Reviews

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.

1
Department of Nephrology,
Dialysis and Transplantation,
International Renal Research
Institute of Vicenza (IRRIV),
San Bortolo Hospital,
Vicenza, Italy.
2
Davidson School of Chemical
Engineering, Purdue
University College of
Engineering, West Lafayette,
IN, USA.
*e-mail: clarkw@purdue.edu
https://doi.org/10.1038/
s41581-018-0002-x
Haemodialysis is an extracorporeal blood cleansing tech-
nique that is used to remove metabolic waste products
that accumulate in patients with end-stage renal disease
(ESRD). Solutes and water are removed through semi-
permeable membranes using different mass separation
mechanisms (diffusion, convection and adsorption).
Traditionally, dialysis membranes have been broadly clas-
sified on the basis of their composition (cellulosic or non-
cellulosic) and water permeability (low or high flux)1. The
evolution of biomaterials and improved fibre production
(spinning) technology have resulted in new membranes
with specific characteristics and refined properties that
mandate a reconsideration of traditional membrane classi-
fication schemes2. The incorporation of innovative manu-
facturing processes, such as polymer blending3 and surface
functionalization4, has led to a consideration of several
other parameters for membrane categorization, including
new permeability indices5, hydrophilic versus hydrophobic
balance6, adsorption capacity7 and electrical potential8.
In this Review, we provide an overview of the state
of the art in membranes and dialysers that are used for
chronic haemodialysis treatment and related therapies.
We provide a brief historical perspective and discuss the
characteristics of commonly used membranes (includ-
ing the materials technology that underlies membrane
composition) and the way in which they are assembled
into a dialyser. We highlight the different mechanisms
that mediate solute removal (mainly diffusion and
convection), with particular emphasis on the key part
played by blood–membrane interactions. We pres-
ent an updated membrane classification scheme and a
description of conventional and new parameters that
are used to characterize and quantify membrane solute
and water transport. Finally, we discuss the utilization
of membranes and dialysers in clinical practice, with an
emphasis on newer and emerging applications.
A history of dialysis membranes
Although other approaches were previously used on a
small scale9,10, the rotating drum kidney was the first hae-
modialysis membrane configuration that was employed
to treat large numbers of patients11. This device com-
prises a 30 m cellophane tube (inner diameter = 35 mm)
that is wrapped in a spiral manner around a cylinder
that rotates in a stationary dialysate bath (Supplementary
Fig. 1a). Although dialysis could be provided without
a blood pump owing to the very low resistance of the
blood compartment, the low transmembrane pressures
(TMPs) that were generated by this system severely lim-
ited ultrafiltration capabilities. Another limitation of this
membrane system was its large extracorporeal blood vol-
umes (500–700 ml). A modified system in which higher
blood compartment pressures allowed for adequate
ultrafiltration was later developed12.
The next device that was widely used, the coil dialyser
(Supplementary Fig. 1a), had technological characteristics

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Key points
• Traditional schemes for the classification of dialysis membranes, based simply on
composition and water permeability, are outdated and new approaches are needed.
• Dialyser utilization in clinical practice has evolved over time and is now dominated by
devices with synthetic high-flux membranes.
• Rational treatment prescription by clinicians requires an understanding of the basic
mechanisms underlying solute and water removal in dialysis — namely, diffusion,
convection, adsorption and ultrafiltration.
• New therapies (including expanded haemodialysis) that utilize membranes designed
to produce a high degree of internal filtration are undergoing clinical evaluation as
potential alternatives to convective therapies, such as on-line haemodiafilitration.
• The clinically acceptable amount of albumin loss for extracorporeal therapies remains
to be defined.
that differed substantially from those of the rotating
drum13. The functional unit of this dialyser, cellophane tub-
ing surrounded by a fibreglass screen, was wound together
in a single coil located in a large cylindrical drum to which
a recirculating volume of dialysate was delivered. High
blood compartment pressures could be achieved as a result
of narrow blood channels that were produced by specific
spacing of the screen around the tubing and the addition
of a blood pump. However, this geometry also produced
high blood compartment resistances, which resulted in
high TMPs and substantial obligatory ultrafiltration vol-
umes that could not be predicted or reliably controlled. The
commercial version of this device (the ‘twin coil’) consisted
of two coils with a total surface area of 1.8 m2 (ref.14).
The Kiil dialyser15 employed a parallel blood–dialysate
flow configuration in which the blood compartment was
created by a series of cellophane flat sheet membranes sup-
ported by plastic boards. Diffusive mass transfer efficiency
was aided by narrow blood channels (created by compres-
sion of the boards) and the use of a new thin-walled cellu-
losic membrane, cuprophan. Later adaptations that were
used in the 1960s and 1970s included multiple-use16 and
disposable17 versions (Supplementary Fig. 1b).
Although the availability of all of these devices
allowed the use of clinical dialysis to grow, they had
many limitations, especially the high blood compart-
ment volumes required and the inefficient mass transfer
characteristics. In the late 1960s, the hollow-fibre
artificial kidney (Supplementary Fig. 1c) revolutionized
dialysis by providing improved geometry in terms of
blood rheology and solute mass transfer18. The specific
advantages provided by this configuration included
an improved surface-area:volume ratio in the blood
compartment (that is, shorter diffusion path lengths)
and decreased boundary layer effects with acceptable
end-to-end pressure drops, which made the hollow-fibre
configuration the main choice in clinical dialysis.
At present, approximately 300 million hollow-fibre
haemodialysers are utilized annually worldwide.
Hollow-fibre membranes
General considerations. Dialysis membranes have
traditionally been categorized on the basis of their mate-
rial composition into cellulosic and synthetic membrane
groups1,19,20 (Supplementary Table 1). Although unmod-
ified cellulosic membranes were used extensively in
the past, their use has dropped precipitously over the
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past decades to the point of effective absence from
the market. Although the performance and functional
characteristics of some modified cellulosic membranes
are similar to those of synthetic membranes, the use
of modified cellulosic membranes continues to fall.
Therefore, the remainder of our discussion focuses
primarily on synthetic membranes.
Synthetic membranes were originally developed for a
dialysis application >40 years ago to address the relative
bioincompatibility21–23 and limited permeability19,20 of
unmodified cellulosic membranes. Furthermore, although
the structure of early cellulosic membranes (wall thick-
ness ≤ 15 µm) facilitated diffusive transport, the inherently
low water permeability prevented the application of cellu-
losic membranes in convective therapies. The very thick
walls of the earliest synthetic membranes (~100 µm) were
not conducive to diffusion-based therapies; thus, their
use was originally limited to haemofiltration (purely
convection-based). Subsequent modifications, especially
substantial reductions in wall thickness, allowed synthetic
membranes to be adapted for high-flux haemodialysis and
haemodiafiltration. Contemporary synthetic membranes
generally have a wall thickness of 20–50 µm.
Similar to cellulosic membranes, some synthetic
membranes, including sulfonated polyacrylonitrile
(AN69) and poly(methyl methacrylate) (PMMA)24,25,
are structurally symmetric, as they have a uniform com-
position that extends through the entire wall thickness
(Fig. 1). However, the majority of synthetic membranes
that are used for contemporary haemodialysis have an
asymmetric structure in which a thin inner ‘skin’ layer
(width approximately ≤ 1 µm) at the membrane–blood
interface serves as the primary size-discriminating
element in solute removal26. The remaining wall thick-
ness (the ‘stroma’) acts as a support structure that also
provides a substantial surface area for the removal of
molecules by adsorption. As opposed to the compact
nature of the skin layer, the structure of the stroma is
relatively open (‘macroporous’) and typically has a
sponge-like or finger-type structure (Fig. 1).
Production of hollow-fibre dialysis membranes. The
production of a hollow-fibre membrane is a combina-
tion of art and science. We describe the sequence of steps
involved in the production (based on diffusion-induced
phase separation27,28) of an asymmetric polyethersulfone
(PES) membrane, which is present in dialysers that are
commonly prescribed in clinical practice.
The process begins with the development of a pol-
ymer solution that contains the miscible components
PES and polyvinylpyrrolidone (PVP). PVP is necessary
to impart sufficient hydrophilicity to allow wettability
and prevent excessive protein deposition and platelet
adhesion on exposure to blood. The PVP content and
molecular weight largely determine the rheology of the
polymer solution and the ultimate structure of the stroma
layer. The polymer solution containing PVP is extruded
through the outer ring of an annular nozzle (termed a
‘spinneret’) that has two concentric openings, whereas
another solution, a solvent–non-solvent mixture termed
the ‘bore liquid’, is injected through the inner tube. At the
outlet of the spinneret, the bore fluid comes into contact
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a Poly(methyl methacrylate) (Toray Medical)
b Amembris (B. Braun Medical)
c Polyethersulfone (Membrana 3M)
d Helixone (Fresenius Medical Care)
e Polyethersulfone Polynephron (Nipro Corporation)
f Polyethersulfone (Baxter International and Gambro)
g Medisulfone (Medica)
Fig. 1 | Structural characteristics of some commercially
available synthetic dialysis membranes. Scanning
electron micrographs of the fibre (left), fibre wall (middle)
and a magnified cross-sectional view of the internal skin
layer (right). For reference, the inner diameter of the fibres
is ~200 μm. Different structural features of the membranes
are discernible, and the membranes have varying degrees
of asymmetric configuration, ranging from minimum
asymmetry (sponge-like; parts a–e) to maximum
asymmetry (finger-type; parts f,g).
with the polymer solution and precipitation is initiated,
thus creating the inner lumen of the hollow fibre.
With the basic hollow-fibre structure established,
the solution leaving the spinneret is immersed in a
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coagulation bath, resulting in a controlled precipita-
tion that converts the original homogeneous liquid
polymer solution into a two-phase system comprising
a polymer-rich phase (which forms the rigid membrane)
and a polymer-poor phase (which forms the pores). The
water content of both the luminal space and the wall of
the membrane is then reduced in a systematic manner to
enable controlled shrinkage of pores, which is induced
by capillary forces. Controlled pore shrinkage is a cru-
cial step for membrane performance as it substantially
influences the pore size distribution and pore density of
the final product. The pore density is a major determi-
nant of both the hydraulic permeability (expressed as
the ultrafiltration coefficient, Kuf ) and the small-solute
diffusive permeability (expressed as the mass trans-
fer coefficient–area product; KoA) of the membrane.
In addition, mean pore size and pore size distribution
substantially influence Kuf and the sieving properties of
the membrane for different solutes (Fig. 2). Although the
ultrafiltration coefficient of a dialyser (ml/h/mmHg/m2)
is a specific property that characterizes a ‘clean’ (that is,
unfouled) membrane, its effective value is influenced by
protein–membrane interactions29.
The KoA parameter is a function of blood flow rate,
dialysate flow rate and dialyser clearance, and is meas-
ured under conditions of zero net ultrafiltration. KoA can
be conceptualized as the maximum clearance obtained
for a dialyser of specific membrane surface area under
the theoretical conditions of infinite blood and dialysate
flow rates30. The condition of zero net ultrafiltration
implies that KoA is a purely diffusive parameter, an
assumption that is valid for all solute–membrane com-
binations with low-flux dialysers. However, a zero net
ultrafiltration condition is not equivalent to no fluid
fluxes across a high-flux dialyser membrane, and a con-
dition of ‘pure diffusion’ is not readily attainable with
this type of device29. The KoA values for small solutes are
minimally influenced in the condition of zero net ultra-
filtration and remain valid for solute removal parameters
for high-flux dialysers when measured in this context.
However, diffusive KoA values for larger solutes (for
example, β2-microglobulin (β2m)) cannot be reliably esti-
mated under these conditions, as the convective clear-
ance associated with fluid fluxes (‘internal filtration’)
contributes substantially to total clearance. The concepts
underlying KoA and Kuf are examined further below.
From a single hollow fibre to a full-size haemodialyser.
In preparation for construction of a dialyser, several
thousand (~10,000–17,000) individual hollow fibres are
assembled and wound together to form a ‘bundle’ that
has defined characteristics, including a specific fibre
spatial arrangement and packing density31–44. These
parameters influence the dialysate flow distribution
between fibres, which is an important determinant of
dialysate-side mass transfer. After this fibre bundle is
inserted in the plastic housing of the dialyser, the fibres
are sealed in a two-step process. The first step involves
application of a polyurethane (‘potting’) compound at
either end of the bundle to encapsulate the fibres. The
goals of this step are to avoid fibre lumen obstruction
and minimize the fibre length that is exposed to the
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Pore density x cm2

