Microporous and Mesoporous Materials 319 (2021) 111035

Contents lists available at ScienceDirect

Microporous and Mesoporous Materials

journal homepage: http://www.elsevier.com/locate/micromeso

Adsorption-based strategies for removing uremic toxins from blood

Yuhao Ma a, Shuhui Li b, Marcello Tonelli c, Larry D. Unsworth a, b, *
a
Department of Biomedical Engineering, University of Alberta, Edmonton, AB, T6G 2V2, Canada
b
Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, T6G 1H9, Canada
c
Department of Medicine, University of Calgary, Calgary, Alberta, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Chronic kidney disease leads to the accumulation of uremic toxins within the blood compartment. Engineered
Uremic toxin surface that adsorbs toxins from the blood compartment is a promising approach for clearing uremic toxins not
Porous adsorbent easily removed using membrane-based dialysis techniques. A variety of adsorbent materials have been studied
Molecularly imprinted polymer (MIP)
with the purpose of targeting a general group of toxins or a specific uremic toxin. Some of these structures have
Mixed matrix membrane (MMM)
Fractionated plasma separation and adsorption
also been incorporated into toxin clearance systems, including column adsorption and membrane adsorption.
(FPSA) This review focuses upon, as much as possible, adsorption studies that included the evaluation of uremic toxin
removal. We also discuss certain special adsorbent systems like molecularly imprinted polymer and mixed matrix
membranes. The clinical application of several adsorbent systems in uremic toxin removal is also reviewed.

adsorbent surfaces may allow for the direct removal of protein-bound

and mid-sized uremic toxins.
1. Introduction
A wide variety of different substances are known to accumulate in
the blood compartment in people with kidney failure. Some of these
1.1. Uremic toxins
were identified with toxicity, with their normal and pathologic con­
centrations well documented [5,6]. Herein, we focus upon the most
Uremic toxins include a large group of substances that accumulate in
studied toxins commonly used to evaluate adsorbent-based removal
the blood compartment of patients with chronic kidney disease (CKD)
techniques. Creatinine is usually considered to be representative of small
and kidney failure. Although hemodialysis treatment has been available
uremic toxins that can be easily removed with any dialysis technique
for more than 50 years, the morbidity and mortality associated with
[5]. Creatinine is produced from creatine phosphate through
kidney failure remains extraordinarily high, which suggests that novel
non-enzymic translation, and the serum level of creatinine is an
methods of toxin removal are needed [1]. Uremic toxins are classified
important indicator of renal function [7]. Like creatinine, urea and uric
into three main types, where their physicochemical properties ulti­
acid are two other nonprotein nitrogenous compounds that are typical
mately dictate the extent to which they can be removed using
used clinically to monitor renal function. Urea, as the main
membrane-based dialysis techniques. The first type of toxins are small
nitrogen-containing substance in human urine, was generated in liver
(MW < 500 Da), water-soluble, and readily cleared through a mem­
through “urea cycle”, where two ammonia was combined with a carbon
brane. The second type of toxins are mid-sized (Mw > 500 Da) and
dioxide. Urea plays an important role in the metabolism of waste com­
require larger pore membranes (high flux dialysis) to achieve even a low
pounds containing nitrogen and has historically been used as a marker of
removal rate. The third type of toxin is small (MW < 500Da) and very
kidney dysfunction, although most authorities consider that urea itself is
hard to remove using membrane techniques as they may be tightly
not toxic per se, but rather is a proxy for the true toxins. Uric acid is the
bound to blood proteins that cannot traverse the membrane [2]. A subset
final breakdown product of purine metabolism. A high level of uric acid,
of these toxins is characterized by the covalent modification (i.e. car­
known as hyperuricemia, has been linked to gout as well as an increased
bamylation) of proteins that are also retained in the blood-compartment
risk of cardiovascular disease [8,9]. β2-microglobulin (β2m) aggregates
of people with severe CKD or kidney failure [3,4]. Carbamylated pro­
into amyloid fibers that deposit in the osteoarticular joint tissue of
teins are hard to remove using membranes because the physical prop­
long-term hemodialysis patients, causing dialysis-related amyloidosis
erties of these modified proteins do not differ significantly from normal
[10]. The removal of β2m is well studied and it necessitates a high-flux
proteins, and thus also cannot traverse the membrane. Consequently,

* Corresponding author. Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, T6G 1H9, Canada.
E-mail address: lunswort@ualberta.ca (L.D. Unsworth).

https://doi.org/10.1016/j.micromeso.2021.111035
Received 21 September 2020; Received in revised form 8 February 2021; Accepted 8 March 2021
Available online 18 March 2021
1387-1811/© 2021 Elsevier Inc. All rights reserved.
Y. Ma et al. Microporous and Mesoporous Materials 319 (2021) 111035

Table of Abbreviations MMM1/MMM2/MMM3 Poly(Ethersulfone)/Poly

(Vinylpyrrolidone) Dual Layer Hollow Fiber
940-HOA Zeolite Type MOR Mordenite Zeolites
AST-120 Oral Doses of Activated Carbon-120 NU-1000 Metal–Organic Framework based on Zirconium
BET Brunauer–Emmett–Teller NVP N-Vinylpyrrolidone
BK-PMMA Methedrone p(AAm-MMA) Poly(Acrylamide-Hydroxyethyl Methacrylate)
CKD Chronic Kidney Disease PAA Polyacrylic Acid
CMPF 3-Carboxy-4-Methyl-5-Propyl-2-Furanpropanoic Acid PAC Powdered Activated Carbon
CTMS Chlorotrimethylsilane PAN Polyacrylonitrile
CVD Chemical Vapor Deposite PAn-PSS Polyaniline-Poly(Styrene Sulfonate)
DNBC 3,5-Dinitrobenzoyl Chloride PBS Phosphate-Buffered Saline
DNBZ 3,5-Dinitrobenzoate Group PCB Poly(Carboxybetaine)
DRA Dialysis-Related Amyloidosis PCDs Poly-β-Cyclodextrins
EGMA Methyl Ether Methacrylate PCS p-Cresyl Sulfate
EVOH Poly(Ethylene-Co-Vinyl Alcohol) PES Poly(Ether Sulfone)
f-CNT Heparin-Mimicking Polymers Grafted Carbon Nanotubes PES Polysulfone
FLCs Immunoglobulin Light Chains PES–AC Poly(Ether Sulfone)-Activated Carbon
FPSA Fractionated Plasma Separation and Adsorption PES-PAA-U Urease Modified Polyethersulfone-Poly(Acrylic Acid)
FPSA Fractionated Plasma Separation and Adsorption pHEMA Poly(2-Hydroxyethyl Methacrylate)
GI Gastrointestinal PMMA Poly(Methyl Methacrylate)
HA Hippuric Acid PSAC Pitch-based Spherical Activated Carbon
HJ-1 Hypercrosslinked Polymeric Adsorbent HJ-1 PVP Polyvinylpyrrolidone
HSGD® Hemosorbent Granular Deliganding ROS Renal Oxidative Stress
IS Indoxyl Sulfate SAC Spherical Activated Carbon
ISO International Organization For Standardization SBA-15 Santa Barbara Amorphous-15
LTA Linde Type A sFLC Immunoglobulin Light Chains
MCM-41 Mobil Composition of Matter - 41 SI-ATRP Surface Initiated-Atom Transfer Radical Polymerization
MFI Mordenite Framework Inverted (Silicalite) zeolite SS Sodium Styrene Sulfonate
MIL-100(Fe) Metal-Organic Framework based on Iron (III) XAD-4 Amberlite™ XAD-4 (Rinse)
Carboxylate ZSM-5 Zeolite Socony Mobil-5
MIP Molecularly Imprinted Polymer β2M β2-Microglobulin
MMM Mixed Matrix Membrane

dialyzer or hemodiafiltration [11]. Immunoadsorbent surfaces that uti­
lize monoclonal antibodies [12,13], single-chain variable antibody
fragments (scFv) [13], or the variable domain of the heavy chain of
HCAbs (VHH) [14,15] have been attempted for β2m capture with high
specificity and affinity. The best studied protein-bound toxins for eval­
uating adsorbent surfaces are indoxyl sulfate (IS) and p-cresyl sulfate
(PCS), which play a prominent role in the progression of CKD or liver
disease [16–19]. IS is synthesized as the final metabolite of tryptophan
[20]. As a uremic toxin, pathophysiologic effects of IS include an in­
crease in renal oxidative stress (ROS), the release of endothelial micro­
particles, and an increase of the fibrosis and angiotensinogen expression
in the kidney. It has been found that PCS is the main conjugate form
(>95%) of p-cresol that circulates in vivo [21,22]. Noteworthy, as well, is
that p-cresol is metabolized through mainly sulphation and glucur­
onidation [23,24]. PCS contributes to CKD related insulin resistance and
causes renal tubular cell damage by inducing oxidative stress [25,26].
Both IS and PCS predominantly bind to albumin, which limits their
clearance using hemodialysis. For instance, up to 90% of IS in the blood
compartment can bind reversibly to albumin with a dissociation con­
stant of 13.2 μM [27–29]. Albumin binding of IS severely inhibits the
removal of IS using traditional hemodialysis. Even plasma free (i.e.
unbound) IS is difficult to remove from the blood compartment using
conventional dialysis techniques [30,31]: whether with low or high flux
membranes [32]. Several studies characterize the removal of bilirubin as
a means of evaluating novel dialysis membrane design because it is a
metabolite of hemoglobin that is normally removed via albumin trans­
port by the liver [33]. However a high level of bilirubin may overburden
albumin and excessive bilirubin will deposit in a variety of tissues,
causing hyperbilirubinemia and, sometimes, brain damage [34]. It
should be mentioned that because albumin does play a central role in
binding toxins within the blood, many studies have evaluated the merit
of coating hemodialysis membranes with albumin coating to enhance
toxin adsorption [35,36]. Although this approach makes physiological
sense, the incorporation of an albumin layer presents several problems
in practice. Perhaps the most difficult issue is the use of animal-derived
albumin, which poses the risk of bloodborne infection to the patient
[37]. Recombinant albumin reduces or eliminates this risk, but its high
cost reduces the likelihood of widespread use in clinical practice.
1.2. Adsorbent used or studied in hemodialysis systems
Adsorbent-based strategies for cleaning blood may lead to the
development of wearable cassettes that do not require a membrane or
dialysate. Currently the approach is to integrate these engineered sur­
faces with current hemodialysis systems; by incorporating them within a
column that the dialysate or blood passes through, or by deploying them
at the membrane surface (as illustrated in Graphic Abstract).
Hemoperfusion uses columns filled with beads (e.g. activated char­
coal or resin) to directly adsorb toxins from solution [38]. In this pro­
cess, small molecules are trapped within the pores of the adsorbent
material, but blood cells or large biomolecules can pass through the
column and return to the body without loss of content. Hemoperfusion
with activated charcoal has been involved in the treatment of many
conditions [39]. Charcoal that has been coated with an antibody or
antigen can be used for treatment of autoimmune diseases such as sys­
temic lupus erythematosus [40], rheumatoid arthritis [41,42], and to
remove pathogenic antibodies [43]. Compared to activated charcoal,
some resin materials (i.e. polystyrene) are more effective in removing
lipid-soluble toxins [44]. Also, middle molecular weight molecules that
are not removed effectively using hemodialysis (e.g. β2-microglobulin)

