Ronco 2018
Ronco 2018
Ronco 2018
Haemodialysis membranes
Claudio Ronco1 and William R. Clark2*
Abstract | Haemodialysis is an extracorporeal process in which the blood is cleansed via removal
of uraemic retention products by a semipermeable membrane. Traditionally, dialysis membranes
have been broadly classified on the basis of their composition (cellulosic or noncellulosic) and
water permeability (low flux or high flux). However, advances in materials technology and polymer
chemistry have led to the development of membranes with specific characteristics and refined
properties that mandate a reconsideration of traditional membrane classification systems. For
adequate characterization of these newer types of membranes, additional parameters are now
relevant, including new permeability indices, the hydrophilic or hydrophobic nature of
membranes, adsorption capacity and electrical potential. In this Review, we provide clinicians
with an updated analysis of dialysis membranes and dialysers. We discuss the basic mechanisms
that underlie solute and water removal in dialysis (that is, diffusion, convection, adsorption and
ultrafiltration) in the context of treatments that use highly permeable membranes. Specifically,
we highlight online haemodiafiltration and new therapies (for example, expanded haemodialysis)
that utilize membranes designed to produce a high degree of internal filtration. Finally, we
discuss the considerations that govern the clinically acceptable balance between large-solute
clearance and albumin loss for extracorporeal therapies.
Haemodialysis is an extracorporeal blood cleansing tech- convection), with particular emphasis on the key part
nique that is used to remove metabolic waste products played by blood–membrane interactions. We pres-
that accumulate in patients with end-stage renal disease ent an updated membrane classification scheme and a
(ESRD). Solutes and water are removed through semi- description of conventional and new parameters that
permeable membranes using different mass separation are used to characterize and quantify membrane solute
mechanisms (diffusion, convection and adsorption). and water transport. Finally, we discuss the utilization
Traditionally, dialysis membranes have been broadly clas- of membranes and dialysers in clinical practice, with an
sified on the basis of their composition (cellulosic or non- emphasis on newer and emerging applications.
cellulosic) and water permeability (low or high flux)1. The
evolution of biomaterials and improved fibre production A history of dialysis membranes
(spinning) technology have resulted in new membranes Although other approaches were previously used on a
with specific characteristics and refined properties that small scale9,10, the rotating drum kidney was the first hae-
mandate a reconsideration of traditional membrane classi- modialysis membrane configuration that was employed
fication schemes2. The incorporation of innovative manu- to treat large numbers of patients11. This device com-
facturing processes, such as polymer blending3 and surface prises a 30 m cellophane tube (inner diameter = 35 mm)
functionalization4, has led to a consideration of several that is wrapped in a spiral manner around a cylinder
1
Department of Nephrology, other parameters for membrane categorization, including that rotates in a stationary dialysate bath (Supplementary
Dialysis and Transplantation,
International Renal Research
new permeability indices5, hydrophilic versus hydrophobic Fig. 1a). Although dialysis could be provided without
Institute of Vicenza (IRRIV), balance6, adsorption capacity7 and electrical potential8. a blood pump owing to the very low resistance of the
San Bortolo Hospital, In this Review, we provide an overview of the state blood compartment, the low transmembrane pressures
Vicenza, Italy. of the art in membranes and dialysers that are used for (TMPs) that were generated by this system severely lim-
2
Davidson School of Chemical chronic haemodialysis treatment and related therapies. ited ultrafiltration capabilities. Another limitation of this
Engineering, Purdue We provide a brief historical perspective and discuss the membrane system was its large extracorporeal blood vol-
University College of
Engineering, West Lafayette,
characteristics of commonly used membranes (includ- umes (500–700 ml). A modified system in which higher
IN, USA. ing the materials technology that underlies membrane blood compartment pressures allowed for adequate
*e-mail: clarkw@purdue.edu composition) and the way in which they are assembled ultrafiltration was later developed12.
https://doi.org/10.1038/ into a dialyser. We highlight the different mechanisms The next device that was widely used, the coil dialyser
s41581-018-0002-x that mediate solute removal (mainly diffusion and (Supplementary Fig. 1a), had technological characteristics
λ
Pore size
Pore size
distribution
Solute SC
1,500
150 0.6
1,000
100 0.4
500 0.2
50
0 0 0
20 40 60 80 100 100 200 300 400 500 10 102 103 104 105
TMP (mmHg) Blood flow (ml/min) Molecular weight (Da)
Secondary membrane or gel effect TMP = ΔP – π = (Pb – Pd) – π MCO
High flux (Kuf = 30 ml/h/mmHg × m2) Pb π High flux
Low flux
Mid flux (Kuf = 20 ml/h/mmHg × m2)
Pd Oncotic
Low flux (Kuf = 8 ml/h/mmHg × m2)
Hydrostatic pressure
pressure
Fig. 2 | The manufacturing process influences both the pore size distribution and the pore density of a dialysis
membrane. a | Graph describing the relationship between pore size distribution and pore density, both of which influence
the hydraulic permeability of the membrane. b | Hydraulic permeability is clinically defined by the ultrafiltration coefficient
(Kuf), which is the slope of the linear portion of a plot between ultrafiltration rate (Qf) and transmembrane pressure (TMP).