λ ρ1
Pore density

λ
Pore size

Pore size
distribution

Pore size (Å)

b Ultrafiltration c Membrane d Membrane

UF permeability Dialysate sieving UF
coefficient
Cd Cp Cp
Blood
Blood Blood
Hollow fibre Hollow fibre Hollow fibre
2,500 300 KoA = 1,000
Qf = Kuf · TMP SC = 1 – R = CF/Cp
2,000 250 KoA = 750 1.0
Clearance (ml/min)
Ultrafiltration (ml/h)

200 KoA = 500 0.8

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
area does not contribute to mass exchange. After the
polyurethane undergoes curing, the bundle is cut with
a specialized blade at a defined temperature to control
surface roughness, which influences protein deposition
and coagulation. This phase is also of great importance
for blood flow distribution within the bundle.
Once the casing is sealed with caps at either end,
the integrity of the membrane bundle is assessed by
pressurizing the blood compartment and monitoring pres-
sure changes in the dialysate compartment (an increase in
dialysate pressure is consistent with a fibre leak). Finally, the
finished product is sterilized by different methods, includ-
ing steam, γ-irradiation, electron beam irradiation and eth-
ylene oxide sterilization, although the latter is used rarely
owing to its allergenic potential. Sterilization is expected to
preserve the integrity of the dialyser housing, minimize any
changes in membrane structure and reduce the amount