2
Y. Ma et al. Microporous and Mesoporous Materials 319 (2021) 111035

can be removed using hemoperfusion [45]. Although adsorbent beads
are trapped in a column, the adsorbent material may degrade or become
soluble in the solution and then enter the blood during hemoperfusion,
potentially causing toxicity [46,47].
The uremic toxin removal rate is dependent on the molecular flux
across the semi-permeable membrane separating the blood and dialy­
sate. As molecular flux is highly dependent upon the concentration
gradient, one approach is to increase this concentration gradient by
decreasing the concentration of uremic toxins in dialysate [48,49]. This
can be achieved by increasing the volume of the dialysate used, or by
removing uremic toxins from the dialysate. An adsorbent with a large
surface area, and thus a large capacity to bind toxins from the dialysate,
could be employed for this strategy. Activated carbon and zeolite have
been the most common adsorbents used, for they can adsorb a variety of
uremic toxins and are relatively cheap compared to other types of ma­
terials. Use of dialysate adsorbent satisfies the need to develop a mini­
aturized or a wearable dialyzer that can constantly remove dialysate
toxins within an enclosed dialysate cycling system [50]. The efficiency
of toxin removal within the dialysate using an adsorbent material has
been mentioned as key to wearable hemodialysis systems [51–53].
Traditionally, hemodialysis membranes allow for the passage of
some molecules from the blood compartment to the dialysate. However,
using membranes that can directly adsorb toxins that are hard to remove
from the blood is of sufficient interest. Synthetic membranes currently
use, for instance, hydrophobic membranes (PAN, PMMA, polysulfone,
polyamide) to adsorb materials from the blood. There are examples
where this strategy has been beneficial in lowering morbidity and
mortality during hemodialysis through adsorption. PMMA hemodialysis
membranes were found to effectively adsorb immunoglobulin light
chains (FLCs), reducing patient reports of itching [54,55]. Moreover,
BK-PMMA (large pore PMMA) membranes were found to have a large
adsorption capacity for β2m [56,57].
2. Porous adsorbents for uremic toxin removal
Porous adsorbents are defined by their pore size, which ranges from
micrometers to nanometers. A large internal surface area can provide
high adsorption properties for various substances such as solutes, gas
vapors, and aerosols. Therefore, porous adsorbents were used exten­
sively to adsorb uremic solutes. To the best of our knowledge, activated
carbon, zeolite, mesoporous silica, and polymer materials incorporate
almost all of the uremic toxin adsorption studies. Among them activated
carbon and zeolite based adsorbents are the most extensively studied for
hemoperfusion or dialysate adsorbent. The unique mesoporous structure
and ease for functionalization makes mesoporous silica another choice
suitable for this application, and has been frequently compared with
activated carbon or zeolite based adsorbents. Polymeric materials have a
long history been used in the field of blood purification with an abun­
dance of studies looking at their adsorbent capabilities, or as a com­
posite material with the aforementioned porous materials. Table 1
compares the advantages and disadvantages of these several adsorbent
materials used for removing uremic toxins. That said, Metal–Organic
Frameworks (MOF) based systems has been evaluated as a suitable
adsorbent for water soluble [62] or protein bound [63] uremic toxins.
Carbon nanotubes (CNTs), as another possible adsorbent material with
an even higher surface area than activated carbon, has been used in
some studies of uremic toxin adsorption by forming composite mem­
branes with polymeric materials [64,65]. Table 2 provides an overview
of in vitro studies on uremic toxin removal based on these materials. The
removal capacity listed was the maximum toxin adsorption value re­
ported, or the highest equilibrium adsorption amount, with the initial
toxin concentration also provided for convenience of comparison. It
should be noted that in cases of some low adsorption amount, calcula­
tion was based on the whole composite materials, where only parts or
incorporated particles were functioning as adsorbent.

1.3. Drawbacks of current adsorbents used

2.1. Activated carbon
Although these approaches are theoretically beneficial, there are
some major drawbacks to their general use. Non-specific adsorption is a The earliest and best studied porous adsorbent is activated carbon (a.
major issue for adsorbent materials that directly contact blood. For k.a. activated charcoal). Activated carbon can be produced from
example, adsorbed fibrinogen may promote platelet adhesion and carbonaceous sources like wood, coal, and nutshell. Activation of these
trigger severe clotting [58], and adsorbed factor H may trigger com­ source materials, either through physical or chemical activation, is
plement activation for hemodialysis patients [59]. These deleterious required for carbonization. As early as 1969 there were attempts to use
reactions at the adsorbent surface may induce adverse complications in activated charcoal to lower the level of creatinine in blood [66]. Acti­
an already at-risk population, negating any possible advantage to their vated carbon is still considered the most common adsorbent, which is
use [60]. Not only is this the case, but non-specific adsorption may also due to its high adsorption potential, rapid adsorption dynamics,
lead to an increase in adverse effects as the adsorbent material removes
biomolecules necessary for maintaining health. And by adsorbing Table 1
non-toxins, the sorbent surfaces actually have a decreased ability to bind Summary of advantages and disadvantages of several adsorbent for removal of
toxins. Membrane based adsorption suffers all of these disadvantages as uremic toxins.
well as the fact that even the specific adsorption of molecules will inhibit Adsorbent Advantages Disadvantages
the diffusion of molecules across the membrane [61]. Moreover, the type
adsorption capacity of the membrane is very limited compared to porous Activated • High adsorption capacity • Poor hemocompatibility
particles. Perhaps the only viable approach in the short term is the use of carbon • Immunizing inert • Lack of selective
adsorbents in the dialysate to remove toxins. The major limitation here • Low cost adsorption

is that the cost of increasing water flow is minimal for most high-income Zeolite • Uniform pore size • Partially dissolved in
countries, which reduces the apparent need for developing sorbent • Allow sieving small toxin dialysate
molecules • Adsorption of cations
surfaces for dialysate.
• Modifiable physical properties by from blood/dialysate
For both column and membrane adsorbent, the basic principles various frameworks
determining their abilities are their porous structure and surface
Mesoporous • Uniform pore size • Limited industrial yield
chemistry. In this review paper, porous adsorbents with different surface
silica • Pore size highly variable for • Limited structure
materials for removal of the uremic toxin are introduced, with their different sizes of toxin molecules stability
advantages and limitations presented. We discuss the available studies • Easy surface functionalization
that investigate how adsorbents can be modified to enhance their Polymer • Different adsorbent forms • Poor hemocompatibility
adsorption capacity and/or to address issues that limit their clinical use. (membrane, gel, resin) available • Uneven pore size/shape
We also review several examples of in vivo studies involving the use of • Highly flexible ways of • May trigger
adsorbents for treatment of uremic models, with comparison to routine modification (surface chemistry, immunogenic response
copolymerization, blending)
hemodialysis.