TMP is dominated by hydrostatic pressure differences between the blood (Pb) and dialysate (Pd) compartments, with a small
contribution from plasma oncotic pressure (π). c | Pore density and size also influence diffusive permeability, which is
expressed as the mass transfer coefficient–area product (KoA). This parameter is a function of blood flow rate, dialysate
flow rate and dialyser clearance and can be conceptualized as the maximum clearance obtained for a membrane of a
specific surface area under the theoretical conditions of infinite blood and dialysate flow rates. d | Pore size distribution
also affects membrane sieving properties, which are described by a plot of the solute sieving coefficient (SC) as a function
of molecular weight and radius. Three different membrane profiles are depicted: low flux, high flux and medium cut-off
(MCO). The SC is defined as the ratio between the concentration of the solute in the ultrafiltrate (UF) (Cf) and that in
plasma water (Cp) in the absence of a gradient for diffusion and is the reciprocal of the rejection coefficient (R).
Cd, concentration of the solute in the dialysate.
potting compound as the corresponding membrane pressurizing the blood compartment and monitoring pres-
area does not contribute to mass exchange. After the sure changes in the dialysate compartment (an increase in
polyurethane undergoes curing, the bundle is cut with dialysate pressure is consistent with a fibre leak). Finally, the
a specialized blade at a defined temperature to control finished product is sterilized by different methods, includ-
surface roughness, which influences protein deposition ing steam, γ-irradiation, electron beam irradiation and eth-
and coagulation. This phase is also of great importance ylene oxide sterilization, although the latter is used rarely
for blood flow distribution within the bundle. owing to its allergenic potential. Sterilization is expected to
Once the casing is sealed with caps at either end, preserve the integrity of the dialyser housing, minimize any
the integrity of the membrane bundle is assessed by changes in membrane structure and reduce the amount
of residual chemicals to levels that can be removed with PVP is leached from synthetic membranes, especially
routine rinsing before dialysis treatment. Of note, the entire under specific sterilization conditions46,47. Furthermore,
process of hollow-fibre and dialyser manufacture occurs PVP leaching might be a potential cause of an anaphylactic
in clean rooms to ensure an environment with minimal reaction in a haemodialysis patient48, although the mech-
bacterial load and especially minimal endotoxin. anism is not clear. Finally, various reports have suggested
Scanning electron micrographs of membranes pro- that increases in membrane permeability during bleach-
duced by this procedure (wall thickness 30–35 µm) based reprocessing of high-flux polysulfone dialysers are
demonstrate the variation in structure from the skin layer due to PVP leaching49. Nevertheless, definitive data linking
(a nodular structure consisting of closely packed spheres the above findings to PVP leaching have not been reported.
of polymer material with a diameter of 50–100 nm) to the As our focus in this Review is on the determinants
more external component of the membrane. The polymer of membrane and filter performance in the clinical
density gradually decreases further away from the skin setting, we do not extensively discuss factors that influ-
layer to form the more open stroma layer, which is charac- ence biocompatibility, although a few basic principles
terized by a finger-like structure (Supplementary Fig. 2a,b) are worth highlighting. Complement activation is the
or a sponge-like structure (Supplementary Fig. 2c,d). parameter that is traditionally used for characteriza-
The production process also affects the smoothness of tion of dialysis membrane biocompatibility23. However,
the internal surface of the fibre, as analysed by atomic other indices have been studied, including those related
force microscopy (AFM) (Supplementary Fig. 2e–h). to cytokine activation, effects on inflammatory cells and
The roughness of the internal surface of the fibre coagulation1. Furthermore, certain principles generally
can influence several membrane properties, including governing the exposure of flowing blood to a biomate-
protein interactions and coagulability. One study used rial apply to haemodialysis membranes. First, both the
AFM to analyse the effect of different production meth- inflammatory potential (measured by cytokine and com-
ods on the surface roughness and pore size distributions plement activation and other indices) and the thrombo-
of two membranes of differing PES:PVP composition — genic propensity of a biomaterial are mediated by the
a PES:PVP weight percentage of 18:6 (series A) or 18:3 nature of the layer of proteins that are adsorbed instan-
(series B)45. All other aspects of the membrane prepara- taneously to the surface upon exposure to blood50–52. The
tion process were the same except for the method of heat effect of protein adsorption on membrane performance
treatment just before drying, which used either water is discussed extensively below. Second, in terms of
(95 °C for 30 min) or air (150 °C for 5 min). Changes in thrombogenicity, studies of biomaterials clearly differ-
surface roughness were quantified by Ra, which is the entiate low-flow conditions, in which clotting is medi-
mean distance between the surface and the centre of the ated predominantly by the coagulation pathway, from
reference plane of measurement. Pore-related parame- high-flow conditions, in which shear-induced platelet
ters, including molecular weight cut-off (MWCO) and effects have an important role53. Although not clearly
pore size distribution, were also measured. For both elucidated, both of these phenomena (adsorbed proteins
membrane series, heat treatment clearly attenuated sur- and flow rate) probably influence the thrombogenic
face roughness relative to the untreated membranes, and potential of a dialysis membrane. Finally, it should be
on the basis of the percentage decrease in Ra, the reduc- emphasized that the biocompatibility of a dialysis treat-
tion was more pronounced for the series B membrane. ment modality is a function not only of the membrane
This surface roughness attenuation was particularly but of the entire dialysis system, including the blood tub-
obvious after the heat treatment using air. A higher PVP ing and all other biomaterials in the extracorporeal cir-
content (series A) was associated with consolidation of cuit as well as the fluid to which the patient is exposed.