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of residual chemicals to levels that can be removed with
routine rinsing before dialysis treatment. Of note, the entire
process of hollow-fibre and dialyser manufacture occurs
in clean rooms to ensure an environment with minimal
bacterial load and especially minimal endotoxin.
Scanning electron micrographs of membranes pro-
duced by this procedure (wall thickness 30–35 µm)
demonstrate the variation in structure from the skin layer
(a nodular structure consisting of closely packed spheres
of polymer material with a diameter of 50–100 nm) to the
more external component of the membrane. The polymer
density gradually decreases further away from the skin
layer to form the more open stroma layer, which is charac-
terized by a finger-like structure (Supplementary Fig. 2a,b)
or a sponge-like structure (Supplementary Fig. 2c,d).
The production process also affects the smoothness of
the internal surface of the fibre, as analysed by atomic
force microscopy (AFM) (Supplementary Fig. 2e–h).
The roughness of the internal surface of the fibre
can influence several membrane properties, including
protein interactions and coagulability. One study used
AFM to analyse the effect of different production meth-
ods on the surface roughness and pore size distributions
of two membranes of differing PES:PVP composition —
a PES:PVP weight percentage of 18:6 (series A) or 18:3
(series B)45. All other aspects of the membrane prepara-
tion process were the same except for the method of heat
treatment just before drying, which used either water
(95 °C for 30 min) or air (150 °C for 5 min). Changes in
surface roughness were quantified by Ra, which is the
mean distance between the surface and the centre of the
reference plane of measurement. Pore-related parame-
ters, including molecular weight cut-off (MWCO) and
pore size distribution, were also measured. For both
membrane series, heat treatment clearly attenuated sur-
face roughness relative to the untreated membranes, and
on the basis of the percentage decrease in Ra, the reduc-
tion was more pronounced for the series B membrane.
This surface roughness attenuation was particularly
obvious after the heat treatment using air. A higher PVP
content (series A) was associated with consolidation of
the inner surface polymer nodules into aggregates com-
pared with the more discrete nodules for the series B
membrane. Similarly, AFM analyses of the outer sur-
face of both of these asymmetric membranes showed a
decrease in surface roughness from heat treatment.
The PVP content of the casting solution and the
type of heat treatment also influenced the permeabil-
ity properties of the membrane. Before heat treatment,
dextran-based experiments demonstrated that the
MWCO of both membranes was >200 kDa. Heat treat-
ment with water increased the MWCO value some-
what, whereas heat treatment with air markedly reduced
MWCO to a range (35–45 kDa) that is suitable for dialy-
sis. In general, the investigators noted a direct correlation
between the degree of surface roughness and the degree
of pore size variability. Although the results of this inves-
tigation are not necessarily directly applicable to clinical
observations, they are nevertheless useful findings that
are informative about fundamental membrane properties.
While PVP is a crucial component of synthetic mem-
branes, it is worth noting that some evidence suggests that
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PVP is leached from synthetic membranes, especially
under specific sterilization conditions46,47. Furthermore,
PVP leaching might be a potential cause of an anaphylactic
reaction in a haemodialysis patient48, although the mech-
anism is not clear. Finally, various reports have suggested
that increases in membrane permeability during bleach-
based reprocessing of high-flux polysulfone dialysers are
due to PVP leaching49. Nevertheless, definitive data linking
the above findings to PVP leaching have not been reported.
As our focus in this Review is on the determinants
of membrane and filter performance in the clinical
setting, we do not extensively discuss factors that influ-
ence biocompatibility, although a few basic principles
are worth highlighting. Complement activation is the
parameter that is traditionally used for characteriza-
tion of dialysis membrane biocompatibility23. However,
other indices have been studied, including those related
to cytokine activation, effects on inflammatory cells and
coagulation1. Furthermore, certain principles generally
governing the exposure of flowing blood to a biomate-
rial apply to haemodialysis membranes. First, both the
inflammatory potential (measured by cytokine and com-
plement activation and other indices) and the thrombo-
genic propensity of a biomaterial are mediated by the
nature of the layer of proteins that are adsorbed instan-
taneously to the surface upon exposure to blood50–52. The
effect of protein adsorption on membrane performance
is discussed extensively below. Second, in terms of
thrombogenicity, studies of biomaterials clearly differ-
entiate low-flow conditions, in which clotting is medi-
ated predominantly by the coagulation pathway, from
high-flow conditions, in which shear-induced platelet
effects have an important role53. Although not clearly
elucidated, both of these phenomena (adsorbed proteins
and flow rate) probably influence the thrombogenic
potential of a dialysis membrane. Finally, it should be
emphasized that the biocompatibility of a dialysis treat-
ment modality is a function not only of the membrane
but of the entire dialysis system, including the blood tub-
ing and all other biomaterials in the extracorporeal cir-
cuit as well as the fluid to which the patient is exposed.
Hollow-fibre membrane transport
Blood compartment considerations. Although the
composition of hollow-fibre membranes varies con-
siderably, hollow fibres typically have an inner (blood
compartment) diameter of ~180–220 µm and a length of
20–24 cm (ref.54). Different phenomena imposed by the
standard operating conditions of haemodialysis dictate
the fairly narrow ranges that are acceptable for these
structural parameters. The major incentive to reduce
hollow-fibre inner diameter is the enhancement of dif-
fusive mass transfer due to reduced diffusion path length
within the blood compartment. Furthermore, the inverse
proportionality between channel width and shear rates
(at constant flow rates) leads to attenuated blood-side
boundary layer effects for smaller diameters 55–57.
However, inspection of equation 1, which expresses the
fundamental law (Hagen–Poiseuille) governing the lon-
gitudinal (axial) flow of blood through a cylinder (that is,
the hollow-fibre inner lumen), demonstrates the limits
on the extent to which inner diameter can be reduced58:
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Q B = ΔP ∕(8μL ∕πr 4 )
where QB is the blood flow rate, ΔP is the axial pressure
drop, µ is the blood viscosity, L is the fibre length and r is
the hollow-fibre radius. A more general form of equation
1 expresses the denominator on the right-hand side as
flow resistance as follows:
R = 8μL ∕πr 4
An important implication of the above equations is
that an increase in flow resistance leads to a proportional
increase in the axial (arterial to venous) pressure drop that
is required for attainment of a specific blood flow rate. The
inverse relationship between flow resistance and the fourth
power of the radius is the most important factor that limits
the extent to which hollow-fibre inner diameter can be
reduced. Of note, flow resistance is also directly related to
blood haematocrit through an effect on viscosity59. The
above analysis is based on the assumption that blood flows
in streamlines (i.e., is laminar) in the hollow fibre and
behaves as a Newtonian fluid, for which viscosity defines
the slope of the linear relationship between shear stress
and shear rate58 (see Fig. 4 for additional details).
The construction of the fibre bundle and its incor-
poration into the dialyser casing have important impli-
cations for blood and dialysate flow distribution and,
ultimately, in dialyser performance60–65. In particular, the
arterial blood port must be accurately designed to avoid
preferential flow pathways. Although blood flow velocity
tends to be higher in the inner fibres than in the periph-
eral fibres of the bundle, this effect has been minimized
by improved designs of blood flow distributors, which
can be conical, spiral or tangential31,40. Similar consider-
ations apply to the dialysate path, although flow veloci-
ties in this case tend to be higher in the peripheral fibres
than in the inner fibres. A fibre packing density, which is
defined as the ratio of the cross-sectional area that com-
prises fibres to the total cross-sectional area of the dial-
yser casing, close to 60% seems to be adequate to avoid
channelling of the dialysate flow. Additional aids to avoid
flow channelling include interfibre spacing filaments and
fibre undulation, which provide homogeneous flow dis-
tribution in the dialysate compartment and avoid the
blood–dialysate flow mismatch that negatively affects
the performance of the haemodialyser32,36. In addition,
these features may enhance diffusive mass transfer by
attenuating dialysate-side boundary layer effects.
Effect of membrane pore characteristics on hydrau-
lic flux. Hydraulic flux (water permeability) is the most
common criterion traditionally used to classify dialysis
membranes29. The clinical parameter used to quantify
water permeability is Kuf, which is derived from the rela-
tionship between ultrafiltration rate (Qf ) and TMP over
a clinically relevant range of TMP.
The Hagen–Poiseuille law is also relevant for describ-
ing the relationship between membrane pore structure
and flux. Although minimization of pore size variation is
an important priority, in practice the hollow-fibre spin-
ning process produces a distribution of pore sizes (Fig. 2).
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Nevertheless, a common first-order approximation of
(1) dialysis membrane pore structure is to assume that all
pores are parallel and have the same radius, which results
in ultrafiltrate flow that is perpendicular to the flow of
blood and dialysate24. According to the Hagen–Poiseuille
law, the rate of ultrafiltrate flow is proportional to the
fourth power of the pore radius (that is, r4) at constant
TMP. Thus, the membrane parameters that have the
most substantial influence on water flux are the average
(2) pore size and, to a lesser extent, the pore density per unit
surface area.
Effect of membrane pore characteristics on diffusive
transport. Fick’s law of diffusion defines the diffusive
solute removal rate N (mass/time) as:
N = D ⋅ A(ΔC ∕Δx ) (3)
where D is the solute diffusivity (area/time), A is the
membrane area, ΔC is the transmembrane concentra-
tion gradient and Δx is the diffusion path length55. As
suggested previously, membrane pore density has a
substantial impact on diffusivity (which is specific to
a particular solute–membrane combination), although
membrane wall thickness is also an important determi-
nant of diffusive removal rates (Fig. 2). With increasing
solute molecular weight, pore size limitations become
increasingly important in restricting solute entry and
limiting (‘hindering’) diffusion of molecules that gain
pore entry66,67. Finally, in addition to membrane thick-
ness and diffusivity, the diffusive clearance for a mem-
brane can differ substantially from the expected value
owing to interaction with water molecules (wettability or
hydrophilicity) and specific characteristics of the solute
at a given molecular weight (Fig. 3).
Although the characteristics of the membrane have
an important influence on diffusive solute removal by
a dialyser, the blood and dialysate compartments also
play a substantial part. From an engineering perspective,
diffusive mass transfer in a dialyser is typically expressed
in terms of the overall resistance to mass transfer (RO)
and the overall mass transfer coefficient (KO), which
are inversely related to one another. Overall resistance
to mass transfer takes into account the three major
components of the dialyser57:
R O = RB + RM + RD (4)
where RB, RM and RD are resistances contributed by the
blood compartment, the membrane and the dialysate
compartment, respectively (Fig. 4). As these three param-
eters can be viewed as resistances in series, the overall
resistance to mass transfer for a solute has a ‘controlling’
component, which is the dialyser aspect that contributes
most to the overall resistance. Whereas blood compart-
ment resistance is typically the controlling parameter
for small solutes (irrespective of dialyser type), mem-
brane resistance becomes most important at a specific
molecular weight, with the transition occurring at a
lower molecular weight for low-flux dialysers owing to
rather small mean pore sizes. However, although the
membranes of high-flux dialysers have a more open pore
volume 14 | JUNE 2018 | 399
 Reviews
a Cuprophan (cellulose)
Wall thickness 5–15 μm
200 μm
• Natural polymer
• Hydrophilic (hydrogel)
• Low hydraulic
permeability
• Low sieving properties
• Prevalent use in diffusive
therapy (haemodialysis)
b hydrophobic membranes. Whereas there is a continuum of
δ+
δ–
δ–
Electrical charges
Solute clearance
H2O
Hydrophilicity
Solute molecular weight
c by the introduction of convective transport, which relies
Hydrophilic surface
H2O α Positive
α > 90°
Molecular orientation
Wetted membrane (hydrogen-bond formation)
d during dialysis. The nonspecific adsorption of a plasma
Hydrophilic membrane
Continuous fluid phase in pores
Hydrophilic sites
400 | JUNE 2018 | volume 14
Polysulfone Polyethersulfone Fig. 3 | The physical characteristics of membranes affect
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 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
• Synthetic polymer- • Synthetic polymer- simultaneously. b | Diffusion-based solute clearance ideally
asymmetric microporous declines with increasing solute molecular weight. The
• Hydrophobic structure • Hydrophobic–hydrophilic
observed values, however, can be different from the ideal
• High hydraulic • High hydraulic
permeability permeability line owing to the characteristics of the solute, such as
• High sieving properties • High sieving properties electrical charges, binding of proteins, steric configuration
• 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
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
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+ contact angle; δ, partial charge.
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
that have a molecular weight of >500 Da.
Membrane
cut-off
Effect of membrane pore characteristics on convective
Protein binding transport. Diffusive transport becomes increasingly
limited as effective solute molecular weight increases
(Fig. 3b). This limitation can be overcome to some extent
Polarity of water Hydrophobic surface on the mechanism of solvent drag68. The sieving coeffi-
δ+
cient is classically used to define the convective transport
H2O properties of a membrane for a specific solute. In equa-
region α
tion 5, the sieving coefficient (SC) is the ratio between
the solute concentration in the filtrate (Cf ) and the solute
α < 90°
δ– δ+ concentration in the plasma water (Cp) in the absence of
Chaotic orientation
δ– a diffusion gradient across the membrane2,55:
Negative
region SC = C f∕C p (5)
Rejection effect
The observed (measured) SC values are influenced by
interactions between the membrane and blood elements
Hydrophobic membrane
protein layer, variously known as the secondary mem-
brane, gel or protein cake, reduces effective membrane
permeability immediately upon exposure to blood69–72 in
a process known as fouling. In the convective removal
of specific solutes, the influence of secondary membrane
formation is directly proportional to solute molecular
weight. The proteins found in the highest concentrations
in the plasma, such as albumin, fibrinogen and immu-
noglobulins, are the predominant components of the
Discontinuous fluid phase in pores secondary membrane73,74.
Hydrophobic sites As discussed below in more detail, the phenomenon
of concentration polarization75 also causes in vitro sieving
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© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
 Reviews

