability and fiber
The b2M is a medium-­sized molecule that is used as a geometric structure enhances the internal filtration
marker of middle molecule removal in the dialysis process. process.16 The fiber bundle must have a sufficient number
In both pre-­dialysis and dialysis patients, b2M is associ- of fibers to cover a minimum surface area of 1.6 m2. The
ated with various complications of inflammatory process, number of fibers is essential to determine the cross-­sectional
vascular stiffness, or cognitive dysfunction.11–13 Other types area of the dialyzer, while the length of the fibers and
of middle molecules, such as interleukin (IL)-­6, are cyto- dialyzers is important for optimizing internal and back-­to-­
kines, which increase in circulating blood when kidney back filtration. This mechanism allows a large amount of
function decreases. Elevated IL-­6 in dialysis patients is asso- convection in the dialyzer where filtration occurs in the
ciated with cardiovascular events and left ventricular hyper- proximal part and back filtration compensates in the distal
trophy mortality.14 part.18 The ultrafiltration control system of the dialysis
The MCO membrane in HDx has a tight pore size distri- machine regulates the process and the proper amount of net
bution, resulting in a steeper sieving curve, with MWRO and filtration.19 Thus, the clearance is relatively higher without
MWCO close to each other, and with a cut-­off value nearly the need for the fluid exchange volume normally required
but lower than that of albumin. As a result, these membranes in HDF due to the higher sieving value of medium-­large
have the potential to remove medium to large molecular molecules.8
weight toxins which are increased in several conditions such Figure 2 shows the conditions required to perform HDx.
as sepsis, rhabdomyolysis, and hematological disorders.4 HDx does not require complex devices. Blood flow greater
2 Jonny J, Teressa M. J Investig Med 2022;0:1–4. doi:10.1136/jim-2022-002431
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J Investig Med: first published as 10.1136/jim-2022-002431 on 31 October 2022. Downloaded from http://jim.bmj.com/ on November 20, 2022 by guest. Protected by copyright.
showed that HDx with MCO membrane was not inferior
to online HDF in terms of cardiovascular parameters,
and HDx can be an alternative where online HDF is not
available in dialysis units.26
Other studies also examined the changes in the quality
of life of dialysis patients who were assigned to HDx.
By using the Kidney Disease Quality of Life-­Short Form
(KDQOL-­ SF) questionnaire, Lim et al examined the
quality of life and characteristics of uremic pruritus of
dialysis patients. The results showed that the physical
functioning and physical role domain score was higher
in the MCO group compared with the HF-­HD group.
Figure 2 Essential components of HDx. HDx, expanded In addition, there was also a decrease in the distribution
hemodialysis; MCO, medium cut-­off; MWRO, molecular weight of pruritus in the MCO group after 12 weeks of inter-
retention onset. vention.27 Alarcon et al performed a cohort study called
COREXH to assess the benefits of the MCO membrane
which included quality of life, presence of worsening
than or equal to 300 mL/min and a dialysate flow of more symptoms, and restless legs syndrome (RLS) diagnostic
than or equal to 500 mL/min are sufficient to operate the criteria. The study reported that there was a significant
machine. Water purity is also important to prevent contam-
increase in the domains of symptoms, effects of kidney
ination due to the large amount of back-­filtration.7 The
disease, and burden of kidney disease. A significant
mechanism of routine use of MCO membrane in HDx is no
reduction was also found in the percentage of patients
different from using HF-­HD and does not require special
diagnosed with RLS after 12 months.28
technical or nursing skills related to setting, implementing,
Based on various studies, the MCO membrane with its
and ending dialysis.20
HDx method shows the potential for better removal of
toxins and chronic inflammatory factors compared with
THE APPLICATION OF HDX conventional HD. However, there have been some nega-
The goal of the dialysis process is the removal of uremic tive evaluations on certain aspects. This was reported in
toxins that are similar to those of a human kidney, a study that evaluated the use of HDx in several dialysis
which should be able to remove molecules weighing
units. Some nurses complained of difficulties in priming
up to 50,000 Da.21 The evolution of a more permeable
membranes in automatic machine mode, and some
membrane such as the MCO used in HDx can provide a
patients also required additional anticoagulants during
better clearance outcome than other membranes.
dialysis.29 HDx may still have limitations similar to those
Several studies have been conducted to assess the
of HDF. Protein-­ bound toxin and very large uremic
performance of the MCO membrane in HDx. Krishna-
toxins cannot be treated with HDx, but enhancement of
samy et al conducted a cohort study called REMOVAL
removal of a wide spectrum of uremic toxins via HDx is
HD to determine the safety of using MCO dialyzers and
generally beneficial for dialysis patients.30
the effect of serum albumin changes over 6 months in
HDx can be an option for dialysis patients who do
chronic dialysis patients. The result showed that routine
not achieve maximum results after conventional HD.