the inner surface polymer nodules into aggregates com-
pared with the more discrete nodules for the series B Hollow-fibre membrane transport
membrane. Similarly, AFM analyses of the outer sur- Blood compartment considerations. Although the
face of both of these asymmetric membranes showed a composition of hollow-fibre membranes varies con-
decrease in surface roughness from heat treatment. siderably, hollow fibres typically have an inner (blood
The PVP content of the casting solution and the compartment) diameter of ~180–220 µm and a length of
type of heat treatment also influenced the permeabil- 20–24 cm (ref.54). Different phenomena imposed by the
ity properties of the membrane. Before heat treatment, standard operating conditions of haemodialysis dictate
dextran-based experiments demonstrated that the the fairly narrow ranges that are acceptable for these
MWCO of both membranes was >200 kDa. Heat treat- structural parameters. The major incentive to reduce
ment with water increased the MWCO value some- hollow-fibre inner diameter is the enhancement of dif-
what, whereas heat treatment with air markedly reduced fusive mass transfer due to reduced diffusion path length
MWCO to a range (35–45 kDa) that is suitable for dialy- within the blood compartment. Furthermore, the inverse
sis. In general, the investigators noted a direct correlation proportionality between channel width and shear rates
between the degree of surface roughness and the degree (at constant flow rates) leads to attenuated blood-side
of pore size variability. Although the results of this inves- boundary layer effects for smaller diameters 55–57.
tigation are not necessarily directly applicable to clinical However, inspection of equation 1, which expresses the
observations, they are nevertheless useful findings that fundamental law (Hagen–Poiseuille) governing the lon-
are informative about fundamental membrane properties. gitudinal (axial) flow of blood through a cylinder (that is,
While PVP is a crucial component of synthetic mem- the hollow-fibre inner lumen), demonstrates the limits
branes, it is worth noting that some evidence suggests that on the extent to which inner diameter can be reduced58:
a Cuprophan (cellulose) Polysulfone Polyethersulfone Fig. 3 | The physical characteristics of membranes affect
Wall thickness 5–15 μm Wall thickness 75–100 μm Wall thickness 30 μm their functional properties. a | Membrane thickness and
structure influence functional characteristics. Whereas the
cellulosic cuprophan membrane has a thin wall and is
optimally utilized in diffusion-based haemodialysis, the
original synthetic membranes (for example, polysulfone)
200 μm 200 μm 200 μm had very thick walls, and despite higher permeability, the
performance in diffusion haemodialysis was poor. The
combination of thinner walls and high permeability in
modern synthetic membranes (for example,
polyethersulfone) compared with earlier membranes has
permitted diffusion and convection to be employed
• Natural polymer • Synthetic polymer- • Synthetic polymer- simultaneously. b | Diffusion-based solute clearance ideally
• Hydrophilic (hydrogel) asymmetric microporous declines with increasing solute molecular weight. The
• Low hydraulic • Hydrophobic structure • Hydrophobic–hydrophilic
observed values, however, can be different from the ideal
permeability • High hydraulic • High hydraulic
• Low sieving properties permeability permeability line owing to the characteristics of the solute, such as
• Prevalent use in diffusive • High sieving properties • High sieving properties electrical charges, binding of proteins, steric configuration
therapy (haemodialysis) • Exclusively used for • Combination diffusive- and interaction with water (hydrophilicity). For illustrative
convective therapy convective therapy purposes, water molecules in part b are not drawn to scale.
(haemofiltration) (high-flux haemodialysis
and haemodiafiltration)
c,d | The physicochemical properties of hydrophilic and
b hydrophobic membranes. Whereas there is a continuum of
the fluid phase inside the pores of hydrophilic membranes,
this is not the case for hydrophobic membranes. For this
Solute Steric
configuration
reason, substantial efforts were made to modify synthetic
δ+
membranes by the addition of hydrophilic domains for use
Diffusion-based in haemodialysis, whereas the use of hydrophobic
solute clearance High filtration rates
(convection) membranes has been limited to convective techniques. α,
δ– δ+ contact angle; δ, partial charge.