3
Y. Ma et al.
Table 2
In vitro researches using adsorbent for removal of uremic toxins (results posted were obtained near neutral pH ranged from 6 to 8, at room or physiological temperature
if not otherwise stated).
Adsorbent type Suitable Uremic toxins
strategya
Activated carbon (AC)
zwitterionic poly-carboxybetaine (PCB) hydrogel coating 1 bilirubin
poly (hydroxyethyl methacrylate) coating 1,3 creatinine
poly (hydroxyethyl methacrylate) coating 1,3 creatinine
dextran coating 1,3 bilirubin
NH3 deposition 1,3 uric acid
KOH modified 1,3 indole
4% poly (vinylidene chloride/vinyl chloride) coating 3 creatinine
polyvinylpyrrolidone coating 1 phenylacetic acid
p-cresyl sulfate
indoxyl sulfate
CO2 activation 1 interleukin 1β
Poly (ether sulfone)/activated carbon (PES–AC) hybrid beads 1,3 creatinine
sulfuric acid-treated activated carbon fiber 1,3 urea
suspension-assisted colloidal silica templating treated carbon 1,3 creatinine
beads α-Chymotrypsin
co-deposition with alginate 1,3 uric acid
creatinine
Zeolite
silicalite 1 p-cresol
mordenite 1 creatinine
indoxyl sulfate
gamma-aminobutyric acid modified zeolite 13X 1,3 creatinine
urea
poly (ethylene-co-vinyl alcohol) 3 creatinine
(EVOH)-zeolite–polymer composite nanofibers
polyacrylonitrile (PAN)-zeolite 3 creatinine
composite nanofiber
zeolites and polyethersulfone-zeolite composite membranes 2 indoxyl sulfate
Mesoporous silica
amine-functionalized SBA-15 3 urea
SBA-15/Fe3O4 nanocomposites 1,3 urea
Polymer
polyamide membrane 2 p-cresol
poly (acrylonitrile) membrane 2 p-cresol
polysulfone membrane 2 p-cresol
urease-immobilized polyethersulfone beads 1,3 urea
polysulfone-poly (methyl methacrylate) dual layer hollow fiber 1,3 urea
polystyrene column 1 β2-microglobulin
(β2M)
seed-conjugated polymer Beads 1 β2-microglobulin
(β2M)
poly (cyclodextrins) 1 indoxyl sulfate
oxidized poly (vinylindanone) beads with ninhydrin groups 1,3 urea
poly (carboxybetaine) (PCB) coated polystyrene resin (H103) 1 bilirubin
microparticles
CaCO3 nanoparticle/polystyrene composite 1 interleukin-6
carbonylated hypercrosslinked 1 p-cresol
chloromethylated poly (styrene-co-divinylbenzene)
Molecularly imprinted polymer (MIP)
creatinine-imprinted poly (β-cyclodextrin) 3 creatinine
creatinine-imprinted poly (tetraethoxysilanol) sol–gel 3 creatinine
uric acid-imprinted poly (acrylamide-hydroxyethyl 3 uric acid
methacrylate) p (AAm-MMA) cryogel
Mixed matrix membrane (MMM)
cellulose acetate matrix 2 creatinine
indoxyl sulfate
poly (ethersulfone)/poly (vinylpyrrolidone) dual layer hollow 2 creatinine
fiber (MMM1) indoxyl sulfate
p-cresyl sulfate
hippuric acid
poly (ethersulfone)/poly (vinylpyrrolidone) dual layer hollow 2 creatinine
fiber (MMM2) indoxyl sulfate
p-cresyl sulfate
poly (ethersulfone)/poly (vinylpyrrolidone) dual layer hollow 2 indoxyl sulfate
fiber (MMM3) hippuric acid
heparin-mimicking polymers grafted carbon nanotube/poly 2 creatinine
(ethersulfone) composite membrane
4
Microporous and Mesoporous Materials 319 (2021) 111035
Maximum removal capacity in amount of adsorbed toxin/ Reference
per gram or square meter of adsorbent (Initial toxin
concentration, Medium)
8 mg/g (150 mg/l, BSA solution) [72]
10 mg/g (20 mg/l, PBS) [73]
175 mg/g (100 mg/l, PB) [76]
3–7 mg/g (160 mg/l, PBS) [77]
333.1 mg/g (150 mg/l, water) [78]
300 mg/g (100 mg/l, PBS) [79]
2.5 mg/g (100 mg/l, PBS) [80]
38.9 mg/g (474 mg/l, BSA solution) [125]
3.8 mg/g (40 mg/l, BSA solution)
4.4 mg/g (44 mg/l, BSA solution)
CT275-C1-A1 140 ng/g (312 ng/l, Tyrode buffer) [81]
MN500HSC1-A6 60 ng/g (11 ng/l, Tyrode buffer)
87 mg/g (500 mg/l, Tyrode buffer) [82]
530 mg/g (2310 mg/l, water) [126]
550 mg/g (2000 mg/l, simulated plasma) [127]
165 mg/g (200 mg/l, simulated plasma)
2.03 mg/g (70 mg/l, water) [83]
0.329 mg/g (30 mg/l, water)
106 mg/g (22 mg/l, PB) [47]
37.5 mg/g (140 mg/l, aqueous solution, pH 4.7) [89]
3.7 mg/g (78 mg/l, aqueous solution, pH 5.0)
132 mg/g (100 mg/l, water) [128]
146 mg/g (100 mg/l, water)
25 mg/g (22 mg/l, water) [91]
880 mg/m2 (23 mg/l, water) [129]
1.3 mg/g (35 mg/l, PBS) [130]
542.6 mg/g (2310 mg/l, water) [96]
490 mg/g (2280 mg/l, simulated serum) [101]
21 mg/g (22 mg/l, PBS) [47]
0.3 mg/g (22 mg/l, PBS) [47]
37.3 mg/g (22 mg/l, PBS) [47]
75.1 mg/g (800 mg/l, water) [118]
27.6 mg/g (2500 mg/l, water) [119]
1.3 mg/g (63.5 mg/l, PBS) [111]
7.3 mg/g (440 mg/l, PBS) [117]
45 mg/g (780 mg/l, PBS) [116]
192 mg/g (1800 mg/l, PBS) [120]
20.75 mg/g (150 mg/l, BSA solution) [131]
6.59 mg/g (150 mg/l, 100% FBS)
25.6 ng/g (1000 ng/l, human plasma) [132]
141.5 mg/g (100 mg/l, NaCl solution) [121]
6 mg/g (180 mg/l, PB) [133]
0.8 mg/g (100 mg/l, water) [134]
687.6 mg/g (40 mg/l, water) [135]
148.6–186.6 mg/g (35 mg/l, human serum)
25 mg/g membrane (12–136 mg/l, water) [136]
13 mg/g membrane (53–247 mg/l, water)
2825 mg/m2 (136 mg/l, human plasma) [137]
255 mg/m2, or 12.85 mg/g membrane (247 mg/l, human
plasma)
160 mg/m2, or 2.68 mg/g membrane (uremic
concentrations, human plasma)
784 mg/m2 (471 mg/l, human plasma)
2549 mg/m2 (100 mg/l, PBS) [138]
367 mg/m2 (40 mg/l, human plasma)
380 mg/m2 (40 mg/l, human plasma)
500 mg/m2 (40 mg/l, human plasma) [139]
2478 mg/m2 (110 mg/l, human plasma)
1.4 mg/g membrane (50 mg/l, PBS) [65]
(continued on next page)
Y. Ma et al.
Table 2 (continued )
Adsorbent type Suitable
strategya
polyethersulfone matrix 2 p-cresol
Metal–Organic Frameworks (MOF)
MIL-100(Fe) 1,3
NU-1000 1,3
Carbon nanotubes (CNTs)
Multiwalled Carbon Nanotubes, Poly (3,4- 2 p-cresol
Ethylenedioxythiophene):Polystyrenesulfonate (MWCNT/
PEDOT:PSS) Nanofiber Mats
a
The number refers to the specific strategy of application for adsorbent shown in the graphic abstract.
chemically inert, and stable under complex physiological conditions
[67]. Thus, activated carbon is incorporated into almost every artificial
kidney device; however, carbon does not show a high affinity toward
any individual uremic toxin. An evident example is in adsorption of
urea, the major uremic toxin component. Activated carbon has the
lowest urea adsorption when compared to other uremic toxin adsorbents
[48,68]. Activated carbon is also found to have inadequate removal of
middle molecular weight substances [69]. Another issue in using acti­
vated carbon is that it adsorbs both uremic toxins and non-toxins (e.g.
nutrients) alike [70,71].
Activated carbon has been shown to have poor hemocompatibility,
which can not only cause a reduction in its ability to adsorb uremic
toxins, but also lead to major complications like the initiation of the
contact activation pathway leading to coagulation [72]. It is generally
thought that making this surface less hydrophobic will improve hemo­
compatibility [73]. To this end, several attempts at generating activated
carbon that is more hydrophilic have been made. One of the first at­
tempts was a heparin-complexed or albumin coated collodion
micro-encapsulated activated carbon [66]. Both modified activated
carbons were found to maintain the arterial platelet level and did not
lead to the formation of embolizing particles. Both modified activated
carbons performed nearly as efficiently as activated carbon controls in
lowering blood creatinine, with albumin coated activated carbon being
more efficient than the heparin-complexed activated carbon. The
albumin-collodion activated charcoal hemoperfusion were later proved
effective in binding drugs, both in vitro and in vivo [74,75]. Later pHEMA
was coated on activated carbon and was found efficient in removing
creatinine and uric acid through both in vitro and in vivo tests [73]. Lee
and Hsu attempted improving the blood hemocompatibility of spherical
activated carbon (SAC) through coating with poly (hydroxyethyl
methacrylate) (p (HEMA)). The reduction of platelet adsorption to SAC-
p (HEMA) was as good as commercially used hemoperfusion particles
(Kuraray’s DHP). By comparison, the micropore volume for SAC parti­
cles is 0.075 cm3/g and is about half of that for DHP particles. It also
confirmed that the p (HEMA) coating has a very slight effect on the
adsorption capacity of creatinine on SAC particles [76]. Recently a
zwitterionic poly-carboxybetaine (PCB) hydrogel was coated on
powdered activated carbon (PAC). The activated carbon particles were
embedded into the hydrogels via in situ cross-linking. The PCB-PAC
complex showed negligible hemolysis and a low nonspecific protein
adsorption response, without a significant reduction in its adsorption
performance [72]. Dextran coated activated carbon withstood several
ISO recommended tests including inflammatory response, fibrinogen
adsorption, and complement activation [77]. However, the coating
adversely affected adsorption by decreasing the pore size. After coating
with up to 30% dextran, the pore volume of activated carbon decreased
from 2.19 to 1.45 cm3/g. As a result, the total adsorption capacity of the
activated carbon was compromised.
Activated carbon has been modified in an attempt to preferentially
adsorb specific uremic toxins. For uric acid, spherical activated carbon
(PSAC) was modified using chemical vapor deposition of NH3 (NH3-
Microporous and Mesoporous Materials 319 (2021) 111035
Uremic toxins Maximum removal capacity in amount of adsorbed toxin/ Reference
per gram or square meter of adsorbent (Initial toxin
concentration, Medium)
108.7 mg/g membrane (400 mg/l, PB) [140]
creatinine 133.3 mg/g membrane (700 mg/l, PB)
creatinine 30 mg/g membrane (100 mg/l, PBS) [62]
p-cresyl sulfate 26.5 mg/g membrane (18.82 mg/l, water) [63]
4500 mg/m2 membrane (125 mg/l, PBS) [64]
CVD). It was found that NH3-CVD increased surface basicity, total pore
volume (0.73 cm3/g to 0.76 cm3/g), and pHPZC (point of zero charge),
and these changes promoted the adsorption of uric acid [78]. Using KOH
to activate mesoporous carbon led to both increased micropore surface
area and pore volume, as well as a rapid adsorption of indole [79].
Chang et al. prepared micro-encapsulated activated carbon by coating
with poly (vinylidene fluoride) and poly (vinylidene chloride/vinyl
chloride) to drive the adsorption of large lipophilic molecules (e.g.
vitamin B12) as well as small hydrophilic molecules (e.g. creatinine). The
removal of large lipophilic molecules was relatively unaffected by the
presence of the polymer coating, but was as rapid and complete as the
uncoated activated carbon. However, removal of small hydrophilic
molecules was severely affected by the polymer coating properties. Even
the lowest coating concentration yielded an excluding efficiency of
80–85% and was not as good as uncoated activated carbon with ~100%
clearance [80]. With the advantage of the mesoporous structure,
spherical activated carbon particles were prepared by coating with two
different sulphonated styrene divinylbenzene co-polymers that were
further activated using carbon dioxide. The carbons were generated with
surface areas between 400 and 1200 m2/g− 1, and pore volume between
0.2 and 1.4 cm3/g− 1. A loss of mechanical strength was observed but an
increase in the adsorption of IL-1β was observed [81]. Zhao et al. pre­
pared poly (ether sulfone)-activated carbon (PES–AC) hybrid beads
[82]. Depends on the proportion of AC, the surface areas of hybrid beads
varied from 28 to 219 m2/g and the pore volume varied from 5.5 to 2.1
cm3/g. In this case, the adsorption of creatinine was primarily deter­
mined by the amount of activated carbon incorporated and fixed by the
PES layer. In another study, alginate and activated carbon were
co-deposited through electrophoretic deposition onto a steel wire mesh
that led to adsorption of creatinine, ammonia, and uric acid in signifi­
cant quantities, but was still not on par with current materials [83].
There are also studies using particular precursors to prepare more
efficient or cost-effective activated carbon. Jia et al. prepared activated
carbon powders based on polyaniline-poly (styrene sulfonate) (PAn-
PSS) hydrogels [84]. The prepared particles were found to have 54%
pore volume (mesopore volume/total pore volume) and an average pore
diameter of 2.87 nm. On its own this adsorbent featured a high amine
content, which may help intensify interaction with certain adsorbates by
the formation of a hydrogen bond. Compared to coconut shell activated
carbon, PAn-PSS hydrogel activated carbon exhibited higher adsorption