a b transfer resistance to the diffusive removal of large solutes.

100 Furthermore, fouling has a considerable effect on con-

Resistance to transport (%)

Bulk flow RO = RB + RM + RD
RB Transition layer vective solute clearances, especially for molecules >10 kDa
75
Solute transport

RM (ref.72). These constraints are particularly relevant in con-

Boundary layer
Proteins 50 ditions involving high ultrafiltration rates, which promote
RM Membrane
secondary membrane formation by more effectively deliv-
Boundary layer 25 RB ering plasma proteins to the membrane surface through
RD
RD Transition layer convection (versus lower ultrafiltration rates).
Bulk flow
0 In typical haemodialysis operating conditions,
10 102 103 104 105
log solute molecular weight (Da)
the water permeability characteristics for a standard
high-flux dialyser result in a fairly large drop in the
c Vmax d blood compartment axial pressure during treatment.
Hollow fibre Hollow fibre
The pressure drop is sufficiently large that, at some point
dV= Sh High shear rate
r dr
Blood SC = 1 – R along the length of the dialyser, the blood compartment
pressure is less than the dialysate compartment pressure
1 1

V = 0 V = ½Vmax in normal operating conditions. Thus, especially consid-

Hollow fibre Hollow fibre
ering the oncotic effects of plasma proteins in the blood
Low shear rate
r
Sh Blood
SC2 = 1 – R2
compartment, there is a point at which the ultrafiltrate
begins to be driven from the dialysate to the blood, as
dV
πr 2 T=–η
dr opposed to the ‘standard’ (blood–dialysate) direction in
the more proximal part of the dialyser (Fig. 5). In fact, this
V At wall: Shw = 4Q3 = 4Vπr = 4V
2

πr πr3 r combination of filtration and ‘backfiltration’ (refs76–80)

is considered to be the predominant mechanism by
Fig. 4 | Factors that affect diffusive and convective mass transfer. a | The overall which larger compounds are removed during standard
resistance to solute transport (RO) comprises three components: blood compartment high-flux haemodialysis81–84, as explained further below.
resistance (RB), membrane resistance (RM) and dialysate compartment resistance (RD).
The concentration of a molecule that is removed
b | The relative contribution to overall resistance for solutes of different molecular weights.
c | For small solutes, RB can be greater than RM, underlining the importance of high blood
from the blood by convection in the proximal part of a
flow rates and high velocity (V) gradients at the blood–membrane interface (wall shear high-flux dialyser is substantially reduced once it crosses
rate (Shw)). Shear rates influence not only the diffusive boundary layer but also the plasma the membrane owing to the combination of sieving
protein layer (secondary membrane) adsorbed to the surface. d | In convective modalities, and the diluting effect of dialysate flow. When a por-
high shear rates reduce the effects of both the secondary membrane (functional layer) tion of the dialysate is reinfused back into the blood
and the accumulation of partially rejected solutes (concentration polarization), with the as backfiltrate in the distal segment of the dialyser, the
sieving coefficient (SC) approximating the ideal value of the reciprocal of the rejection amount of solute re-infused by solvent drag is negligi-
coefficient of the membrane (R). Of note, R in part b is the diffusive mass transfer ble compared with that removed in the proximal part of
resistance and R in part d is the rejection coefficient. η, blood viscosity; Q, blood flow the dialyser owing to the blood–dialysate concentration
rate; r, hollow-fibre radius; T, shear stress (force per unit membrane surface area). Parts
difference, even if the filtration and backfiltration rates
b–d are reproduced from Ronco, C., Ghezzi, P. M., Brendolan, A., Crepaldi, C. & La Greca, G.
The haemodialysis system: basic mechanisms of water and solute transport in
are similar. In fact, the reinfused fluid can be considered
extracorporeal renal replacement therapies. Nephrol. Dial. Transplant. 13 (Suppl. 6), an ‘internal’ substitution fluid because the concentration
3–9 (1998), by permission of Oxford University Press (ref.55). of the solute of interest is essentially zero. As such, in
the context of high-flux haemodialysis, this mechanism
has been termed ‘internal haemodiafiltration’ or, more
profiles (obtained from test solutions that do not contain commonly, internal filtration (Fig. 5).
protein) to differ from those in the clinical setting. In the Maximizing the extent of internal filtration dur-
theoretically ideal situation, the SC is inversely related to ing high-flux haemodialysis through a combination
the rejection coefficient (R) as follows: of increased membrane permeability (increased pore
size)85 and higher axial blood compartment resistance
SC = 1− R (6) (decreased hollow-fibre inner diameter)39,86 can provide
clinically meaningful increases in large-solute clearance.
However, the above secondary membrane and con- Internal filtration rates are estimated to be as high as
centration polarization phenomena cause deviations 60 ml/min (~3.5 l/h)79, and new membrane designs may
from this ideal relationship (Fig. 4d). be able to extend this range. However, strict control of
dialysate quality is clearly of paramount importance in
Other mechanisms that influence solute removal. high-flux haemodialysis.
Conventional membranes that are used in haemodi- Membrane adsorption is also a consideration
alysis generally provide high clearance rates for small for large-solute removal during high-flux therapies.
solutes such as urea and creatinine, irrespective of flux. Membrane composition and structure (pore size)
However, membranes in current use, even those that are influence adsorptive removal, both qualitatively (that
traditionally considered to be highly permeable, provide is, the specific plasma proteins that are adsorbed)
limited clearance of compounds >10 kDa for several rea- and quantitatively73,74. The adsorptive removal of a
sons. Although these membranes have relatively large low-molecular-weight protein (for example, β2m) that
mean pore sizes (at least in comparison to unmodified is normally eliminated by the kidneys is considered
cellulosic membranes), they still offer substantial mass distinct from the more general process of secondary