δ–
Electrical charges structure, the membrane itself rapidly becomes the con-
trolling resistance in this case also as solute molecular
weight increases55. In general, this is the case for solutes
Solute clearance
membrane formation for two reasons7,87,88. First, because expresses Kuf in units of ml/h/mmHg, this parameter is
the mass of large proteins, such as albumin, fibrinogen frequently normalized to membrane surface area, as dis-
and immunoglobulins, adsorbed during secondary cussed below. Finally, the European Dialysis (EUDIAL)
membrane formation is a minute fraction of their cir- working group defines a high-flux dialyser as having an
culating plasma pools, this process has no relevant ultrafiltration coefficient >20 ml/h/mmHg/m2 and a β2m
effect on their plasma concentrations. Furthermore, the SC >0.6 (ref.99).
adsorption of such molecules is limited to the nominal Classification schemes that focus even more on solute
(blood-contacting) surface of the hollow fibre because permeability properties have been proposed. These new
they generally do not have access to the much larger classification systems acknowledge the importance of
surface area of the internal pore structure (as discussed larger molecules and the need to incorporate additional
below, albumin is an exception to this general rule). membrane classes that have extended removal spectra.
Second, adsorptive removal of smaller proteins that gain High-flux and ‘protein-leaking’ membranes have been
access to the large surface area of the internal pore struc- defined on the basis of a combination of water perme-
ture can be quantitatively important, thereby contributing ability, β2m removal parameters (sieving coefficient or
to clinically relevant decreases in plasma concentrations clearance) and albumin parameters (sieving coefficient
during treatment. Substantial amounts of β2m and other or amount removed)95. In this system, the high-flux class
low-molecular-weight proteins can be adsorbed by some is defined by a water permeability of 20–40 ml/h/mmHg/
membranes, contributing to a reduction in post-dialysis m2, a β2m SC of 0.7–0.8 and albumin loss of < 0.5 g (on
protein concentration (Supplementary Fig. 3). the basis of a 4 h haemodialysis treatment), whereas the
same parameters defining a protein-leaking membrane
New membrane classification are >40 m/h/mmHg/m2, 0.9–1.0, and 2–6 g, respectively.
As more knowledge has been gained over the past several Although not explicitly stated, these values correspond
years about compounds that contribute to uraemic toxicity, to ‘virgin’ membrane performance and do not reflect
it is clear that peptides, proteins and protein-bound potential diminutions during treatment as a result of
compounds are potentially important categories of secondary membrane effects.
toxins89–92. The peptide and protein category com- Two new membrane classes, medium cut-off (MCO)
prises >25 low-molecular-weight proteins that are as large and high cut-off (HCO), have been proposed, extending
as 51 kDa (ref.92). However, as discussed earlier, removal of the earlier classification scheme. The HCO class is char-
these molecules might be limited during diffusion-based acterized by a substantial increase in water permeability
therapies that utilize conventional high-flux dialys- (relative to both the high-flux and the protein-leaking
ers. In previous attempts to address this limitation, classes) and a virgin β2m SC of 1.0 (ref.100). However, the
‘protein-permeable’ membranes with larger mean pore high albumin loss rates associated with this membrane
sizes were developed93–95, although excessive albumin class generally preclude their long-term use for patients
losses were raised as a major concern95. Nevertheless, with ESRD101. In addition, this membrane has been used
these larger uraemic toxins are generally considered to be for fairly limited time periods in clinical conditions in
clinically important, and more effective dialytic removal which the potential risks due to albumin loss are con-
strategies might improve patient outcomes. sidered reasonable in relation to the potential benefits.
As new therapies are developed to address current Several studies have reported the use of an HCO mem-
limitations, membrane classification schemes also need brane for patients with myeloma-associated acute kidney
to evolve. As mentioned earlier, Kuf is the most commonly injury specifically to target augmented removal of free
used parameter for classification purposes; a value of antibody light chains to promote renal recovery102–104.
12 ml/h/mmHg differentiates low-permeability and Clinical experience with HCO membranes in critically
high-permeability dialysers according to the US Food ill patients receiving continuous renal replacement ther-
and Drug Administration96. However, this regulatory apy, specifically for the removal of inflammatory medi-
(versus clinical) definition was originally based on the ators, has also been the subject of several studies105–107,
requirement of using a dialysis machine with an auto- although the role of HCO membranes in clinical practice
mated ultrafiltration control system in conjunction with remains unclear.
a high-permeability dialyser to avoid fluid balance errors. On the basis of experiments involving determination
As ultrafiltration control is now a standard feature of all of dextran sieving coefficients over a wide molecular
dialysis machines, the clinical relevance of this definition weight range, a new solute removal parameter for the
is now debatable. Furthermore, this definition provides characterization of modern highly permeable mem-
little insight into the depuration capabilities of a dialyser; branes has been proposed100,108. This new parameter, the
for example, it does not recognize the category of ‘molecular weight retention onset’ (MWRO) index, is
high-efficiency dialysers, for which the primary criterion generated from a standard solute sieving coefficient ver-
is small-solute clearance rather than water flux97. sus molecular weight profile, as with the classic MWCO.