capacity of creatinine. Surendra et al. prepared activated carbon from
parthenium weed (Parthenium hysterophorus), an inexpensive source
material [85]. Compared to commercial grade activated carbon,
parthenium-based activated carbon was found to have a smaller surface
area (260 m2/g vs. 686 m2/g), and a larger pore diameter (37 Å vs. 19
Å). The parthenium based activated carbon was able to remove p-cresol
with a close but still lower equilibrium amount, up to an equilibrium
adsorbent concentration of 500 mg/L. Another study done by Bakas
et al. compared p-cresol adsorption between granular activated alumina
and granular activated charcoal [86]. Although a surface area of 360
and 800 m2/g was found for activated alumina and activated charcoal,
5
Y. Ma et al.
they showed a very similar maximum monolayer adsorption capacity of
55.80 mg/g and 56.61 mg/g for p-cresol adsorption, respectively.
Therefore, activated alumina might be considered as another low-cost
option with similar adsorption capacity as activated charcoal.
2.2. Zeolite
Zeolite is an aluminum silicate that occurs in nature and can be
produced synthetically. It is composed of SiO4 and AlO4 tetrahedra
formed with the stoichiometric unit cell formula [87]:
Mx/m [(AlO2 )x (SiO2 )y ]⋅zH2 O
where M is the cation type with the valence value m, and z represents the
number of water molecules in each unit cell. To balance the negative
charge due to the substitution of Si4+ by Al3+, a variety of cations can be
utilized: K+, Na+, Mg2+, Ca2+. The ionic nature of most zeolites lends
itself to the formation a more hydrophilic surface than that of activated
carbon [88]. Besides variations in the cationic composition, the Si/Al
ratio can be tuned to generate a range of framework structures, pore
sizes, and extents of hydrophobicity; allowing for tailored properties
that may enhance the adsorption of specific toxins. Thus they are used as
both adsorbent materials as well as molecular sieves for separating
molecules.
The application of zeolites to the removal of uremic toxins has sys­
tematically evaluated their physical and chemical properties (pore size,
hydrophobicity, grain size, charge compensating cations, etc.) in order
to adjust adsorption performance. Zeolites with different framework
structures were prepared, and the adsorption of both free water-soluble
toxins (urea, etc.) and protein-bound uremic toxins (p-cresol, etc.) were
characterized [89]. Five tested uremic toxins (Urea, Uric acid, Creati­
nine, p-Cresol and Indoxyl sulfate) were estimated with the dimension of
0.3–0.5 nm, which fit into channels of most studied zeolites with the
exception for Linde Type A (LTA). LTA has a small micropore dimension
of 0.41 nm and adsorbs all toxins at low levels. Zeolites with a high Si/Al
ratio, as shown by mordenite (MOR)-Z9 and silicalite (MFI), present
hydrophobic channel surface. Adsorption of p-cresol is highly favored by
MFI. The superior adsorption towards p-cresol for MFI was shown as fast
equilibrium time and high adsorption amount [47,89]. However, for
adsorption of indoxyl sulfate no such advantage was observed. It was
also found that creatinine adsorption increases strongly when the Si/Al
ratio changed from 6.1 to 10 in MOR. The inclusion of different cations
within the Si/Al framework can drastically affect the overall charge and
hydration properties of the zeolite. The adsorption of uric acid on a Ca2+
and K+ exchanged framework was comparatively higher than on a Na+
exchanged framework. The adsorption of indoxyl sulfate on a K+
exchanged framework was comparatively higher than on the other
cation exchanged framework, and was as high as that on a hydrophobic
uncharged framework. Other factors like grain size and hydrothermal
treatment were also found to influence the adsorption properties.
Interestingly, the adsorption result for creatinine shows that MOR has a
specific high affinity towards creatinine than any other framework. A
mechanistic study revealed that in pure water, the adsorption of creat­
inine onto mordenite was accompanied by the protonation of creatinine
molecules (Fig. 1) [90]. When adsorption was performed on partially
Fig. 1. Protonation of creatinine when adsorbed onto mordenite. Reproduced
with permission from Ref. [86], Copyright © 2008 Elsevier Inc.
6
Microporous and Mesoporous Materials 319 (2021) 111035
exchanged forms of mordenite, it is possible that a cationic exchange
between the protonated creatinine and other cations occurred. Mor­
denite could potentially be incorporated into hemodialysis equipment to
specifically remove creatinine from blood, but a further in vivo test is still
required to prove this specificity in a more complex blood environment.
In addition, since creatinine (like urea) is generally considered to be a
proxy for uremic toxins rather than a toxin per se, it remains to be
determined whether this function would prove clinically useful.
Others have studied how to integrate zeolites into blood purification
systems, looking at combining them with a variety of different substrates
such as nanofiber matrices and membranes. Such a composite structure
is thought to ensure their immobilization, while minimizing adverse
effects associated with solution exposure and the resulting adsorption
capability. Ebara et al. developed a zeolite-polymer composite nanofiber
mesh incorporated into a portable blood purification system [91]. The
nanofiber system was electrospun using poly (ethylene-co-vinyl alcohol)
(EVOH) with dispersed zeolite particles. Various types of zeolite were
incorporated into the fibers as a bead-like structure p (EVOH), and the
adsorption of creatinine measured. Zeolite type 940-HOA (Beta, Si/Al =
500) exhibited an optimal adsorption capacity, but it was found that the
p (EVOH) matrix created an adsorption barrier that decreased the
adsorption efficiency even when more zeolite was incorporated. Inter­
estingly, it was observed that under a continuous flow condition,
creatinine adsorption was found to be much lower than without flow;
suggesting fluid dynamics around the matrix may be a crucial factor in
the application of these materials. To overcome the barrier effect for
these nanofiber matrices, the same group continued their work by
varying the composition of ethylene in EVOH, thus resulting in a less
crystallized structure and a higher amount of adsorbed creatinine [92].
The composite fibers also showed much less cytotoxicity than free
zeolite particles. Similarly, dispersed zeolite within polyacrylonitrile
(PAN)-zeolite nanofiber membranes were electrospun by John et al.
[93]. Again the 940-HOA (Beta) zeolite had the highest adsorption ca­
pacity, and when compared with free zeolite powders, both 840 (ZSM-5)
and 940 zeolites incorporated into membranes exhibited even higher
adsorption capacity. This effect seems contradictory to the barrier effect
created by the nanofibers. For such a surprising result, the experiment
itself might be questionable because different testing protocols were
used for free powders and the nanofiber composite, and thus may result
in control powder samples having less exposure to creatinine solutions.
The preparation of PES-zeolite membrane for IS removal was fabricated
by a spin-coating method followed by liquid-liquid phase separation in
water [94]. Among ten types of zeolite, with five different frameworks,
only P87 and P371 showed any adsorption of indoxyl sulfate. When P87
was incorporated into the PES membrane it showed a similar removal
rate of indoxyl sulfate compared to the P87 powder. They further
studied the effect of pH and salt ions on adsorption of IS, and suggest
that electrostatic attraction is possibly the main force responsible for
indoxyl sulfate adsorption.
Although some progress has been made regarding zeolite application
to toxin removal, one major drawback remains, viz., when exposed to
blood solutions the zeolite may dissolve [95]. The dissolution of zeolite
would allow aluminum or silicon to enter blood, directly or indirectly (e.
g. from the dialysate). Unlike activated carbon with a wide range of pore
dimensions, zeolites may get the pore size tuned to fit that of uremic
toxins to exclude some organic molecules [89]. Nevertheless, zeolite
may still adsorb sodium, calcium and potassium ions from blood or
dialysate, therefore these ions have to be monitored and dialysate so­
lutions altered to compensate for any loss associated with the zeolite
[95].
2.3. Mesoporous silica
Another porous adsorbent is mesoporous silica. Hexagonal pores
arranged by MCM-41 and SBA-15 are two of the most common types of
mesoporous silica-based materials. Similar to a zeolite, a uniform pore
Y. Ma et al.
distribution can be formed in mesoporous silica, but with a much larger
scale of size variation (2 nm–200 nm) [96]. Furthermore, mesoporous
silica can be modified with different chemicals to introduce function­
ality. For example, it was found that amino- and carboxylic-containing
molecules can be grafted onto the silica surface through chemisorp­
tion [97–100]; another advantage over using a zeolite based system.
Silica features easy surface functionality, which may allow for testing
various surface chemistries. Amine-functionalized mesoporous silica
was synthesized by introducing 3-aminopropyl to the mesoporous silica
SBA-15 surface, and this brought about a slight decrease in pore diam­
eter from 6.5 to 5.6 nm and a decrease in pore volume from 0.8 to 0.3
cm3/g [96]. Amine-modified and unmodified mesoporous silica
exhibited a much higher adsorption capacity of urea than commercially
used activated carbon, this is despite the fact that activated carbon has a
much lower pore diameter and higher surface area as determined using
BET. Both amine-modified and unmodified surface were proposed to
adsorb urea molecules by forming hydrogen bonds (Fig. 2). Addition­
ally, this research focused attention on the fact that not only did the
amine modified mesoporous silica demonstrate the highest adsorption
capacity, it also showed a much higher nominal rate constant than any
other tested subject. Therefore, the author suggested that such an
advantage would allow for an increased dialysate flow to achieve higher
uremic toxin clearance efficiency. In another study SBA-15/Fe3O4
composites were prepared and the adsorption of urea was tested [101].
Conjugation with Fe3O4 offers an easy way of nanoparticle recovery
through magnetic field. The surface area of SBA-15/Fe3O4 decreased
dramatically from 1167 m2/g for bare SBA-15 to 311 m2/g, but the pore
volume shows only a slight decrease from 0.93 to 0.76 cm3/g. It was also
noted that SBA-15/Fe3O4 composites showed a compromised perfor­
mance of urea adsorption as compared to SBA-15.
Despite these unique features attributed to mesoporous silica,
toxicity concerns may arise with the presence of silanol groups found on
their surface, which has been found to cause hemolysis by interaction
with blood cell membrane [102]. Since the mesopores were created
under a metastable state, the structural stability under stress might be a
concern in real practices when a compact loading is required [103]. In
addition, the relatively higher cost and lower thermal stability
compared to zeolite may limit its wide applications as achieved for
zeolite based adsorbent [104].
2.4. Polymer
Polymer systems have several inherent properties that make them
Fig. 2. Urea adsorption mechanism on (left) unmodified and (right) amine modified mesoporous silica SBA-15. Reproduced with permission from Ref. [92],
Copyright © 2016 Elsevier B.V.
7
Microporous and Mesoporous Materials 319 (2021) 111035
suitable for use as adsorbents of uremic toxins. The relative ease of
forming macroscopic structures like membranes, fibers, or resin beads,
coupled with tunable mechanical and chemical properties allows for the
use of polymers that can tolerate interacting with the blood environ­
ment. Changes, even at the monomer level, may greatly impact the
ability to adsorb specific uremic toxins in varied amounts compared to
activated carbon, zeolite, or silica systems. Dialysis membranes based on
synthetic polymers (e.g., PMMA) have shown good solute permeability
and a higher degree of biocompatibility than natural polymers (e.g.,
cellulose based) [57,105]. It was found that during dialysis, replacing
the PMMA membrane in each dialysis session resulted in the reduction