use of MCO dialyzers was declared safe and did not
Although several studies have shown HDx may bring
result in a significant fall in serum albumin. There were
promising and better benefits, larger scale studies with a
no immediate or medium-­term effects observed regarding
symptoms, functional status, or nutrition on the use of longer period of time and further innovations are needed
the MCO membrane.22 These results were similar to a to present more significant impact on dialysis patients.
cohort study conducted by Bunch et al, which described
the results and trends in serum albumin levels in patients CONCLUSION
switching from conventional HF-­HD to HDx. The study
The innovation of the MCO membrane, also known as the
also reported that there were no adverse events associ-
HRO membrane, has allowed the development of a new
ated with the use of MCO membrane.23
renal replacement therapy concept called HDx. HDx is
Zickler et al reported albumin levels dropped signifi-
easier to perform because it does not require additional
cantly after 4 weeks of MCO dialysis but increased after
equipment or a specific dialysis nurse. By promoting the
an additional 8-­ week period. In addition, HDx also
removal of more middle to large molecule toxins which
increased the removal of chronic inflammatory factors
conventional HD previously failed to achieve, HDx may
over an additional 4-­ week and 8-­ week period. This
play a key role in providing effective clearance in dialysis
indicated that HDx decreased the expression of tumor
patients. Furthermore, future randomized control trials
necrosis factor (TNF)-α and IL-­ 6 genes.24 Another
are warranted to reveal long-­term outcomes and more
study demonstrated that the use of the MCO dialyzer
potential benefits.
membrane significantly reduced the rate of infection
when compared with conventional hemodialysis.25
Contributors JJ—conception, data collection, data analysis, drafting
Moreover, a randomized controlled trial (CARTOON manuscript, revision and final approval. MT—conception, data collection,
Study) also compared cardiovascular outcomes between data analysis, drafting manuscript, revision and final approval. Both authors
patients undergoing HDx and online HDF. The result contributed equally.

Jonny J, Teressa M. J Investig Med 2022;0:1–4. doi:10.1136/jim-2022-002431 3

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J Investig Med: first published as 10.1136/jim-2022-002431 on 31 October 2022. Downloaded from http://jim.bmj.com/ on November 20, 2022 by guest. Protected by copyright.
Funding The authors have not declared a specific grant for this research from 12 Cheung AK, Rocco MV, Yan G, et al. Serum beta-­2 microglobulin levels predict
any funding agency in the public, commercial or not-­for-­profit sectors. mortality in dialysis patients: results of the HemO study. J Am Soc Nephrol
2006;17:546–55.
Competing interests None declared.
13 Smith LK, He Y, Park J. β 2-­microglobulin is a systemic pro-­aging factor that
Patient consent for publication Not required. impairs cognitive function and neurogenesis. Nat Med 2015:1–8.
Ethics approval Not applicable. 14 Rao M, Guo D, Perianayagam MC, et al. Plasma interleukin-­6 predicts
cardiovascular mortality in hemodialysis patients. Am J Kidney Dis
Provenance and peer review Not commissioned; externally peer reviewed. 2005;45:324–33.
Open access This is an open access article distributed in accordance with 15 Ronco C, Ronco C. Hemodiafiltration: technical and clinical issues. Blood Purif
the Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, 2015;40:2–11.
which permits others to distribute, remix, adapt, build upon this work non-­ 16 Fiore GB, Ronco C. Principles and practice of internal hemodiafiltration. Contrib
commercially, and license their derivative works on different terms, provided Nephrol 2007;158:177–84.
the original work is properly cited, an indication of whether changes were 17 Ronco C, Brendolan A, Lupi A, et al. Effects of a reduced inner diameter of
made, and the use is non-­commercial. See: http://creativecommons.org/​ hollow fibers in hemodialyzers. Kidney Int 2000;58:809–17.
licenses/by-nc/4.0/. 18 Lorenzin A, Neri M, Clark WR, et al. Modeling of internal filtration in Theranova
Hemodialyzers. Contrib Nephrol 2017;191:127–41.
ORCID iDs 19 Fiore GB, Guadagni G, Lupi A, et al. A new semiempirical mathematical model
Jonny Jonny http://orcid.org/0000-0002-8564-7430 for prediction of internal filtration in hollow fiber hemodialyzers. Blood Purif
Maria Teressa http://orcid.org/0000-0002-6162-6272 2006;24:555–68.
20 Heyne N. Expanded hemodialysis therapy: prescription and delivery. Contrib
Nephrol 2017;191:153–7.
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4 Jonny J, Teressa M. J Investig Med 2022;0:1–4. doi:10.1136/jim-2022-002431