Although still fairly rudimentary, the revised mem- The MWRO is defined as the molecular weight at which
brane definition that was used for the HEMO Study is an the SC value first reaches 0.9 (whereas the MWCO corre-
improvement98. In this definition, the two criteria for a sponds to a SC of 0.1). The investigators rationalized this
high-flux dialyser are Kuf >14 ml/h/mmHg and first-use approach by suggesting that the MWRO index, which
β2m clearance >20 ml/min, whereas a first-use β2m clear- provides insights about pore size distribution, supple-
ance <10 ml/min defines a low-flux dialyser98. Although ments information provided by the MWCO, which is
the US Food and Drug Administration classification primarily correlated with mean pore size. The steepness
Inner diameter 200 μm Inner diameter 180 μm of the sieving coefficient versus molecular weight profile
300 300 is determined mostly by the proximity of the values of
n = 10 n = 10
these two parameters, as reiterated recently85. As part
Clearance (ml/min)
Clearance (ml/min)
250 250
200 200 of this work100,108, a classification scheme was proposed
P <0.01 in which the MWCO and the MWRO are utilized in
150 150
100 100 combination to define different dialyser classes.
50 50
Although extending the removal spectrum of modern
dialysis membranes beyond the capabilities of standard
0 0
high-flux devices is highly desirable, the design challenge
ea
ea
ea
ea
In 2
in
In 2
in
P
P
B1
B1
ul
ul
Ur
Cr
curves (Fig. 6a–c) and the corresponding sieving coefficient early time points (especially in convective treatments),
profiles (Fig. 6d) for three classes of membranes (high flux, with a subsequent ‘breakthrough’ at later time points,
MCO and HCO) reveal that as the separation between which is consistent with saturation of membrane binding
MWRO and MWCO decreases, the profile of the curve sites or reduced pore access due to fouling. Therefore,
becomes steeper, resulting in increased removal of large caution should be exercised in the interpretation of the
uraemic toxins and decreased loss of albumin. Although sieving coefficients for low-molecular-weight proteins
standard high-flux membranes made the development of for highly adsorptive membranes.
convective therapies possible, MCO membranes repre- In a 1986 study using a 1.3 m2 high-flux polysulfone
sent the basis for a new diffusion-based therapy called dialyser, researchers measured the sieving coefficients
‘expanded haemodialysis’ (refs84,85). of several low-molecular-weight proteins (11.8–55 kDa)
during post-dilution haemofiltration72. The prescribed
Clinical assessment of membranes blood flow rate and ultrafiltration rate was 200 ml/min
Following the clinical introduction of the first highly and 55 ml/min, respectively, with a mean TMP of
permeable dialysis membrane, AN69, in the late 1960s17 160 mmHg. On the basis of an assumed mean haema-
and the subsequent development of polysulfone and tocrit of 30% for the patient population, an average
other membranes for high-flux haemodialysis and filtration fraction of 40–45% can be estimated from the
haemodiafiltration109–111, clinical studies characterizing classic, plasma-based equation. Serial sieving coefficient
their performance were published, beginning in the late estimates were made during the first 20 min; peak val-
1980s87,112–122. These studies focused mostly on quanti- ues for each low-molecular-weight protein occurred in
fying the removal of β2m (molecular weight 11.8 kDa) the first 10 min. For each protein, a significant decrease
after its identification as the precursor of an amy- was observed between the peak sieving coefficient and
loid protein that is deposited specifically in patients the 20 min value (P < 0.05). Furthermore, the effect was
undergoing chronic haemodialysis123,124. These studies directly proportional to the molecular weight of the pro-
demonstrated that substantial β2m removal is possi- tein as no measurable filtration of solutes with a molecular
ble with high-flux dialysers used in the haemodialysis weight >30 kDa was observed after 20 min of treatment.
mode, which occurs through both transmembrane and These fairly unconvincing data can be mostly attributed
adsorptive mechanisms, and showed that unmodified to the combination of low blood flow rate, inadequate
cellulosic membranes are essentially impermeable to membrane surface area and high filtration fraction, all of
β2m. Furthermore, the major β2m removal mechanism which promote secondary membrane formation.
was membrane-specific, as transmembrane removal pre- For equivalent ultrafiltration rates up to ~6.5 l/h
dominated for polysulfone-based filters whereas adsorp- (with a blood flow rate of 300 ml/min), the clearance of
tion was the predominant mechanism for AN69 and low-molecular-weight proteins of 12–33 kDa is supe-
some PMMA dialysers. Finally, many of these studies rior with post-dilution haemodiafiltration compared
provided haemodiafiltration performance data, although with pre-dilution haemodiafiltration125,126. This benefit
the substitution volumes that were used were generally of the post-dilution mode has been attributed to the
less than those currently used in clinical practice. greater accumulation of the partially rejected proteins
In one study117, high-flux synthetic (AN69, polysul- at the blood–membrane interface (that is, concentra-
fone and PES) dialysers with a surface area of 1.6–1.9 m2 tion polarization)69,127 — it is this ‘submembranous’
were used for haemodialysis, haemodiafiltration and protein concentration on which the convective forces
haemofiltration in a small number of patients. A blood act. Because the degree of polarization is directly pro-
flow rate of 450 ml/min was prescribed for all therapies, portional to the extent of protein rejection, the relative
and both convective therapies were performed in the benefit of the post-dilution mode increases in proportion
post-dilution mode with online substitution fluid. The to the molecular weight of the solute. However, this same
mean ultrafiltration volume was 20.8 litres and 30.6 litres principle applies to albumin removal, making the balance
in haemodiafiltration and haemofiltration, respectively, between optimized removal of low-molecular-weight
which was derived from the reported mean ultrafil- proteins and minimized albumin losses a very important
tration rate for each modality. On the basis of effluent consideration in post-dilution haemodiafiltration.