of a large-sized uremic toxin and free immunoglobulin light chains
(sFLC), which suggests PMMA may serve as an sFLC adsorbent [106].
Polysulfone and polyamide were found with a high adsorption capacity
for p-cresol [47]. In study of adsorbent for mid-sized uremic toxins, such
as β2-microglobulin (β2M) and α-1-microglobulin (α-1-m), commercially
available columns based on cellulose [107–110], polystyrene
[111–113], and styrene-divinylbenzene copolymer [114] have been
used, among which the column with the highest removal performance
ever reported shows a 99% rate of decline for β2M, far exceeding that for
high-flux dialysis membranes (23–37%) [115].
With a large variety of types and compositions, polymer adsorbents
can be made with different adsorption properties based on their struc­
tural diversity and high potential for functionalization. Poly-β-cyclo­
dextran has been used for the removal of indoxyl sulfate. Jia et al.
prepared cross-linked poly-β-cyclodextrins (PCDs) as a water-soluble
adsorbent for IS [116]. PCDs have an inner hydrophobic cavity and an
external hydrophilic shell, therefore the cavity is able to accommodate
diverse hydrophobic molecules and the IS adsorption was proven to be
the hydrophobic interactions between the indole ring and cavity of
β-CD, plus hydrogen bonding. A binding capability of 45 mg/g was
achieved by PCD. In addition, PCDs demonstrated an improved removal
rate of IS when introduced into dialysis systems. As is established in the
literature, dialysis-related amyloidosis (DRA) is caused by the accumu­
lation of β2M, which then turns to amyloid fibrils. Seung et al. found one
peptide segment (Lys-Asp-Trp-Ser-Phe-Tyr-Leu-Leu-Tyr-Tyr) derived
from β2M are capable of forming amyloid fibrils. After immobilization of
this peptide on polymer beads of HiCore resin, the peptide is able to
accrete β2M in the form of fibrils on the bead surface (Fig. 3) [117]. It is
suggested that these seed-immobilized beads work as a highly specific
β2M removal system.
Special designs of polymer adsorbent have been used for urea
adsorption. Zhao et al. prepared a urease-immobilized polyethersulfone
Y. Ma et al.
Fig. 3. Proposed β2M-removal strategy harnessing nucleation-dependent amyloidogenesis. Reproduced with permission from Ref. [110], Copyright © 2020
American Institute of Chemical Engineers.
beads to remove urea. Urease was covalently bound to surface of
carboxyl polyethersulfone (PES) beads for enzymatic decomposition of
urea [118]. Compared to unmodified PES beads without urea adsorp­
tion, the urease immobilized PES beads (PES-PAA-U) reached a urea
removal amount 75.1 mg/g. Moreover, the urease immobilized PES
beads maintained 89.2% activity even after 15 days of incubation in
PBS.
Pei et al. prepared a polysulfone-poly (methyl methacrylate) dual
layer hollow fiber aimed for urea removal through both adsorption and
filtration [119]. Cornelus et al. prepared a modified poly (vinyl­
indanone) beads that presents ninhydrin groups that binds urea [120].
Ninhydrin groups were obtained by one-step halogenation and Korn­
blum oxidation of indanone groups present in macroporous poly­
vinylindanone beads. The surface area of ninhydrin containing beads
was determined to be 1.7 m2/g and is close to the 1.5 m2/g from before
oxidation. The urea binding capacity of sorbent particles was found
increased gradually up till saturation with oxidation time (Fig. 4). A
maximum urea binding capacity of 192 mg/g was reached.
For removal of phenolic compounds like p-cresol, commercially
available Amberlite XAD-4 resin has been recognized as the best syn­
thetic polymer adsorbent. However, its capacity for adsorption is
compromised by its hydrophobic surface when removing toxins from
aqueous solution. To this end, Huang prepared a hypercrosslinked
polymeric adsorbent HJ-1 from chloromethylated poly (styrene-co-
divinylbenzene) (PS) [121]. The modified resin (HJ-1) exhibited higher
polarity compared to chloromethylated poly (styr­
ene-co-divinylbenzene) and was even more polar than non-polar XAD-4.
HJ-1 has a surface area of 727 m2/g, similar to 750 m2/g for XAD-4, but
with a lower pore volume of 0.59 cm3/g as around half to that for
XAD-4. The adsorption test, under aqueous solution, revealed that HJ-1
has a higher adsorption capacity of phenol and p-cresol compared to
commercial XAD-4 resin. Polymeric microspheres are also used as an
adsorbent for uremic toxins. Zhang et al. prepared co-polymer p
(HEMA-co-NVP) microspheres, which was cross-linked with N,
N′ -methylene bisacrylamide (MBA) [122]. The microspheres were
chemically modified with 3,5-dinitrobenzoyl chloride (DNBC), to obtain
3,5-dinitrobenzoate group (DNBZ) bound surface. The DNBZ bound p
(HEMA-co-NVP) microspheres have a fair high adsorption capacity for
Fig. 4. Reaction scheme of the oxidation of indanone groups into ninhydrin groups, and plot of the urea binding capacity of sorbent beads as function of oxidation
time. Reproduced with permission from Ref. [113], Copyright © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
8
Microporous and Mesoporous Materials 319 (2021) 111035
creatinine with the saturated adsorption amount of 25 mg/g, 20 times as
much compared to unmodified p (HEMA-co-NVP) microspheres.
There are some drawbacks commonly related to polymer adsorbents.
As it is mentioned above, dialysis membrane based on polymers may
suffer from its adsorption properties, which may pose negative effects on
its diffusion rate, hemocompatibility, and reusability. The porous
structure in polymeric materials was generally found to be non-uniform
and unordered, resulting in a system that is difficult to optimize the pore
size or shape for specific types of toxins.
One common problem for these porous adsorbents used in vivo is the
indiscriminate adsorption between toxins and non-toxins, which could
reduce levels of essential substances such as vitamins or trace elements.
For application in hemoperfusion, the performance of porous adsorbents
has been significantly weakened by their poor hemocompatibility.
Activated carbon, for example, has non-specific blood protein adsorp­
tion that cannot be avoided once activated carbon is exposed to blood,
and this can cause significant clinical problems, including particulate
micro-emboli formation, hemolysis, and blood coagulation [77,123,
124]. To overcome these limitations, further surface functionalization or
surface modification is required.
3. Some adsorbent techniques for uremic toxin removal
3.1. Molecularly imprinted polymer (MIP)
Molecularly imprinted polymer (MIP) systems have been recognized
recently as a promising tool in applications like sensors [141] and
adsorbent [133]. MIP is a polymer substrate that can bind with high
specificity towards target molecules (Fig. 5). In brief, monomers are
polymerized and cross-linked around a template molecule. While MIP is
formed either a non-covalent or reversible covalent interaction may
occur between MIP and the template. Upon template removal, a binding
pocket specific for this template molecule is then left [142].
MIP has been utilized for specific binding of uremic toxins, with
creatinine being the most used molecules for imprinting. Tsai and Syu
prepared creatinine imprinted MIP, using β-Cyclodextrin as the mono­
mer and epichlorohydrin as the cross-linking agent [133]. The molar
ratio between monomer to template and monomer to the cross-linking
Y. Ma et al.
Fig. 5. Basics of molecularly imprinted polymer (MIP). (1) The template molecule (T) forms complex with functional monomers (M); (2) Co-polymerization occurs
with both M and cross-linker (CL) to form polymeric network around the template; (3) Removal of template to create complementary binding cavities that can bind
template molecules with high specificity. Reproduced with permission from Ref. [137], Copyright © 2003 American Chemical Society.
agent were optimized for maximum adsorption of creatinine. Creatinine,
N-hydroxysuccinimide, and 2-pyrrolidinone were chosen for compari­
son of their adsorption. The results of adsorption on binary and ternary
mixture solution suggest that the creatinine imprinted poly (β-CD) has
recognition ability for creatinine. The specific binding effect of MIP to
creatinine was further confirmed by the capping of hydroxyl groups of
the imprinted poly (β-CD) with chlorotrimethylsilane (CTMS). Another
work by the Syu group was done on the preparation of creatinine
imprinted sol-gel [134], an inorganic polymer matrix that has always
been used as a matrix for molecularly imprinting. This study suggested
that solvent played an important role in specific binding, that the
imprinting factor, measured by comparing adsorbed creatinine amount
in imprinted sol-gel to non-imprinted sol-gel, in water was much higher
than that in methanol. It was found that the solvent also affected the
competitive adsorption. Under the methanol solution, adsorption by the
imprinted sol-gel on mixture solution of N-hydrox­
ysuccinimide/2-pyrrolidinone/creatinine failed to show any selectivity
towards creatinine. While in water the imprinted sol-gel did have the
highest bound amount of creatinine than other compounds, as it also did
in binary mixture solutions comprised of creatinine and other
compounds.
Although MIP has high specificity for the imprinted molecules, its
capacity for toxin adsorption is low compared to other adsorbents,
which may reduce its clinical utility. We did not identify any studies of
MIP imprinted to bind middle-sized or protein bound uremic toxins.
However studies have shown MIP with larger template molecules like
proteins is challenging, due to their large size, flexible structure and
presence of abundant groups for recognition, and therefore nonspecific
binding or cross binding of similar sized proteins is common [143,144].
3.2. Mixed matrix membrane (MMM)
Sorbent membranes were developed as early as the 1970s by Enka
[145–149]. However, persistent problems with everything from fabri­
cation to purification of adsorbents used presented significant barriers to
Fig. 6. Schematic illustration of mixed matrix membrane (MMM) for blood purification. Reproduced with permission from Ref. [147], Copyright © 2012 Acta
Materialia Inc. Published by Elsevier Ltd.
9
Microporous and Mesoporous Materials 319 (2021) 111035
commercialization [150,151]. That said, there has been recent interest
in mixed matrix membranes (MMM), which can clear toxins by both
diffusion and adsorption [137,152,153]. In MMM, the adsorptive par­
ticles are embedded in a membrane that serves as a macroporous matrix,
and another particle-free membrane layer is introduced to directly
interact with the blood compartment so as to minimize hemocompati­
bility issues (Fig. 6). Compared to a column adsorbent, MMM embeds
activated carbon particles more firmly to prevent release, while the
membrane still maintains a high flux rate.
Cellulose acetate and polyethersulfone (PES)/polyvinylpyrrolidone
(PVP) polymer blend (PES as a membrane-forming polymer blended
with PVP to improve hydrophilicity) [137,152] have been used as a
macroporous matrix, and activated carbon was used in both cases as the
adsorptive particle. Dimitrios et al. developed three generations of
MMM based on poly (ethersulfone)/poly (vinylpyrrolidone) dual layer
hollow fiber [137–139]. Key factors such as fiber inner diameter, pore
size and surface roughness have been adjusted in each generation to
reach better outcomes of flux, protein leakage and protein adsorption.
The three generations of MMM (MMM1, MMM2, and MMM3), together
with reference membranes, were compared in terms of PUBT removal
(Fig. 7), and the graph shows improved IS and hippuric acid (HA)
removal and flux rate (ultrafiltration coefficient, KUF) from MMM1 to
MMM3.
With heparin-mimicking polymers grafted carbon nanotubes (f-
CNT), Zhao et al. prepared a hemocompatibility enhanced MMM [65].
Heparin-mimicking polymer (contained the sodium styrene sulfonate
(SS) and methyl ether methacrylate (EGMA) units) was grafted to CNT
through surface initiated-atom transfer radical polymerization
(SI-ATRP) (Fig. 8), and the obtained f-CNT was incorporated into PES
membrane through spin coating of f-CNT/PES dispersion followed by
liquid–liquid phase separation. Blending of f-CNT into the PES mem­