NATURE REvIEWS | NePHrology volume 14 | JUNE 2018 | 401

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Reviews
membrane formation for two reasons7,87,88. First, because
the mass of large proteins, such as albumin, fibrinogen
and ­immunoglobulins, adsorbed during secondary
membrane formation is a minute fraction of their cir-
culating plasma pools, this process has no relevant
effect on their plasma concentrations. Furthermore, the
adsorption of such molecules is limited to the nominal
(blood-contacting) surface of the hollow fibre because
they generally do not have access to the much larger
surface area of the internal pore structure (as discussed
below, albumin is an exception to this general rule).
Second, adsorptive removal of smaller proteins that gain
access to the large surface area of the internal pore struc-
ture can be quantitatively important, thereby contributing
to clinically relevant decreases in plasma concentrations
during treatment. Substantial amounts of β2m and other
low-molecular-weight proteins can be adsorbed by some
membranes, contributing to a reduction in post-dialysis
protein concentration (Supplementary Fig. 3).
New membrane classification
As more knowledge has been gained over the past several
years about compounds that contribute to uraemic toxicity,
it is clear that peptides, proteins and protein-bound
compounds are potentially important categories of
toxins89–92. The peptide and protein category com-
prises >25 low-molecular-weight proteins that are as large
as 51 kDa (ref.92). However, as discussed earlier, removal of
these molecules might be limited during diffusion-based
therapies that utilize conventional high-flux dialys-
ers. In previous attempts to address this limitation,
‘protein-permeable’ membranes with larger mean pore
sizes were developed93–95, although excessive albumin
losses were raised as a major concern95. Nevertheless,
these larger uraemic toxins are generally considered to be
clinically important, and more effective dialytic removal
strategies might improve patient outcomes.
As new therapies are developed to address current
limitations, membrane classification schemes also need
to evolve. As mentioned earlier, Kuf is the most commonly
used parameter for classification purposes; a value of
12 ml/h/mmHg differentiates low-permeability and
high-permeability dialysers according to the US Food
and Drug Administration96. However, this regulatory
(versus clinical) definition was originally based on the
requirement of using a dialysis machine with an auto-
mated ultrafiltration control system in conjunction with
a high-permeability dialyser to avoid fluid balance errors.
As ultrafiltration control is now a standard feature of all
dialysis machines, the clinical relevance of this definition
is now debatable. Furthermore, this definition provides
little insight into the depuration capabilities of a dialyser;
for example, it does not recognize the category of
high-efficiency dialysers, for which the primary criterion
is small-solute clearance rather than water flux97.
Although still fairly rudimentary, the revised mem-
brane definition that was used for the HEMO Study is an
improvement98. In this definition, the two criteria for a
high-flux dialyser are Kuf >14 ml/h/mmHg and first-use
β2m clearance >20 ml/min, whereas a first-use β2m clear-
ance <10 ml/min defines a low-flux dialyser98. Although
the US Food and Drug Administration classification
402 | JUNE 2018 | volume 14
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
expresses Kuf in units of ml/h/mmHg, this parameter is
frequently normalized to membrane surface area, as dis-
cussed below. Finally, the European Dialysis (EUDIAL)
working group defines a high-flux dialyser as having an
ultrafiltration coefficient >20 ml/h/mmHg/m2 and a β2m
SC >0.6 (ref.99).
Classification schemes that focus even more on solute
permeability properties have been proposed. These new
classification systems acknowledge the importance of
larger molecules and the need to incorporate additional
membrane classes that have extended removal spectra.
High-flux and ‘protein-leaking’ membranes have been
defined on the basis of a combination of water perme-
ability, β2m removal parameters (sieving coefficient or
clearance) and albumin parameters (sieving coefficient
or amount removed)95. In this system, the high-flux class
is defined by a water permeability of 20–40 ml/h/mmHg/
m2, a β2m SC of 0.7–0.8 and albumin loss of < 0.5 g (on
the basis of a 4 h haemodialysis treatment), whereas the
same parameters defining a protein-leaking membrane
are >40 m/h/mmHg/m2, 0.9–1.0, and 2–6 g, respectively.
Although not explicitly stated, these values correspond
to ‘virgin’ membrane performance and do not reflect
potential diminutions during treatment as a result of
secondary membrane effects.
Two new membrane classes, medium cut-off (MCO)
and high cut-off (HCO), have been proposed, extending
the earlier classification scheme. The HCO class is char-
acterized by a substantial increase in water permeability
(relative to both the high-flux and the protein-leaking
classes) and a virgin β2m SC of 1.0 (ref.100). However, the
high albumin loss rates associated with this membrane
class generally preclude their long-term use for patients
with ESRD101. In addition, this membrane has been used
for fairly limited time periods in clinical conditions in
which the potential risks due to albumin loss are con-
sidered reasonable in relation to the potential benefits.
Several studies have reported the use of an HCO mem-
brane for patients with myeloma-associated acute kidney
injury specifically to target augmented removal of free
antibody light chains to promote renal recovery102–104.
Clinical experience with HCO membranes in critically
ill patients receiving continuous renal replacement ther-
apy, specifically for the removal of inflammatory medi-
ators, has also been the subject of several studies105–107,
although the role of HCO membranes in clinical practice
remains unclear.
On the basis of experiments involving determination
of dextran sieving coefficients over a wide molecular
weight range, a new solute removal parameter for the
characterization of modern highly permeable mem-
branes has been proposed100,108. This new parameter, the
‘molecular weight retention onset’ (MWRO) index, is
generated from a standard solute sieving coefficient ver-
sus molecular weight profile, as with the classic MWCO.
The MWRO is defined as the molecular weight at which
the SC value first reaches 0.9 (whereas the MWCO corre-
sponds to a SC of 0.1). The investigators rationalized this
approach by suggesting that the MWRO index, which
provides insights about pore size distribution, supple-
ments information provided by the MWCO, which is
primarily correlated with mean pore size. The steepness
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 Reviews

a Blood in Blood out Fig. 5 | Analysis of pressure profiles in hollow-fibre

haemodialysers. a | Schematic representation of pressure
profiles inside a hollow-fibre haemodialyser. b | Study in a
60
2 m2 haemodialyser carried out with a scintigraphic analysis
of the concentration of a nondiffusible marker molecule
along the length of the fibres at zero net filtration. In this
40 Blood Dialysate condition, direct filtration and backfiltration are equal, and
pressure pressure
the change in concentration of the marker molecule along
∆P (mmHg) 20 the length of the fibre bundle permits calculation of the
cross-filtration flux in both directions. c | The same study
carried out in two haemodialysers with a different fibre
0
configuration (inner diameter is 200 µm (left) versus 180 µm
(right)) demonstrates a different degree of filtration or
–20 backfiltration and a consequent effect on large-molecule
Ultrafiltration Backfiltration clearance. The marginal effect on small molecules and the
–40 considerable effect on larger molecules (see the bar
0 L/2 L graphs) confirm the importance of convective transport
Fibre length that is determined by the internal filtration mechanism
b (which is typical of high-flux dialysis). d | Scintigraphic
studies allow the pressure profiles inside the haemodialyser
to be analysed. The point of inversion of the transmembrane
pressure moves towards the venous end of the dialyser
when net ultrafiltration increases. Despite very high
ultrafiltration rates, a small amount of backfiltration always
occurs owing to the increase in oncotic pressure generated
by increasing protein concentration in the distal portion of
the fibres. C1 and C3 represent the concentration of the
radiomarker molecule at the inlet and outlet of the
haemodialyser, respectively. C2a, C2b, and C2c represent the
peak concentrations of the radiomarker molecule defining
the point of inversion from direct filtration to backfiltration
along the length of the dialyser at different blood flows. ΔP,
pressure change; B12, vitamin B12; Crea, creatinine; L,
c dialyser length; P, phosphate; Qf, ultrafiltration rate. Part a is
adapted with permission from Canaud, B., Bosc, J. Y., Leray, H.
& Stec, F. Microbiological purity of dialysate for on-line
substitution fluid preparation. Nephrol. Dial. Transplant.
15 (Suppl. 2), 21–30 (2000), by permission of Oxford
University Press (ref.156). The graphs in part c are adapted
with permission from ref.82, American Society of Nephrology.