collection, the total β2m removal was approximately High-flux haemodialysis and online post-dilution
100–125 mg, 175–200 mg and 225–250 mg for patients haemodiafiltration were compared in 45 patients with
undergoing haemodialysis, haemodiafiltration and ESRD (mean haematocrit, 0.30) who were treated over
haemofiltration, respectively (the differences between a 1-year period with the same high-flux 1.7 m2 polyary-
the three modalities were significant for all three dial- lethersulfone dialyser128. The mean delivered blood flow
ysers investigated). The β2m SC for the polysulfone and rate in the haemodialysis and haemodiafiltration groups
PES dialysers (measured at 5 min and 180 min of treat- was 286 ml/min and 269 ml/min, respectively, whereas
ment) were approximately 0.50–0.65 in the haemodia- the mean ultrafiltrate volume in the haemodiafiltration
filtration and haemofiltration modes. In addition, the group was 21 litres over a mean treatment period of
values of the β2m SC for the AN69 dialyser were low 4.1 h. On the basis of these mean values, the estimated
(~0.10) at 5 min in both the haemodiafiltration and ultrafiltration rate was approximately 85 ml/min, which
the haemofiltration modes but increased significantly results in an estimated filtration fraction of 0.43. Over
(P < 0.05) at 180 min to approximately 0.4 in haemodia- the 12-month study period, the mean pretreatment
filtration mode and 0.6 in haemofiltration mode. These serum concentration of β2m decreased modestly and to
AN69 data suggest that β2m adsorption predominates at a similar extent in both groups, although β2m clearance
a b c
HF MCO HCO
Pore density x cm2
in
in
ea
in
in
ea
in
in
m
m
B1
B1
B1
ob
ob
ob
m
Ur
Ur
Ur
β
β
2
2
bu
bu
bu
gl
gl
gl
Al
Al
Al
yo
yo
yo
M
M
Pore size (Å) Pore size (Å) Pore size (Å)
d
1.0
MWRO
HCO MCO
0.8 HF
LF
0.6
SC
0.4
Albumin
(68 kDa)
0.2 β2m
MWCO (12 kDa)
0.0
100 1,000 10,000 100,000
log molecular weight (Da)
Fig. 6 | Performance characteristics of haemodialysis membranes derived from a suggested new classification
system. Pore size distribution curves are schematically depicted for three classes of membranes, high flux (HF; part a),
medium cut-off (MCO; part b) and high cut-off (HCO; part c), as well as their sieving coefficient (SC) profiles (part d). As the
interval between molecular weight retention onset (MWRO) and molecular weight cut-off (MWCO) decreases, the profile
of the curve becomes steeper, increasing the removal of large uraemic toxins (such as β2-microglobulin (β2m)) while
decreasing the loss of albumin (part d). A low-flux (LF) membrane is shown for comparison. B12, vitamin B12. Part d is
adapted with permission from ref.85, Karger.
was significantly higher in the haemodiafiltration group 60 ml/min and 90 ml/min, respectively. The efficacy of
than in the haemodialysis group (61 ml/min versus β2m removal was assessed by the difference between
38 ml/min; P < 0.001). The researchers hypothesize that pretreatment and post-treatment serum β2m concentra-
slow intercompartment mass transfer in the body might tions, whereas albumin losses were estimated from serial
account for this finding. Furthermore, the decrease measurements of albumin concentration in the diafiltrate
in the serum concentration of complement factor D using a modified area under the curve approach.
(molecular weight 24 kDa) was significantly greater in The efficacy of β2m removal was linearly related to
the haemodiafiltration group than in the haemodialysis the substitution fluid rate for each dialyser. At a fluid
group over the study period (P < 0.001). substitution rate of 90 ml/min, the β2m removal rate for
The relationship between β2m removal and albumin most dialysers ranged between 65% and 75%. Peak val-
loss during online post-dilution haemodiafiltration ues of instantaneous albumin removal rates (in mg/min)
was assessed in a group of patients who were treated occurred at the earliest measurement time point (10 min)
with eight different high-flux dialysers of surface area and subsequently decreased in an exponential manner.
1.3–1.5 m2 (ref.129). Whereas the substitution fluid rate Furthermore, cumulative albumin loss for a given treat-
was variable (30 ml/min, 60 ml/min or 90 ml/min, ment had a strong dependence on substitution fluid rate
and a constant dialysate flow rate of 600 ml/min), the — this relationship tended to be nonlinear for dialysers
prescribed blood flow rate remained constant in each with greater albumin permeability. For a substitution
patient (mean 292 ml/min) in this population, and the fluid rate of 90 ml/min, albumin loss (normalized to a
mean haematocrit was 36%. On the basis of these mean treatment time of 4 h) was approximately 0.4–7 g. On the
values and an assumed net ultrafiltration rate of 10 ml/min, basis of these data, the investigators proposed a dialyser
the mean filtration fraction can be estimated as 0.21, membrane classification system in which low, medium
0.38 and 0.54 at substitution fluid rates of 30 ml/min, and high values for β2m removal rate (0–50%, >50–70%
and >70%, respectively) are evaluated in conjunction volumes are also associated generally with greater albu-
with similar gradations of albumin loss (0–2 g, 2–5 g min loss, without a concomitant benefit of increased
and >5 g, respectively). β2m removal139. This observation is a predictable conse-
Another study evaluated the possibility that adapta- quence of albumin polarization at the membrane surface
tions in dialyser design could ameliorate the relationship due to the combination of high ultrafiltration rates and
between β2m removal and albumin loss in post-dilution haemoconcentration, as described previously.