brane remarkably improved both the hemocompatibility of the mem­
brane and its ability to clear creatinine from the blood compartment.
Although the advancement in MMM has proved a promising
approach to clearing uremic toxins, it should be noted that this
Y. Ma et al.
Fig. 7. (a) IS and (b) HA removal of MMM1, MMM2, MMM3 and reference membranes. Reproduced with permission from Ref. [132], Copyright © 2020 The
Authors. Published by Elsevier B.V. Note that the starred data in the graph marked with “current study” refers to results from the reference paper.
technique is still membrane-based and that it relies on diffusion of
uremic toxins through the matrix to the dialysate or to the embedded
particles. Thus, large biomolecules bound with uremic toxins with high
affinity are unable to diffuse into MMM and would remain in circulation,
potentially causing toxicity for the patient.
4. In vivo test performances of several adsorbent systems
Although hemodialysis is necessary to sustain life in patients with
kidney failure, a variety of uremic toxins are not readily cleared from the
blood using these techniques. For example, protein-bound uremic toxins
are hardly cleared by current dialysis approaches at all and higher levels
of these toxins are associated with adverse clinical outcomes such as
cardiovascular events [154–156]. Contemporary adsorbent techniques
were found to be a more efficient than conventional hemodialysis for
clearing such toxins. Most of the in vivo studies were conducted in either
of two forms: oral adsorption or extra-corporeal adsorption.
Oral doses of activated carbon (AST-120; Kremezin®) has been used
to adsorb uremic toxins from the gastrointestinal tract (GI), thereby
preventing their uptake into blood and reducing blood levels [157,158].
AST-120 is composed of spherical particles (~0.2–0.4 mm in diameter),
which are mainly porous microcrystalline carbon with a surface area
over 1600 m2/g [159,160]. Administration of AST-120 in nephrectomy
animal models resulted in a decreased level of serum creatinine and
urinary protein [157]. More specific studies revealed that by decreasing
IS levels in vivo, AST-120 significantly reduced the ratio of oxidized al­
bumin, and therefore the role of AST-120 in inhibiting oxidative stress in
CKD was determined [161]. In addition, AST-120 has been reported to
improve low bone turnover that results from uremia, another IS asso­
ciated disease [162]. One recent study suggests progression of athero­
sclerosis in CKD could be suppressed with treatment of AST-120 [163].
Over decades, some clinical data suggests that AST-120 might slow the
rate of loss in native kidney function, thereby delaying or preventing the
need for hemodialysis [164,165]. However, whether AST-120 truly does
improve clinical outcomes in this population is controversial and it is not
widely used in practice.
To enhance the removal of protein-bound toxins as compared to
conventional hemodialysis, a technique called fractionated plasma
separation and adsorption (FPSA) was created. Here the albumin frac­
tion is first separated by filtration through an albumin permeable
membrane, and is then purified by perfusion over a neutral resin
adsorbent and an anion exchanger and then returned to the plasma [166,
167]. Both neutral and anion exchange adsorbents are able to compet­
itively remove protein bound toxins from albumin, while anion
exchanger is highly efficient in elimination of anionic albumin-bound
toxins such as bilirubin and bile acid [168]. Whole blood is then dia­
lyzed through the high-flux dialyzer (Fig. 9). The system has been
commercialized with the brand name Prometheus®. FPSA was
10
Microporous and Mesoporous Materials 319 (2021) 111035
specifically designed to remove albumin-bound toxins, for liver or kid­
ney failure issues, as albumin was considered to be the main binding
protein for hydrophobic solutes [28]. In vivo study in CKD patients
showed that the reduction rate of p-cresyl sulfate by FPSA exceeded the
reduction rate given by high-flux hemodialysis [169]. In a similar study,
the removal rate on FPSA treated patients for several protein-bound
uremic toxins including phenylacetic acid, indoxyl sulfate and p-cresol
were increased respectively by 130, 187, and 127% in comparison to
conversional high-flux hemodialysis [170]; although the high-flux
clearance rates of these toxins is quite poor with the latter. The pre­
sent studies have proven that FPSA is more capable of removing
albumin-bound toxins in CKD patients than high-flux hemodialysis. In
practice, it was shown that the separation of albumin resulted in a
sieving effect where a large portion of albumin failed to cross Albu­
flow®. For this reason, the toxins that bound to albumin were returned
to circulation. To achieve optimal albumin separation, more precisely
determined membrane cut-off sizes are to be expected. In early FPSA
system, fibrinogen was only involved in the secondary circuit to a
limited degree, but there were studies that blamed coagulation abnor­
mality for CKD patients on the toxin binding of fibrinogen [171,172],
and therefore fibrinogen or even other minor proteins may have to be
involved for clearance. Although the adsorbents used exhibited a high
capacity for toxin binding and a high ability for lowering their blood
concentration, non-specific adsorption was still unavoidable. Adsorp­
tion of both pro- and anticoagulant factors onto the anion exchange resin
have been shown to cause severe thrombosis, which is a significant
obstacle to clinical use. Other safety parameters such as cortisol, triio­
dothyronine, or total plasma protein were not significantly altered
enough to cause concern. An investigation that addresses these issues is
still needed.
It is known that toxin binding impairs protein function by influ­
encing their ability to interact with other proteins as required to main­
tain homeostasis. Albumin from chronic hemodialysis patients
underwent significant conformational changes and displayed a
decreased capacity for binding pharmaceuticals [173]. Nikolaev pre­
pared carbonic hemosorbents (HSGD®), a type of activated carbon
produced by pyrolysis of nitrogen-containing synthetic (4-vinyl­
pyridine-styrene-divinyl-benzene copolymer) resins, with a pore volume
of 2.4 cm3/g and a bulk density of 0.06 g/cm3. It was found HSGD coated
with albumin as a promising method to deligand protein-bound toxins
such as bilirubin [174], fatty and bile acids, phenols, CMPF, hippuric
acid, and IS [175] from albumin. The molecular level restoration of
human serum albumin in terms of conformation and ligand-binding
activity was confirmed by this method. After extra-corporeal treat­
ment by deliganding adsorbent, restoration of conformation and
complex-forming capacity occurred for uremic albumin [176].
Y. Ma et al.
Fig. 8. Illustration of heparin-mimicking polymers (PSS/PEGMA) grafted on carbon nanotubes. Reproduced with permission from Ref. [133], Copyright © 2014
Elsevier B.V.
5. Conclusion and future perspective
Unlike small free water-soluble uremic toxins, protein-bound and
middle-sized uremic toxins cannot be removed easily using conventional
hemodialysis. This is problematic as these toxins have been associated
with adverse outcomes. In this area, better solutions may be achieved
with the use of adsorbent materials. Current research of adsorbents in­
volves removal of both water soluble and protein bound uremic toxin.
Some of these studies investigated specific adsorption towards
certain toxins, such as mordenite or MIP towards creatinine, or urease/
ninhydrin containing surface towards urea. To our best knowledge
11
Microporous and Mesoporous Materials 319 (2021) 111035
nearly all of these specific adsorbents are for water soluble toxins, and
adsorbents for protein bound ones are yet to be explored.
In general, a highly porous structure is necessary to achieve sufficient
adsorption that is relevant to clinical applications. Surface modification,
either through altering surface chemistry or attaching bioactive mole­
cules, may improve the capture of certain toxin molecules. For hemo­
perfusion adsorbents, it will be of interest with the property to deligand
and bind protein bound toxins, or to bind middle molecules that both are
not efficiently removed through dialysis. For dialysate or peritoneal
adsorbent a high saturation capacity of adsorption is the preferred
property. In some blood purification situations where a high flux is
Y. Ma et al.
Fig. 9. Shematic illustration of fractionated plasma separation and adsorption
(FPSA) system. Reproduced with permission from Ref. [163], Copyright © 2013
the Authors. © 2013 Artificial Organs, International Center for Artificial Organs
and Transplantation and Wiley Periodicals, Inc.
required, membrane based adsorption strategy such as MMM might be
the preferred option.
Clinically, activated carbon and zeolite based adsorbent is by far the
best studied material and to our knowledge is included in most
commercialized adsorbent systems. Despite the fact that the superior
removal rates have been achieved by these adsorbents, when compared
to hemodialysis, there are still significant challenges that need to be
addressed in future studies: 1. Improvement of hemocompatibility to not
trigger any adverse issues, and without sacrificing adsorption perfor­
mance; 2. Selectively bind uremic toxins without affecting required
protein and nutrient blood composition; and 3. Those adsorbent mate­
rials exhibiting specificity towards certain uremic toxins, their capacity
of removal shall be higher or comparable to commercially available
porous activated carbon or zeolite, and still affordable.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgment
This work was supported by the Strategic Research Project grant
from Alberta Innovates, and by NSERC Discovery Grant. There is no
conflict of interest.
References
[1] H. Fujii, S. Goto, M. Fukagawa, Role of uremic toxins for kidney, cardiovascular,
and bone dysfunction, Toxins 10 (2018) 202.
[2] H.A. Mutsaers, E.G. Stribos, G. Glorieux, R. Vanholder, P. Olinga, Chronic kidney
disease and fibrosis: the role of uremic retention solutes, Front. Med. 2 (2015) 60.
[3] S. Kalim, S.A. Karumanchi, R.I. Thadhani, A.H. Berg, Protein carbamylation in
kidney disease: pathogenesis and clinical implications, Am. J. Kidney Dis. 64
(2014) 793–803.
[4] A.F. Perna, D. Ingrosso, C. Lombardi, F. Acanfora, E. Satta, C.M. Cesare,
E. Violetti, M.M. Romano, N.G. De Santo, Possible mechanisms of homocysteine
toxicity, Kidney Int. 63 (2003) S137–S140.
[5] R. Vanholder, R. De Smet, G. Glorieux, A. Argiles, U. Baurmeister, P. Brunet,
W. Clark, G. Cohen, P.P. De Deyn, R. Deppisch, B. Descamps-Latscha, T. Henle,
A. Jorres, H.D. Lemke, Z.A. Massy, J. Passlick-Deetjen, M. Rodriguez,
B. Stegmayr, P. Stenvinkel, C. Tetta, C. Wanner, W. Zidek, E. Grp, Review on
uremic toxins: classification, concentration, and interindividual variability,
Kidney Int. 63 (2003) 1934–1943.
[6] F. Duranton, G. Cohen, R. De Smet, M. Rodriguez, J. Jankowski, R. Vanholder,
A. Argiles, E.U.T.W. Grp, Normal and pathologic concentrations of uremic toxins,
J. Am. Soc. Nephrol. 23 (2012) 1258–1270.
[7] F.A. Mcgilloway, Medical surgical nursing - assessment and management of
clinical problems - lewis,Sm, Collier,Ic, J. Adv. Nurs. 9 (1984) 233–234.
12
Microporous and Mesoporous Materials 319 (2021) 111035
[8] M. Heinig, R.J. Johnson, Role of uric acid in hypertension, renal disease, and
metabolic syndrome, Cleve. Clin. J. Med. 73 (2006) 1059–1064.
[9] N. Katsiki, M. Doumas, V.G. Athyros, A. Karagiannis, Hyperuricemia as a risk
factor for cardiovascular disease, Expert Rev Cardiovas 13 (2015) 19–20.
[10] S. Yamamoto, J.J. Kazama, I. Narita, H. Naiki, F. Gejyo, Recent progress in
understanding dialysis-related amyloidosis, Bone 45 (2009) S39–S42.
[11] G. Eknoyan, G.J. Beck, A.K. Cheung, J.T. Daugirdas, T. Greene, J.W. Kusek,
M. Allon, J. Bailey, J.A. Delmez, T.A. Depner, J.T. Dwyer, A.S. Levey, N.W. Levin,
E. Milford, D.B. Ornt, M.V. Rocco, G. Schulman, S.J. Schwab, B.P. Teehan,
R. Toto, H.S. Grp, Effect of dialysis dose and membrane flux in maintenance
hemodialysis, N. Engl. J. Med. 347 (2002) 2010–2019.
[12] L. Vallar, P.M.P. Costa, A. Teixeira, M. Pfister, R. Barrois, P.P. Costa, C. Rivat,