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

is to maximize the removal of large uraemic toxins while

Ur
Cr

Ur
Cr

d also maintaining albumin losses in a clinically accept-

able range for long-term treatment of patients with
Transmembrane pressure (mmHg)

C1 C2a C2b C2c C3 ESRD. The updated classification system mentioned

Qf = 150 previously includes MCO membranes that incorporate
Qf = 90 high-retention onset (HRO) properties — this mem-
Qf = 30 brane class may hold promise in addressing the challenge
of achieving acceptable albumin losses85. In comparison to
HCO membranes, the MCO class is intended to preserve
0 the β2m sieving characteristics and to improve the clear-
ance of other large-molecular-weight solutes (for example,
free antibody light chains) while demonstrating a marked
reduction in albumin permeability, which is influenced
0 4 8 12 16 20 24 28 primarily by the relative differences between MWRO and
Distance along fibre (cm)
MWCO (Supplementary Table 2). Pore size distribution

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© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Reviews
curves (Fig. 6a–c) and the corresponding sieving coefficient
profiles (Fig. 6d) for three classes of membranes (high flux,
MCO and HCO) reveal that as the separation between
MWRO and MWCO decreases, the profile of the curve
becomes steeper, resulting in increased removal of large
uraemic toxins and decreased loss of albumin. Although
standard high-flux membranes made the development of
convective therapies possible, MCO membranes repre-
sent the basis for a new diffusion-based therapy called
‘expanded haemodialysis’ (refs84,85).
Clinical assessment of membranes
Following the clinical introduction of the first highly
permeable dialysis membrane, AN69, in the late 1960s17
and the subsequent development of polysulfone and
other membranes for high-flux haemodialysis and
haemodiafiltration109–111, clinical studies characterizing
their performance were published, beginning in the late
1980s87,112–122. These studies focused mostly on quanti-
fying the removal of β2m (molecular weight 11.8 kDa)
after its identification as the precursor of an amy-
loid protein that is deposited specifically in patients
undergoing chronic haemodialysis123,124. These studies
demonstrated that substantial β2m removal is possi-
ble with high-flux dialysers used in the haemodialysis
mode, which occurs through both transmembrane and
adsorptive mechanisms, and showed that unmodified
cellulosic membranes are essentially impermeable to
β2m. Furthermore, the major β2m removal mechanism
was membrane-specific, as transmembrane removal pre-
dominated for polysulfone-based filters whereas adsorp-
tion was the predominant mechanism for AN69 and
some PMMA dialysers. Finally, many of these studies
provided haemodiafiltration performance data, although
the substitution volumes that were used were generally
less than those currently used in clinical practice.
In one study117, high-flux synthetic (AN69, polysul-
fone and PES) dialysers with a surface area of 1.6–1.9 m2
were used for haemodialysis, haemodiafiltration and
haemofiltration in a small number of patients. A blood
flow rate of 450 ml/min was prescribed for all therapies,
and both convective therapies were performed in the
post-dilution mode with online substitution fluid. The
mean ultrafiltration volume was 20.8 litres and 30.6 litres
in haemodiafiltration and haemofiltration, respectively,
which was derived from the reported mean ultrafil-
tration rate for each modality. On the basis of effluent
collection, the total β2m removal was approximately
100–125 mg, 175–200 mg and 225–250 mg for patients
undergoing haemodialysis, haemodiafiltration and
haemofiltration, respectively (the differences between
the three modalities were significant for all three dial-
ysers investigated). The β2m SC for the polysulfone and
PES dialysers (measured at 5 min and 180 min of treat-
ment) were approximately 0.50–0.65 in the haemodia-
filtration and haemofiltration modes. In addition, the
values of the β2m SC for the AN69 dialyser were low
(~0.10) at 5 min in both the haemodiafiltration and
the haemofiltration modes but increased significantly
(P < 0.05) at 180 min to approximately 0.4 in haemodia-
filtration mode and 0.6 in haemofiltration mode. These
AN69 data suggest that β2m adsorption predominates at
404 | JUNE 2018 | volume 14
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
early time points (especially in convective treatments),
with a subsequent ‘breakthrough’ at later time points,
which is consistent with saturation of membrane binding
sites or reduced pore access due to fouling. Therefore,
caution should be exercised in the interpretation of the
sieving coefficients for low-molecular-weight proteins
for highly adsorptive membranes.
In a 1986 study using a 1.3 m2 high-flux polysulfone
dialyser, researchers measured the sieving coefficients
of several low-molecular-weight proteins (11.8–55 kDa)
during post-dilution haemofiltration72. The prescribed
blood flow rate and ultrafiltration rate was 200 ml/min
and 55 ml/min, respectively, with a mean TMP of
160 mmHg. On the basis of an assumed mean haema-
tocrit of 30% for the patient population, an average
filtration fraction of 40–45% can be estimated from the
classic, plasma-based equation. Serial sieving coefficient
estimates were made during the first 20 min; peak val-
ues for each low-molecular-weight protein occurred in
the first 10 min. For each protein, a significant decrease
was observed between the peak sieving coefficient and
the 20 min value (P < 0.05). Furthermore, the effect was
directly proportional to the molecular weight of the pro-
tein as no measurable filtration of solutes with a molecular
weight >30 kDa was observed after 20 min of treatment.
These fairly unconvincing data can be mostly attributed
to the combination of low blood flow rate, inadequate
membrane surface area and high filtration fraction, all of
which promote secondary membrane formation.
For equivalent ultrafiltration rates up to ~6.5 l/h
(with a blood flow rate of 300 ml/min), the clearance of
low-molecular-weight proteins of 12–33 kDa is supe-
rior with post-dilution haemodiafiltration compared
with pre-dilution haemodiafiltration125,126. This benefit
of the post-dilution mode has been attributed to the
greater accumulation of the partially rejected proteins
at the blood–membrane interface (that is, concentra-
tion polarization)69,127 — it is this ‘submembranous’
protein concentration on which the convective forces
act. Because the degree of polarization is directly pro-
portional to the extent of protein rejection, the relative
benefit of the post-dilution mode increases in proportion
to the molecular weight of the solute. However, this same
principle applies to albumin removal, making the balance
between optimized removal of low-molecular-weight
proteins and minimized albumin losses a very important
consideration in post-dilution haemodiafiltration.
High-flux haemodialysis and online post-dilution
haemodiafiltration were compared in 45 patients with
ESRD (mean haematocrit, 0.30) who were treated over
a 1-year period with the same high-flux 1.7 m2 polyary-
lethersulfone dialyser128. The mean delivered blood flow
rate in the haemodialysis and haemodiafiltration groups
was 286 ml/min and 269 ml/min, respectively, whereas
the mean ultrafiltrate volume in the haemodiafiltration
group was 21 litres over a mean treatment period of
4.1 h. On the basis of these mean values, the estimated
ultrafiltration rate was approximately 85 ml/min, which
results in an estimated filtration fraction of 0.43. Over
the 12-month study period, the mean pretreatment
serum concentration of β2m decreased modestly and to
a similar extent in both groups, although β2m clearance
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 Reviews

a b c

HF MCO HCO
Pore density x cm2

Pore density x cm2

Pore density x cm2

ea

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
than in the haemodialysis group (61 ml/min versus
38 ml/min; P < 0.001). The researchers hypothesize that
slow intercompartment mass transfer in the body might
account for this finding. Furthermore, the decrease
in the serum concentration of complement factor D
(molecular weight 24 kDa) was significantly greater in
the haemodiafiltration group than in the haemodialysis
group over the study period (P < 0.001).
The relationship between β2m removal and albumin
loss during online post-dilution haemodiafiltration
was assessed in a group of patients who were treated
with eight different high-flux dialysers of surface area
1.3–1.5 m2 (ref.129). Whereas the substitution fluid rate
was variable (30 ml/min, 60 ml/min or 90 ml/min,
and a constant dialysate flow rate of 600 ml/min), the
prescribed blood flow rate remained constant in each
patient (mean 292 ml/min) in this population, and the
mean haematocrit was 36%. On the basis of these mean
values and an assumed net ultrafiltration rate of 10 ml/min,
the mean filtration fraction can be estimated as 0.21,
0.38 and 0.54 at substitution fluid rates of 30 ml/min,
60 ml/min and 90 ml/min, respectively. The efficacy of
β2m removal was assessed by the difference between
pretreatment and post-treatment serum β2m concentra-
tions, whereas albumin losses were estimated from serial
measurements of albumin concentration in the diafiltrate
using a modified area under the curve approach.
The efficacy of β2m removal was linearly related to
the substitution fluid rate for each dialyser. At a fluid
substitution rate of 90 ml/min, the β2m removal rate for
most dialysers ranged between 65% and 75%. Peak val-
ues of instantaneous albumin removal rates (in mg/min)
occurred at the earliest measurement time point (10 min)
and subsequently decreased in an exponential manner.
Furthermore, cumulative albumin loss for a given treat-
ment had a strong dependence on substitution fluid rate
— this relationship tended to be nonlinear for dialysers
with greater albumin permeability. For a substitution
fluid rate of 90 ml/min, albumin loss (normalized to a
treatment time of 4 h) was approximately 0.4–7 g. On the
basis of these data, the investigators proposed a dialyser
membrane classification system in which low, medium
and high values for β2m removal rate (0–50%, >50–70%