haemodiafiltration130. This crossover randomized trial The factors that might potentially influence albu-
involved a modified polysulfone filter that, according to min loss during post-dilution haemodiafiltration have
the manufacturer, has a more open structure in the mem- been evaluated135. These investigators assessed poly-
brane region adjacent to the skin layer than the standard sulfone dialysers with surface areas of 1.5–2.2 m2 and
high-flux polysulfone dialyser (surface area 1.4 m2 for PMMA dialysers with surface areas of 1.6–2.1 m 2.
both membranes). This adaptation is intended to increase Patients were treated with either a ‘manual’ infusion
the β2m sieving coefficient and reduce the albumin siev- technique, in which the dialysis nurse adjusts the substi-
ing coefficient (on the basis of in vitro determinations). tution fluid rate according to the TMP, or an automated
In this trial, mean blood flow rate and treatment time technique, in which the dialysis machine continuously
were approximately 405 ml/min and 4.9 h, respectively, adjusts the infusion rate on the basis of several param-
whereas total convection volume (substitution fluid eters, including membrane type, haematocrit, total
and net fluid loss) was approximately 30 litres in both protein concentration, blood flow rate and ultrafiltra-
groups. The percentage reduction in the serum concen- tion rate, with an established maximum TMP. Of note,
tration of low-molecular-weight proteins ranging from almost half of the 37 treatments that were performed
11.8 kDa (β2m) to 33 kDa (α1-microglobulin) was signif- with the automated technique had to be switched to the
icantly greater (P <0.05) for the modified dialyser than manual mode owing to high TMP values (>250 mmHg)
for the standard dialyser, as was the mass removal (on that were not adequately modulated by automated infu-
the basis of diafiltrate sampling). However, mean albu- sion rate changes. Overall, the mean albumin loss was
min loss was also significantly higher for the adapted 3.13 ± 2.5 g per session, was linearly related to TMP and
filter versus the standard filter (4.25 g versus 3.01 g was significantly higher in the automated group than
per treatment; P = 0.03). Thus, the permeability for in the manual infusion control group (3.92 ± 3.06 g ver-
low-molecular-weight proteins and albumin for these two sus 2.37 ± 1.67 g; P = 0.01). Furthermore, multivariate
dialysers correlated reasonably well in the clinical setting. regression analysis showed that TMP was the only sig-
Prescribed ultrafiltration rates that are necessary nificant predictor of albumin loss (P = 0.002), although
to achieve convection volumes >23 litres per session, the predictive value of membrane type almost reached
recently established by consensus guidelines90,131–134, are statistical significance (P = 0.054). However, no associa-
predicated on attaining fairly high blood flow rates and tion was observed between diafiltrate albumin loss and
on the dialyser achieving TMP values up to 300 mmHg. serum albumin concentration during this fairly short
However, in many patients, these conditions are asso- (3–4 month) study.
ciated with prominent haemoconcentration and sec- These albumin loss data135 are generally consistent
ondary membrane effects, which result in frequent with results from other post-dilution haemodiafiltration
pressure alarms and potential treatment interruptions. studies, and these investigators recommend that clinical
Contemporary dialysis machines utilize different concerns about albumin loss should not limit the use of
approaches in an attempt to mitigate these effects135–138, post-dilution haemodiafiltration. Nevertheless, efforts
enabling a distinction to be made between ‘maximum’ have been focused on the development of alternative
convection volumes (defined by the blood flow rate convective techniques that preserve the depuration
and TMP parameters discussed above) and convec- capabilities of post-dilution haemodiafiltration while
tion volumes that are more realistically attainable in also overcoming some of the complexities and techni-
the operating conditions of a given haemodiafiltration cal limitations of this modality141–143. In various ways,
treatment. As discussed below, although these mitigating these alternative approaches aim to reduce haemo-
technologies are designed to maximize the substitution concentration and attenuate fouling effects so that
volume, treatments employing them still frequently TMP and albumin losses can be maintained in clini-
result in operating TMP values that cannot be sustained cally acceptable ranges. However, there are insufficient
throughout a treatment. clinical data to warrant these alternative techniques
The considerable variation in Kuf, which is defined supplanting post-dilution haemodiafiltration as the
by the linear portion of the ultrafiltration rate versus standard convective modality when haemodiafiltration
TMP profile, during a post-dilution haemodiafiltra- is the chosen therapy. Furthermore, the superiority of
tion treatment can substantially influence the ability to post-dilution haemodiafiltration over standard high-flux
achieve a desired convection volume139,140. Furthermore, haemodialysis is still a matter of debate.