Immunoadsorption procedure as a potential method for the specific beta-2-
microglobulin removal from plasma of patients with chronic-renal-failure,
J. Chromatogr. B Biomed. Appl. 664 (1995) 97–106.
[13] G.A. Ameer, E.A. Grovender, H. Ploegh, D. Ting, W.F. Owen, M. Rupnick,
R. Langer, A novel immunoadsorption device for removing beta(2)-microglobulin
from whole blood, Kidney Int. 59 (2001) 1544–1550.
[14] L.J. Zhang, B. Zang, C.D. Huang, J. Ren, L.Y. Jia, One-step preparation of a VHH-
based immunoadsorbent for the extracorporeal removal of 2-microglobulin,
Molecules (2019) 24.
[15] C.D. Huang, J. Ren, F.L. Ji, S. Muyldermans, L.Y. Jia, Nanobody-Based high-
performance immunosorbent for selective beta 2-microglobulin purification from
blood, Acta Biomater. 107 (2020) 232–241.
[16] S. Liabeuf, T.B. Drueke, Z.A. Massy, Protein-bound uremic toxins: new insight
from clinical studies, Toxins 3 (2011) 911–919.
[17] L. Dou, E. Bertrand, C. Cerini, V. Faure, J. Sampol, R. Vanholder, Y. Berland,
P. Brunet, The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial
proliferation and wound repair, Kidney Int. 65 (2004) 442–451.
[18] R. Vanholder, E. Schepers, A. Pletinck, E.V. Nagler, G. Glorieux, The uremic
toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review, J. Am. Soc.
Nephrol. 25 (2014) 1897–1907.
[19] M. Black, B.H. Billing, Hepatic bilirubin udp-glucuronyl transferase activity in
liver disease and gilberts syndrome, N. Engl. J. Med. 280 (1969) 1266.
[20] S.C. Leong, T.L. Sirich, Indoxyl sulfate—review of toxicity and therapeutic
strategies, Toxins 8 (2016) 358.
[21] A.W. Martinez, N.S. Recht, T.H. Hostetter, T.W. Meyer, Removal of p-cresol
sulfate by hemodialysis, J. Am. Soc. Nephrol. 16 (2005) 3430–3436.
[22] H. de Loor, B. Bammens, P. Evenepoel, V. De Preter, K. Verbeke, Gas
chromatographic-mass spectrometric analysis for measurement of p-cresol and its
conjugated metabolites in uremic and normal serum, Clin. Chem. 51 (2005)
1535–1538.
[23] T. Niwa, K. Maeda, T. Ohki, A. Saito, K. Kobayashi, A gas chromatographic-mass
spectrometric analysis for phenols in uremic serum, Clinica chimica acta,
international journal of clinical chemistry 110 (1981) 51–57.
[24] N. Ogata, N. Matsushima, T. Shibata, Pharmacokinetics of wood creosote:
glucuronic acid and sulfate conjugation of phenolic compounds, Pharmacology
51 (1995) 195–204.
[25] L. Koppe, N.J. Pillon, R.E. Vella, M.L. Croze, C.C. Pelletier, S. Chambert, Z. Massy,
G. Glorieux, R. Vanholder, Y. Dugenet, H.A. Soula, D. Fouque, C.O. Soulage, p-
Cresyl sulfate promotes insulin resistance associated with CKD, J. Am. Soc.
Nephrol. 24 (2013) 88–99.
[26] H. Watanabe, Y. Miyamoto, D. Honda, H. Tanaka, Q. Wu, M. Endo, T. Noguchi,
D. Kadowaki, Y. Ishima, S. Kotani, M. Nakajima, K. Kataoka, S. Kim-Mitsuyama,
M. Tanaka, M. Fukagawa, M. Otagiri, T. Maruyama, p-Cresyl sulfate causes renal
tubular cell damage by inducing oxidative stress by activation of NADPH oxidase,
Kidney Int. 83 (2013) 582–592.
[27] T. Niwa, Uremic toxicity of indoxyl sulfate, Nagoya J. Med. Sci. 72 (2010) 1–11.
[28] L. Viaene, P. Annaert, H. de Loor, R. Poesen, P. Evenepoel, B. Meijers, Albumin is
the main plasma binding protein for indoxyl sulfate and p-cresyl sulfate,
Biopharm Drug Dispos. 34 (2013) 165–175.
[29] E. Devine, D.H. Krieter, M. Ruth, J. Jankovski, H.D. Lemke, Binding affinity and
capacity for the uremic toxin indoxyl sulfate, Toxins 6 (2014) 416–429.
[30] A. Dhondt, R. Vanholder, W. Van Biesen, N. Lameire, The removal of uremic
toxins, Kidney Int. 58 (2000) S47–S59.
[31] A. Enomoto, M. Takeda, A. Tojo, T. Sekine, S.H. Cha, S. Khamdang, F. Takayama,
I. Aoyama, S. Nakamura, H. Endou, T. Niwa, Role of organic anion transporters in
the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity,
J. Am. Soc. Nephrol. 13 (2002).
[32] T. Niwa, Removal of protein-bound uraemic toxins by haemodialysis, Blood Purif.
35 (2013) 20–25.
[33] T.W. Sedlak, M. Saleh, D.S. Higginson, B.D. Paul, K.R. Juluri, S.H. Snyder,
Bilirubin and glutathione have complementary antioxidant and cytoprotective
roles, Proc. Natl. Acad. Sci. U.S.A. 106 (2009) 5171–5176.
[34] T. Kamisako, Y. Kobayashi, K. Takeuchi, T. Ishihara, K. Higuchi, Y. Tanaka, E.
C. Gabazza, Y. Adachi, Recent advances in bilirubin metabolism research: the
molecular mechanism of hepatocyte bilirubin transport and its clinical relevance,
J. Gastroenterol. 35 (2000) 659–664.
[35] L. Uzun, A. Denizli, Bilirubin removal performance of immobilized albumin in a
magnetically stabilized fluidized bed, J. Biomater. Sci. Polym. Ed. 17 (2006)
791–806.
[36] S. Sideman, L. Mor, J.M. Brandes, S. Lupovitch, Preparation of a biocompatible
albumin-coated ion-exchange resin for bilirubin removal from the blood of
jaundiced newborns, J. Biomed. Mater. Res. 17 (1983) 91–107.
[37] G. Lonnemann, Chronic inflammation in hemodialysis: the role of contaminated
dialysate, Blood Purif. 18 (2000) 214–223.
Y. Ma et al.
[38] M.H. Rahman, S.S. Haqqie, M.D. McGoldrick, Acute hemolysis with acute renal
failure in a patient with valproic acid poisoning treated with charcoal
hemoperfusion, Hemodialysis international, Int. Symp. Home Hemodialysis 10
(2006) 256–259.
[39] J. Winchester, A. Boldur, C. Oleru, C. Kitiyakara, Use of Dialysis and
Hemoperfusion in Treatment of Poisoning, Handbook of Dialysis, Boston Little
Brown, Boston, 1994.
[40] D.S. Terman, G. Buffaloe, G. Cook, M. Sullivan, C. Mattioli, R. Tillquist, J.C. Ayus,
Extracorporeal immunoadsorption - initial experience in human systemic lupus-
erythematosus, Lancet 2 (1979) 824–826.
[41] A. Ault, New direction for treatment of rheumatoid arthritis offered in USA,
Lancet 353 (1999), 1071-1071.
[42] J. Caldwell, R.M. Gendreau, D. Furst, A pilot study using a staph protein A column
(Prosorba (R)) to treat refractory rheumatoid arthritis, J. Rheumatol. 26 (1999)
1657–1662.
[43] R.M. Hakim, E. Milford, J. Himmelfarb, R. Wingard, J.M. Lazarus, R.M. Watt,
Extracorporeal removal of anti-hla antibodies in transplant candidates, Am. J.
Kidney Dis. 16 (1990) 423–431.
[44] J.L. Rosenbaum, M.S. Kramer, R.M. Raja, Amberlite hemoperfusion in the
treatment of acute drug intoxication, Int. J. Artif. Organs 2 (1979) 316–318.
[45] S. Yamamoto, J.J. Kazama, T. Wakamatsu, Y. Takahashi, Y. Kaneko, S. Goto,
I. Narita, Removal of uremic toxins by renal replacement therapies: a review of
current progress and future perspectives, Renal Replacement Therapy 2 (2016)
43.
[46] R.A. Van Wagenen, M. Steggall, D.J. Lentz, J.D. Andrade, Activated carbons for
medical applications. In vitro microparticle characterization and solute
adsorption, Biomater. Med. Dev. Artif. Organs 3 (1975) 319–364.
[47] V. Wernert, O. Schaf, V. Faure, P. Brunet, L. Dou, Y. Berland, P. Boulet, B. Kuchta,
R. Denoyel, Adsorption of the uremic toxin p-cresol onto hemodialysis
membranes and microporous adsorbent zeolite silicalite, J. Biotechnol. 123
(2006) 164–173.
[48] G. Dunea, Replacement of renal-function by dialysis - a textbook of dialysis, 2nd
edition - drukker,W, parsons,Fm, Maher,Jf, JAMA, J. Am. Med. Assoc. 252
(1984), 1768-1768.
[49] J. Mulder, Basic Principles of Membrane Technology, Springer Science & Business
Media, 2012.
[50] V. Gura, C. Ronco, A. Davenport, The wearable artificial kidney, why and how:
from holy grail to reality, Semin. Dial. 22 (2009) 13–17.
[51] C. Ronco, A. Davenport, V. Gura, Toward the wearable artificial kidney,
Hemodial. Int. 12 (2008) S40–S47.
[52] C. Ronco, A. Davenport, V. Gura, A wearable artificial kidney: dream or reality?
Nat. Clin. Pract. Nephrol. 4 (2008) 604–605.
[53] H.D. Polaschegg, Wearable dialysis: what is missing? Hemodialysis: New Methods
and Future Technology 171 (2011) 226–230.
[54] W. Oshihara, H. Nagao, H. Megano, J. Arai, M. Koide, M. Takada, Trial use of a
polymethylmethacrylate membrane for the removal of free immunoglobulin light
chains in dialysis patients, NDT plus 3 (2010) i3–i7.
[55] I. Aoike, Clinical significance of protein adsorbable membranes - long-term
clinical effects and analysis using a proteomic technique, Nephrol. Dial.
Transplant. 22 (2007) 13–19.
[56] J.M. Campistol, J.V. Torregrosa, E. Ponz, B. Fenollosa, beta(2)-microglobulin
removal by hemodialysis with polymethylmethacrylate membranes,
Polymethylmethacrylate a Flexible Membrane for a Tailored Dialysis 125 (1999)
76–85.
[57] M. Pascual, N. TolkoffRubin, J.A. Schifferli, Is adsorption an important
characteristic of dialysis membranes? Kidney Int. 49 (1996) 309–313.
[58] S.D. Sun, Y.L. Yue, X.H. Huang, D.Y. Meng, Protein adsorption on blood-contact
membranes, J. Membr. Sci. 222 (2003) 3–18.
[59] R. Deppisch, E. Ritz, G.M. Hansch, M. Schols, E.W. Rauterberg,
Bioincompatibility - perspectives in 1993, Kidney Int. 45 (1994) S77–S84.
[60] A.K. Cheung, Biocompatibility of hemodialysis membranes, J. Am. Soc. Nephrol.
1 (1990) 150–161.
[61] H. Vonbaeyer, F. Kochinke, R. Schwerdtfeger, Cascade plasmapheresis with
online membrane regeneration - laboratory and clinical-studies, J. Membr. Sci. 22
(1985) 297–315.
[62] C.L. Cheng-Xiong Yang, Yi-Meng Cao, Xiu-Ping Yan, Metal–organic framework
MIL-100(Fe) for artificial kidney application, RSC Adv. 2014 (2014)
40824–40827.
[63] S. Kato, K.-i. Otake, H. Chen, I. Akpinar, C.T. Buru, T. Islamoglu, R.Q. Snurr, O.
K. Farha, Zirconium-based metal–organic frameworks for the removal of protein-
bound uremic toxin from human serum albumin, J. Am. Chem. Soc. 141 (2019)
2568–2576.
[64] S.-C. Yen, Z.-W. Liu, R.-S. Juang, S. Sahoo, C.-H. Huang, P. Chen, Y.-S. Hsiao, J.-
T. Fang, Carbon nanotube/conducting polymer hybrid nanofibers as novel
organic bioelectronic interfaces for efficient removal of protein-bound uremic
toxins, ACS Appl. Mater. Interfaces 11 (2019) 43843–43856.
[65] C.X. Nie, L. Ma, Y. Xia, C. He, J. Deng, L.R. Wang, C. Cheng, S.D. Sun, C.S. Zhao,
Novel heparin-mimicking polymer brush grafted carbon nanotube/PES composite
membranes for safe and efficient blood purification, J. Membr. Sci. 475 (2015)
455–468.
[66] T.M.S. Chang, Removal of endogenous and exogenous toxins by a
microencapsulated absorbent, Can. J. Physiol. Pharmacol. 47 (1969) 1043.
[67] H. Marsh, F. Rodríguez-Reinoso, Chapter 1 - introduction to the scope of the text,
in: H. Marsh, F. Rodríguez-Reinoso (Eds.), Activated Carbon, Elsevier Science Ltd,
Oxford, 2006, pp. 1–12.
13
Microporous and Mesoporous Materials 319 (2021) 111035
[68] S. Stefoni, L. Coli, G. Feliciangeli, L. Baldrati, V. Bonomini, Regular
hemoperfusion in regular dialysis treatment - a long-term study, Int. J. Artif.
Organs 3 (1980) 348–353.
[69] J. Chen, W. Han, J. Chen, W. Zong, W. Wang, Y. Wang, G. Cheng, C. Li, L. Ou,
Y. Yu, High performance of a unique mesoporous polystyrene-based adsorbent for
blood purification, Regenerative biomaterials 4 (2016) 31–37.
[70] R.C. Bansal, J.-B. Donnet, F. Stoeckli, Active Carbon, Marcel Dekker, 1988.
[71] M.C. Annesini, V. Piemonte, L. Turchetti, Removal of albumin-bound toxins from
albumin-containing solutions: tryptophan fixed-bed adsorption on activated
carbon, Chem. Eng. Res. Des. 88 (2010) 1018–1023.
[72] N.N. Cai, Q.S. Li, J.M. Zhang, T. Xu, W.Q. Zhao, J. Yang, L. Zhang, Antifouling
zwitterionic hydrogel coating improves hemocompatibility of activated carbon
hemoadsorbent, J. Colloid Interface Sci. 503 (2017) 168–177.
[73] J.D. Andrade, K. Kunitomo, R. Vanwagen, B. Kastigir, D. Gough, W.J. Kolff,
Coated adsorbents for direct blood perfusion - hema/activated carbon, T Am Soc
Art Int Org 17 (1971) 222.
[74] T.M.S. Chang, E. Espinosamelendez, T.E. Francoeur, N.R. Eade, Albumin-
collodion activated-charcoal hemoperfusion in the treatment of severe
theophylline intoxication in a 3-year-old patient, Pediatrics 65 (1980) 811–814.
[75] T.M.S. Chang, J.F. Coffey, C. Lister, E. Taroy, A. Stark, Methaqualone,
methyprylon, and glutethimide clearance by acac microcapsule artificial kidney -
in-vitro and in patients with acute intoxication, T Am Soc Art Int Org 19 (1973)
87–91.
[76] C.J. Lee, S.T. Hsu, Preparation of spherical encapsulation of activated carbons and
their adsorption capacity of typical uremic toxins, J. Biomed. Mater. Res. 24
(1990) 243–258.
[77] C.A. Howell, S.R. Sandeman, Y. Zheng, S.V. Mikhalovsky, V.G. Nikolaev, L.
A. Sakhno, E.A. Snezhkova, New dextran coated activated carbons for medical
use, Carbon 97 (2016) 134–146.
[78] C.J. Liu, X.Y. Liang, X.J. Liu, Q. Wang, L. Zhan, R. Zhang, W.M. Qiao, L.C. Ling,