NATURE REvIEWS | NePHrology volume 14 | JUNE 2018 | 405

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Reviews
and >70%, respectively) are evaluated in conjunction
with similar gradations of albumin loss (0–2 g, 2–5 g
and >5 g, respectively).
Another study evaluated the possibility that adapta-
tions in dialyser design could ameliorate the relationship
between β2m removal and albumin loss in post-dilution
haemodiafiltration130. This crossover randomized trial
involved a modified polysulfone filter that, according to
the manufacturer, has a more open structure in the mem-
brane region adjacent to the skin layer than the standard
high-flux polysulfone dialyser (surface area 1.4 m2 for
both membranes). This adaptation is intended to increase
the β2m sieving coefficient and reduce the albumin siev-
ing coefficient (on the basis of in vitro determinations).
In this trial, mean blood flow rate and treatment time
were approximately 405 ml/min and 4.9 h, respectively,
whereas total convection volume (substitution fluid
and net fluid loss) was approximately 30 litres in both
groups. The percentage reduction in the serum concen-
tration of low-molecular-weight proteins ranging from
11.8 kDa (β2m) to 33 kDa (α1-microglobulin) was signif-
icantly greater (P <0.05) for the modified dialyser than
for the standard dialyser, as was the mass removal (on
the basis of diafiltrate sampling). However, mean albu-
min loss was also significantly higher for the adapted
filter versus the standard filter (4.25 g versus 3.01 g
per treatment; P = 0.03). Thus, the permeability for
low-molecular-weight proteins and albumin for these two
dialysers correlated reasonably well in the clinical setting.
Prescribed ultrafiltration rates that are necessary
to achieve convection volumes >23 litres per session,
recently established by consensus guidelines90,131–134, are
predicated on attaining fairly high blood flow rates and
on the dialyser achieving TMP values up to 300 mmHg.
However, in many patients, these conditions are asso-
ciated with prominent haemoconcentration and sec-
ondary membrane effects, which result in frequent
pressure alarms and potential treatment interruptions.
Contemporary dialysis machines utilize different
approaches in an attempt to mitigate these effects135–138,
enabling a distinction to be made between ‘maximum’
convection volumes (defined by the blood flow rate
and TMP parameters discussed above) and convec-
tion volumes that are more realistically attainable in
the operating conditions of a given haemodiafiltration
treatment. As discussed below, although these mitigating
technologies are designed to maximize the substitution
volume, treatments employing them still frequently
result in operating TMP values that cannot be sustained
throughout a treatment.
The considerable variation in Kuf, which is defined
by the linear portion of the ultrafiltration rate versus
TMP profile, during a post-dilution haemodiafiltra-
tion treatment can substantially influence the ability to
achieve a desired convection volume139,140. Furthermore,
delivery frequently falls short for treatments in which
maximum convection volumes are prescribed, whereas
treatment prescriptions that accommodate the var-
iations in the ultrafiltration rate–TMP relationship
are much more likely to achieve the prescribed (albeit
lower) convection volume139. In addition to treatment
delivery shortfalls, prescribed maximum convection
406 | JUNE 2018 | volume 14
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
volumes are also associated generally with greater albu-
min loss, without a concomitant benefit of increased
β2m removal139. This observation is a predictable conse-
quence of albumin polarization at the membrane surface
due to the combination of high ultrafiltration rates and
haemoconcentration, as described previously.
The factors that might potentially influence albu-
min loss during post-dilution haemodiafiltration have
been evaluated135. These investigators assessed poly-
sulfone dialysers with surface areas of 1.5–2.2 m2 and
PMMA dialysers with surface areas of 1.6–2.1 m 2.
Patients were treated with either a ‘manual’ infusion
technique, in which the dialysis nurse adjusts the substi-
tution fluid rate according to the TMP, or an automated
technique, in which the dialysis machine continuously
adjusts the infusion rate on the basis of several param-
eters, including membrane type, haematocrit, total
protein concentration, blood flow rate and ultrafiltra-
tion rate, with an established maximum TMP. Of note,
almost half of the 37 treatments that were performed
with the automated technique had to be switched to the
manual mode owing to high TMP values (>250 mmHg)
that were not adequately modulated by automated infu-
sion rate changes. Overall, the mean albumin loss was
3.13 ± 2.5 g per session, was linearly related to TMP and
was significantly higher in the automated group than
in the manual infusion control group (3.92 ± 3.06 g ver-
sus 2.37 ± 1.67 g; P = 0.01). Furthermore, multivariate
regression analysis showed that TMP was the only sig-
nificant predictor of albumin loss (P = 0.002), although
the predictive value of membrane type almost reached
statistical significance (P = 0.054). However, no associa-
tion was observed between diafiltrate albumin loss and
serum albumin concentration during this fairly short
(3–4 month) study.
These albumin loss data135 are generally consistent
with results from other post-dilution haemodiafiltration
studies, and these investigators recommend that clinical
concerns about albumin loss should not limit the use of
post-dilution haemodiafiltration. Nevertheless, efforts
have been focused on the development of alternative
convective techniques that preserve the depuration
capabilities of post-dilution haemodiafiltration while
also overcoming some of the complexities and techni-
cal limitations of this modality141–143. In various ways,
these alternative approaches aim to reduce haemo-
concentration and attenuate fouling effects so that
TMP and albumin losses can be maintained in clini-
cally acceptable ranges. However, there are insufficient
clinical data to warrant these alternative techniques
supplanting post-dilution haemodiafiltration as the
standard convective modality when haemodiafiltration
is the chosen therapy. Furthermore, the superiority of
post-dilution haemodiafiltration over standard high-flux
haemodialysis is still a matter of debate.
Efforts to extend the permeability spectrum of
high-flux synthetic membranes might enable the
presumption of a need for a convection-based therapy to
be challenged5,79,84,108,144–146. By virtue of larger pore sizes,
increased membrane diffusivity is one mechanism by
which the removal of large solutes is augmented with the
previously mentioned MCO class of dialysers (relative
www.nature.com/nrneph