delivery frequently falls short for treatments in which Efforts to extend the permeability spectrum of
maximum convection volumes are prescribed, whereas high-flux synthetic membranes might enable the
treatment prescriptions that accommodate the var- presumption of a need for a convection-based therapy to
iations in the ultrafiltration rate–TMP relationship be challenged5,79,84,108,144–146. By virtue of larger pore sizes,
are much more likely to achieve the prescribed (albeit increased membrane diffusivity is one mechanism by
lower) convection volume139. In addition to treatment which the removal of large solutes is augmented with the
delivery shortfalls, prescribed maximum convection previously mentioned MCO class of dialysers (relative
to standard high-flux membranes). However, although fluid administration5,144. Clinical outcome data for the new
haemodialysis using this type of dialyser is technically therapy (‘expanded haemodialysis’) that is made possible
diffusion-based, most large-solute removal still occurs by this class of dialysers will help establish its clinical role
by convection through the mechanism of internal filtra- in the future, especially in relation to haemodiafiltration.
tion, as discussed earlier. For MCO and other dialysers, The appropriate balance between low-molecular-weight
the effect of this mechanism is intentionally augmented protein removal and albumin loss can be raised a final time
through increases in the mean pore size and reductions here147. In addition to the opinion that albumin losses of up
in the inner diameter of hollow fibres. Preliminary data to 4 g per session are clinically acceptable135, a retrospective
suggest that this class of dialysers has depuration capabil- analysis of Japanese patients reported a significantly higher
ities that approach those of online post-dilution haemo- survival in patients with ESRD who sustained albumin
diafiltration without the need for (exogenous) substitution losses >3 g per treatment than in those patients with lower
albumin losses148. The investigators attributed this finding substantial changes in membrane performance. For
to the beneficial removal of protein-bound uraemic toxins. example, functionalization of the internal surface of an
The data from this study can be viewed in the context of AN69 membrane resulted in altered coagulation prop-
peritoneal dialysis, in which albumin losses of approxi- erties and electronegativity150,151. In addition, function-
mately 4 g per day (30 g per week) are typical149. These con- alization of a PES membrane via covalent linkage with
siderations notwithstanding, the clinically acceptable limit vitamin E152–154 led to a clinically meaningful reduction
of albumin loss during extracorporeal dialysis treatments in circulating reactive oxygen species that are generated
remains to be defined more clearly. at the blood–membrane interface. These new modifica-
tions may develop further in the future, suggesting that
Membrane functionalization membrane properties should be characterized on the
The production process and polymeric composition deter- basis of not only classic parameters but also indices that
mine the final characteristics and functional properties of a are capable of assessing these new features. Finally, in the
membrane. The internal skin layer is of crucial importance future, entirely new types of membranes might be applied
because it represents the true barrier for mass separation to novel haemodialysis therapies, such as silicon-based
and is the portion of the membrane that comes in direct nanopore membranes for an implantable device155.
contact with the blood. The characteristics of the internal
surface are responsible for the blood–membrane interac- Conclusions
tions, including phenomena such as coagulation, platelet The bidirectional process of mass separation between
adhesion and protein deposition. A substantial reduction the blood and the dialysate involves several mecha-
in activation of the clotting cascade and membrane fouling nisms of interaction between the fluid phases and the
has been achieved by improvement of the inner surface membrane barrier. The nature of the fluid phases,
design and smoothness. Specific physicochemical pro- the characteristics of the solutes and the structure
cesses have been applied during membrane production of the membrane represent a combination of elements
to improve the characteristics of the membrane inner sur- that are involved in the final process of mass separation
face. These efforts have resulted in increased permeability, and dialysis. The development of a unifying classifica-
improved haemocompatibility and reduced fouling effects tion system for dialysis membranes is extremely complex
during prolonged utilization. and must be multidimensional. When overly simplistic
Several membranes that are routinely used in dialy- schemes are used, membranes that have substantial dif-
sis display characteristic surface modification through ferences of potential clinical importance cannot be differ-
oxidation, plasma treatment, pervaporation or copol- entiated. Each membrane, although belonging to a classic
ymerization. Membrane surfaces are also modified by category, has a specific area and profile that is dependent
additives, including PVP, polyethylene co-vinyl alcohol on other variables2 (Box 1). Furthermore, a uniform clas-
and polyethylene glycol. Polymer blending (for example, sification of membranes cannot be proposed unless all
polyethyleneoxide-modified polyacrylonitrile, poly- characteristics — in particular, those that may be unique
amide–PES and polyarylethersulfone), macromolecule for a specific membrane — are taken into considera-
inclusion and coating of the inner surface are other tion. For personalized (‘precision’) medicine, a clinician
mechanisms of membrane modification and adaptation can then select a dialysis membrane on the basis of the
for specific clinical uses. Finally, further modifications of specific needs of the individual patient and the desired
the membrane surface can be obtained by polymer func- clinical results while bearing in mind that cost and
tionalization via chemical reactions, molecular imprint- cost-effectiveness are important considerations.
ing technology, ion implantation and photochemical
modification. In the future, these processes might achieve Published online 05 May 2018
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