to standard high-flux membranes). However, although
haemodialysis using this type of dialyser is technically
diffusion-based, most large-solute removal still occurs
by convection through the mechanism of internal filtra-
tion, as discussed earlier. For MCO and other dialysers,
the effect of this mechanism is intentionally augmented
through increases in the mean pore size and reductions
in the inner diameter of hollow fibres. Preliminary data
suggest that this class of dialysers has depuration capabil-
ities that approach those of online post-dilution haemo-
diafiltration without the need for (exogenous) substitution
Box 1 | Multidimensional classification of dialysis membranes
Use of a radar plot can provide a multidimensional classification of dialysis
membranes (see the figure). The value for each parameter ranges from a
minimum value at the centre to a maximum value at the circumference.
The parameters are as follows.
Nature and composition
The major compositional distinction is between cellulosic (natural) and
noncellulosic (synthetic) membranes. Noncellulosic synthetic membranes
(polyamide, polysulfone, polyethersulfone (PES), polyacrylonitrile (PAN),
polymethylmethacrylate (PMMA) and others) and modified cellulosic
membranes are almost exclusively used in clinical practice. In new
synthetic membranes, polymer blending enhances both biocompatibility
and performance.
Structure
Most synthetic hollow fibres have a complex structure with a finely porous
internal skin layer and an external support structure. The support structure
may be sponge-like or finger-like, depending on the production method.
Ultrafiltration coefficient
The ultrafiltration coefficient (Kuf; ml/h/mmHg/m2; also known as the
hydraulic permeability coefficient) for a membrane is the ratio of the
ultrafiltration rate (Qf; ml/h/m2) to the transmembrane pressure (TMP;
mmHg). On the basis of water flux only, for low-flux membranes
Kuf < 10 ml/h/mmHg/m2, whereas for high-flux membranes Kuf = 20–40 ml/h/
mmHg/m2 and mid-flux membranes have intermediate Kuf values. However,
modern classification schemes also incorporate solute removal parameters
(see main text and below).
Molecular weight retention onset
The molecular weight retention onset (MWRO) governs the shape of the
solute sieving curve for a membrane and describes the molecular weight
and radius at which the sieving coefficient (SC) value is 0.9. Membranes
with a tight pore size distribution that were designed to have a steep
sieving curve have been produced with the aims of minimizing the
molecular weight interval between the MWRO and the molecular weight
cut-off (MWCO) and maintaining the MWCO at a value close to the
molecular weight of albumin. These membranes are described as medium
cut-off (MCO) membranes.
Biocompatibility
Although the biocompatibility of dialysis membranes can be judged by
several criteria, complement activation has been the most widely studied
parameter. Other criteria include thrombogenicity, contact activation and
cytokine generation.
Hydrophilicity
The material composition of a membrane affects its interaction with water.
Cellulosic membranes are hydrophilic whereas early synthetic membranes
were highly hydrophobic. Modifications and new polymer blending have
resulted in synthetic membranes that are less hydrophobic so that the
combination of diffusive and convective mass transfer for solute removal is
now possible.
Surface functionalization
The characteristics of the internal surface of the membrane are important
for the interaction with the blood. New biochemical and physical
NATURE REvIEWS | NePHrology
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Reviews
fluid administration5,144. Clinical outcome data for the new
therapy (‘expanded haemodialysis’) that is made possible
by this class of dialysers will help establish its clinical role
in the future, especially in relation to haemodiafiltration.
The appropriate balance between low-molecular-weight
protein removal and albumin loss can be raised a final time
here147. In addition to the opinion that albumin losses of up
to 4 g per session are clinically acceptable135, a retrospective
analysis of Japanese patients reported a significantly higher
survival in patients with ESRD who sustained albumin
losses >3 g per treatment than in those patients with lower
Composition
Nature Structure
Ko Kuf
MWRO MWCO
Thickness Biocompatibility
ζ-Potential Hydrophilicity
Surface
functionalization
processes enable modification of the inner surface of hollow fibres by
several techniques (see the main text for examples).
ζ-Potential
The ζ-potential is the electric potential at the blood–membrane interface
due to the presence of electronegative charges located in the skin layer of
the membrane. The process of polymerization, the chemical composition
of the membrane and polymer blending potentially contribute to the
ζ-potential of a membrane.
Thickness
The thickness of a membrane determines the distance that solutes must
diffuse between the blood and the dialysate. The original cellulosic
membranes were 15 µm thick, which was subsequently reduced to 5 µm.
The original synthetic membranes were 70–100 µm thick, which has been
reduced to 30 µm or less with a concomitant reduction of the thickness of
the internal skin layer to approximately 1 µm or less.
Molecular weight cut-off
The molecular weight cut-off (MWCO) is defined as the solute molecular
weight that corresponds to a SC value of 0.1. Pore size distribution
substantially influences the MWCO value of a membrane and is of critical
importance as it approaches the molecular weight of albumin owing to its
effect on unwanted albumin losses during treatment.
Diffusive mass transfer coefficient
The diffusive mass transfer coefficient (Ko) is a theoretical parameter to
describe membrane performance in diffusion in ideal conditions of
unlimited blood flow and dialysate flow. The final characteristics of a
membrane should be normalized to the membrane surface area (KoA). Ko
and KoA are important parameters to define membrane diffusive transport
capacity for a specific haemodialyser–solute combination.
Figure adapted with permission from ref.85, Karger.
volume 14 | JUNE 2018 | 407
Reviews

albumin losses148. The investigators attributed this finding
to the beneficial removal of protein-bound uraemic toxins.
The data from this study can be viewed in the context of
peritoneal dialysis, in which albumin losses of approxi-
mately 4 g per day (30 g per week) are typical149. These con-
siderations notwithstanding, the clinically acceptable limit
of albumin loss during extracorporeal dialysis treatments
remains to be defined more clearly.
Membrane functionalization
The production process and polymeric composition deter-
mine the final characteristics and functional properties of a
membrane. The internal skin layer is of crucial importance
because it represents the true barrier for mass separation
and is the portion of the membrane that comes in direct
contact with the blood. The characteristics of the internal
surface are responsible for the blood–membrane interac-
tions, including phenomena such as coagulation, platelet
adhesion and protein deposition. A substantial reduction
in activation of the clotting cascade and membrane fouling
has been achieved by improvement of the inner surface
design and smoothness. Specific physicochemical pro-
cesses have been applied during membrane production
to improve the characteristics of the membrane inner sur-
face. These efforts have resulted in increased permeability,
improved haemocompatibility and reduced fouling effects
during prolonged utilization.
Several membranes that are routinely used in dialy-
sis display characteristic surface modification through
oxidation, plasma treatment, pervaporation or copol-
ymerization. Membrane surfaces are also modified by
additives, including PVP, polyethylene co-vinyl alcohol
and polyethylene glycol. Polymer blending (for example,
polyethyleneoxide-modified polyacrylonitrile, poly-
amide–PES and polyarylethersulfone), macromolecule
inclusion and coating of the inner surface are other
mechanisms of membrane modification and adaptation
for specific clinical uses. Finally, further modifications of
the membrane surface can be obtained by polymer func-
tionalization via chemical reactions, molecular imprint-
ing technology, ion implantation and photochemical
modification. In the future, these processes might achieve
substantial changes in membrane performance. For
example, functionalization of the internal surface of an
AN69 membrane resulted in altered coagulation prop-
erties and electronegativity150,151. In addition, function-
alization of a PES membrane via covalent linkage with
vitamin E152–154 led to a clinically meaningful reduction
in circulating reactive oxygen species that are generated
at the blood–membrane interface. These new modifica-
tions may develop further in the future, suggesting that
membrane properties should be characterized on the
basis of not only classic parameters but also indices that
are capable of assessing these new features. Finally, in the
future, entirely new types of membranes might be applied
to novel haemodialysis therapies, such as silicon-based
nanopore membranes for an implantable device155.
Conclusions
The bidirectional process of mass separation between
the blood and the dialysate involves several mecha-
nisms of interaction between the fluid phases and the
membrane barrier. The nature of the fluid phases,
the characteristics of the solutes and the structure
of the membrane represent a combination of elements
that are involved in the final process of mass separation
and dialysis. The development of a unifying classifica-
tion system for dialysis membranes is extremely complex
and must be multidimensional. When overly simplistic
schemes are used, membranes that have substantial dif-
ferences of potential clinical importance cannot be differ-
entiated. Each membrane, although belonging to a classic
category, has a specific area and profile that is dependent
on other variables2 (Box 1). Furthermore, a uniform clas-
sification of membranes cannot be proposed unless all
characteristics — in particular, those that may be unique
for a specific membrane — are taken into considera-
tion. For personalized (‘precision’) medicine, a clinician
can then select a dialysis membrane on the basis of the
specific needs of the individual patient and the desired
clinical results while bearing in mind that cost and
cost-effectiveness are important considerations.
Published online 05 May 2018

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Acknowledgements
The authors thank M. Storr (Baxter International), S. Bowry
(Fresenius Medical Care), R. Baldini (B. Braun Medical),
L. Fecondini (Medica), L. Frattini (Medtronic), W. Oshihara
(Toray Medical), A. Simionato (Asahi Kasei Medical) and
S. Takashi (Nipro Corporation) for their invaluable comments
and the generous provision of membrane images. The
authors recognize the seminal contributions to end-stage
renal disease therapy made by L. Henderson, who passed
away in 2017. He was a source of inspiration for many of us,
and we owe him a debt of gratitude for his exemplary
leadership in the field.
Author contributions
Both authors contributed to researching data for the article
and writing, reviewing and editing the article before
submission.
Competing interests
C.R. has received consultant or honoraria fees from Astute
Medical, Ortho Clinical Diagnostics, Baxter International,
Asahi Kasei Medical, General Electric, Jafron Biomedical,
Estor Medical and Toray Medical. W.R.C. was formerly
employed by Baxter International, has received consulting
fees from Baxter International and owns Baxter International
stock; he is also a consultant with Medtronic, Nikkiso
America and Astute Medical.
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Supplementary information
Supplementary information is available for this paper at
https://doi.org/10.1038/s41581-018-0002-x.
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