Surface modification of pitch-based spherical activated carbon by CVD of NH(3)
to improve its adsorption to uric acid, Appl. Surf. Sci. 254 (2008) 6701–6705.
[79] T. Mitome, Y. Uchida, Y. Egashira, K. Hayashi, A. Nishiura, N. Nishiyama,
Adsorption of indole on KOH-activated mesoporous carbon, Colloid. Surface.
Physicochem. Eng. Aspect. 424 (2013) 89–95.
[80] R. Sipehia, R.A.B. Bannard, T.M.S. Chang, Poly(Vinylidene fluoride)-coated or
poly(vinylidene chloride vinyl chloride)-coated activated-charcoal for the
adsorption of large lipophilic molecules with exclusion of small hydrophilic
molecules, J. Membr. Sci. 47 (1989) 293–299.
[81] D.J. Malik, G.L. Warwick, M. Venturi, M. Streat, K. Hellgardt, N. Hoenich, J.
A. Dale, Preparation of novel mesoporous carbons for the adsorption of an
inflammatory cytokine (IL-1 beta), Biomaterials 25 (2004) 2933–2940.
[82] X.P. Deng, T. Wang, F. Zhao, L.J. Li, C.S. Zhao, Poly(ether sulfone)/activated
carbon hybrid beads for creatinine adsorption, J. Appl. Polym. Sci. 103 (2007)
1085–1092.
[83] C. Jackson, Design and In-Vitro Characterisation of Novel Sorbent Device for
Extracorporeal Blood Filtration and Other Applications, McGill University, 2012.
[84] Y.J. Jia, X.Y. Li, J.C. Jiang, K. Sun, Adsorption of creatinine on polyaniline-poly
(styrene sulfonate) hydrogels based activated carbon particles, Iran. Polym. J.
(Engl. Ed.) 24 (2015) 775–781.
[85] R.K. Singh, S. Kumar, S. Kumar, A. Kumar, Development of parthenium based
activated carbon and its utilization for adsorptive removal of p-cresol from
aqueous solution, J. Hazard Mater. 155 (2008) 523–535.
[86] I. Bakas, K. Elatmani, S. Qourzal, N. Barka, A. Assabbane, I. Aît-Ichou,
A comparative adsorption for the removal of p-cresol from aqueous solution onto
granular activated charcoal and granular activated alumina, J. Mater. Environ.
Sci. 5 (2014) 675–682.
[87] Crystallization, Air–Water Operations, Drying, Adsorption, Membrane
Separations, and Other Mass Transfer Processes, Fluid Mechanics, Heat Transfer,
and Mass Transfer.
[88] J. Pires, M.L. Pinto, A. Carvalho, M.B. de Carvalho, Assessment of hydrophobic-
hydrophilic properties of microporous materials from water adsorption
isotherms, Adsorption 9 (2003) 303–309.
[89] V. Wernert, O. Schaf, H. Ghobarkar, R. Denoyel, Adsorption properties of zeolites
for artificial kidney applications, Microporous Mesoporous Mater. 83 (2005)
101–113.
[90] D. Berge-Lefranc, H. Pizzala, R. Denoyel, V. Hornebecq, J.L. Berge-Lefranc,
R. Guieu, P. Brunet, H. Ghobarkar, O. Schaf, Mechanism of creatinine adsorption
from physiological solutions onto mordenite, Microporous Mesoporous Mater.
119 (2009) 186–192.
[91] K. Namekawa, M.T. Schreiber, T. Aoyagi, M. Ebara, Fabrication of zeolite-
polymer composite nanofibers for removal of uremic toxins from kidney failure
patients, Biomater Sci-Uk 2 (2014) 674–679.
[92] R. Takai, R. Kurimoto, Y. Nakagawa, Y. Kotsuchibashi, K. Namekawa, M. Ebara,
Towards a Rational Design of Zeolite-Polymer Composite Nanofibers for Efficient
Adsorption of Creatinine, J Nanomater, 2016.
[93] L.M. Lu, C. Samarasekera, J.T.W. Yeow, Creatinine adsorption capacity of
electrospun polyacrylonitrile (PAN)-zeolite nanofiber membranes for potential
artificial kidney applications, J. Appl. Polym. Sci. 132 (2015).
[94] L.M. Lu, J.T.W. Yeow, An adsorption study of indoxyl sulfate by zeolites and
polyethersulfone-zeolite composite membranes, Mater. Des. 120 (2017) 328–335.
[95] R.R. Willis, D.S. Bem, D.L. Ellig, Process and Composition for Removing Toxins
from Bodily Fluids, Google Patents, 2003.
[96] W.K. Cheah, Y.L. Sim, F.Y. Yeoh, Amine-functionalized mesoporous silica for urea
adsorption, Mater. Chem. Phys. 175 (2016) 151–157.
Y. Ma et al.
[97] D. Fine, A. Grattoni, R. Goodall, S.S. Bansal, C. Chiappini, S. Hosali, A.L. van de
Ven, S. Srinivasan, X.W. Liu, B. Godin, L. Brousseau, I.K. Yazdi, J. Fernandez-
Moure, E. Tasciotti, H.J. Wu, Y. Hu, S. Klemm, M. Ferrari, Silicon micro- and
nanofabrication for medicine, Adv Healthc Mater 2 (2013) 632–666.
[98] Q. Wei, H.Q. Chen, Z.R. Nie, Y.L. Hao, Y.L. Wang, Q.Y. Li, J.X. Zou, Preparation
and characterization of vinyl-functionalized mesoporous SBA-15 silica by a direct
synthesis method, Mater. Lett. 61 (2007) 1469–1473.
[99] G.S. Wu, P.H. Li, H.Q. Feng, X.M. Zhang, P.K. Chu, Engineering and
functionalization of biomaterials via surface modification, J. Mater. Chem. B 3
(2015) 2024–2042.
[100] K.Y. Ho, G. McKay, K.L. Yeung, Selective adsorbents from ordered mesoporous
silica, Langmuir 19 (2003) 3019–3024.
[101] R.S. Juang, C.C. Chien, C.L. Yao, S.H. Yu, A.C. Sun, Preparation of magnetically
recoverable mesoporous silica nanocomposites for effective adsorption of urea in
simulated serum, J Taiwan Inst Chem E 91 (2018) 22–31.
[102] M.T. Al Samri, A.V. Biradar, A.R. Alsuwaidi, G. Balhaj, S. Al-Hammadi, S. Shehab,
S. Al-Salam, S. Tariq, T. Pramathan, S. Benedict, T. Asefa, A.-K. Souid, In vitro
biocompatibility of calcined mesoporous silica particles and fetal blood cells, Int.
J. Nanomed. 7 (2012) 3111–3121.
[103] R. Mokaya, Improving the stability of mesoporous MCM-41 silica via thicker more
highly condensed pore walls, J. Phys. Chem. B 103 (1999) 10204–10208.
[104] S.E. Lehman, S.C. Larsen, Zeolite and mesoporous silica nanomaterials: greener
syntheses, environmental applications and biological toxicity, Environ. Sci.: Nano
1 (2014) 200–213.
[105] H. Sugaya, Y. Sakai, Polymethylmethacrylate: from Polymer to Dialyzer,
Polymethylmethacrylate, Karger Publishers, 1999, pp. 1–8.
[106] P. Fabbrini, S. Sirtori, E. Casiraghi, F. Pieruzzi, S. Genovesi, D. Corti, R. Brivio,
G. Gregorini, G. Como, M.L. Carati, M.R. Vigano, A. Stella,
Polymethylmethacrylate membrane and serum free light chain removal:
enhancing adsorption properties, Blood Purif. 35 (2013) 52–58.
[107] S. Furuyoshi, M. Nakatani, J. Taman, H. Kutsuki, S. Takata, N. Tani, New
adsorption column (lixelle) to eliminate (β2-Microglobulin for direct
hemoperfusion, Ther. Apher. 2 (1998) 13–17.
[108] T. Abe, K. Uchita, H. Orita, M. Kamimura, M. Oda, H. Hasegawa, H. Kobata,
M. Fukunishi, M. Shimazaki, T. Abe, T. Akizawa, S. Ahmad, Effect of beta(2)-
microglobulin adsorption column on dialysis-related amyloidosis, Kidney Int. 64
(2003) 1522–1528.
[109] N. Homma, F. Gejyo, S. Hasegawa, T. Teramura, I. Ei, H. Maruyama, M. Arakawa,
Effects of a new adsorbent column for removing beta-2-microglobulin from
circulating blood of dialysis patients, Dialysis-Related Amyloidosis 112 (1995)
164–171.
[110] F. Gejyo, T. Teramura, I. Ei, M. Arakawa, R. Nakazawa, N. Azuma, M. Suzuki,
S. Furuyoshi, T. Nankou, S. Takata, A. Yasuda, Long-term clinical evaluation of an
adsorbent column (BM-O1) of direct hemoperfusion type for beta(2)-
microglobulin on the treatment of dialysis-related amyloidosis, Artif. Organs 19
(1995) 1222–1226.
[111] V. Davankov, L. Pavlova, M. Tsyurupa, J. Brady, M. Balsamo, E. Yousha,
Polymeric adsorbent for removing toxic proteins from blood of patients with
kidney failure, J. Chromatogr. B 739 (2000) 73–80.
[112] E. Menegatti, C. Ronco, J.F. Winchester, A. Dragonetti, D. Di Simone, A. Davit,
G. Mengozzi, G. Marietti, G. Loduca, M. Mansouri, G.P. Sancipriano, L.M. Sena,
D. Roccatello, Absence of NF-kappa B activation by a new polystyrene-type
adsorbent designed for hemoperfusion, Blood Purif. 23 (2005) 91–98.
[113] M. Santin, M.A. Wassall, G. Peluso, S.P. Denyer, Adsorption of alpha-1-
microglobulin from biological fluids onto polymer surfaces, Biomaterials 18
(1997) 823–827.
[114] M.D. Morena, D.Q. Guo, V.S. Balakrishnan, J.A. Brady, J.F. Winchester, B.
L. Jaber, Effect of a novel adsorbent on cytokine responsiveness to uremic plasma,
Kidney Int. 63 (2003) 1150–1154.
[115] R.A. Odell, P. Slowiaczek, J.E. Moran, K. Schindhelm, Beta2-Microglobulin
kinetics in end-stage renal-failure, Kidney Int. 39 (1991) 909–919.
[116] J.Y. Li, L.L. Han, S.X. Liu, S. He, Y.M. Cao, J. Xie, L.Y. Jia, Removal of indoxyl
sulfate by water-soluble poly-cyclodextrins in dialysis, Colloids Surf. B
Biointerfaces 164 (2018) 406–413.
[117] S. Kang, J.E. Yang, J. Kim, M. Ahn, H.J. Koo, M. Kim, Y.S. Lee, S.R. Paik, Removal
of intact beta 2-microglobulin at neutral pH by using seed-conjugated polymer
beads prepared with beta 2-microglobulin-derived peptide (58-67), Biotechnol.
Prog. 27 (2011) 521–529.
[118] J. Zhang, Z.J. Wang, C. He, X.L. Liu, W.F. Zhao, S.D. Sun, C.S. Zhao, Safe and
effective removal of urea by urease-immobilized, carboxyl-functionalized PES
beads with good reusability and storage stability, ACS Omega 4 (2019)
2853–2862.
[119] M.N.Z. Abidin, P.S. Goh, N. Said, A.F. Ismail, M.H.D. Othman, M.S. Abdullah, B.
C. Ng, H. Hasbullah, S.H.S.A. Kadir, F. Kamal, S. Mansur, Polysulfone/amino-
silanized poly(methyl methacrylate) dual layer hollow fiber membrane for uremic
toxin separation, Separ. Purif. Technol. (2020) 236.
[120] J.A.W. Jong, Y. Guo, D. Hazenbrink, S. Douka, D. Verdijk, J. van der Zwan,
K. Houben, M. Baldus, K.C. Scheiner, R. Dalebout, M.C. Verhaar, R. Smakman, W.
E. Hennink, K.G.F. Gerritsen, C.F. van Nostrum, A ninhydrin-type urea sorbent for
the development of a wearable artificial kidney, Macromol. Biosci. 20 (2020).
[121] J.H. Huang, Treatment of phenol and p-cresol in aqueous solution by adsorption
using a carbonylated hypercrosslinked polymeric adsorbent, J. Hazard Mater. 168
(2009) 1028–1034.
[122] B.J. Gao, Y. Yang, J. Wang, Y. Zhang, Preparation and adsorption characteristic of
polymeric microsphere with strong adsorbability for creatinine, J. Biochem. Mol.
Toxicol. 22 (2008) 166–174.
14
Microporous and Mesoporous Materials 319 (2021) 111035
[123] K.E. Hagstam, L.E. Larsson, H. Thysell, Experimental studies on charcoal
haemoperfusion in phenobarbital intoxication and uraemia including
histopathologic findings, Acta Med. Scand. 180 (1966) 593.
[124] M. Ghannoum, J. Bouchard, T.D. Nolin, G. Ouellet, D.M. Roberts, Hemoperfusion
for the treatment of poisoning: technology, determinants of poison clearance, and
application in clinical practice, Semin. Dial. 27 (2014) 350–361.
[125] M. Sternkopf, S. Thoroe-Boveleth, T. Beck, K. Oleschko, A. Erlenkotter,
U. Tschulena, S. Steppan, T. Speer, C. Goettsch, V. Jankowski, J. Jankowski,
H. Noels, E.U.T.W. Grp, A bifunctional adsorber particle for the removal of
hydrophobic uremic toxins from whole blood of renal failure patients, Toxins 11
(2019).
[126] C.H. Ooi, W.K. Cheah, F.Y. Yeoh, Comparative study on the urea removal by
different nanoporous materials, Adsorption 25 (2019) 1169–1175.
[127] M.Q. Chen, M. Pan, Y.P. Chong, J.T. Wang, D.H. Long, Engineering the outermost
surface of mesoporous carbon beads towards the broad-spectrum blood-cleansing
application, Carbon 130 (2018) 782–791.
[128] V.H. Ramos-Martinez, E. Ramirez-Vargas, F.J. Medellin-Rodriguez, C.A. Avila-
Orta, C.A. Gallardo-Vega, A.B. Jasso-Salcedo, M.L. Andrade-Guel, Zeolite 13X
modification with gamma-aminobutyric acid (GABA), Microporous Mesoporous
Mater. (2020) 295.
[129] L. Lu, C. Samarasekera, J.T. Yeow, Creatinine adsorption capacity of electrospun
polyacrylonitrile (PAN)-zeolite nanofiber membranes for potential artificial
kidney applications, J. Appl. Polym. Sci. 132 (2015).
[130] L. Lu, J.T. Yeow, An adsorption study of indoxyl sulfate by zeolites and
polyethersulfone–zeolite composite membranes, Mater. Des. 120 (2017)
328–335.
[131] Q. Li, J. Yang, N.N. Cai, J.R.N. Zhang, T. Xu, W.A. Zhao, H.S. Guo, Y.N. Zhu,
L. Zhang, Hemocompatible hemoadsorbent for effective removal of protein-bound
toxin in serum, J. Colloid Interface Sci. 555 (2019) 145–156.
[132] Y.M. Chai, J. Chen, T.T. Wang, J. Chen, Y.D. Ma, G.H. Cheng, C.R. Li, Q. Zhang, L.
L. Ou, W.Z. Li, Bead-type polystyrene/nano-CaCO3 (PS/nCaCO(3)) composite: a
high-performance adsorbent for the removal of interleukin-6, J. Mater. Chem. B 7
(2019) 1404–1414.
[133] H.A. Tsai, M.J. Syu, Synthesis of creatinine-imprinted poly(beta-cyclodextrin) for
the specific binding of creatinine, Biomaterials 26 (2005) 2759–2766.
[134] H.A. Tsai, M.J. Syu, Preparation of imprinted poly(tetraethoxysilanol) sol-gel for
the specific uptake of creatinine, Chem. Eng. J. 168 (2011) 1369–1376.
[135] B. Osman, E. Sagdilek, M. Gumrukcu, G. Sarlkaya, Molecularly imprinted
composite cryogel for extracorporeal removal of uric acid, Colloids Surf. B
Biointerfaces 183 (2019).
[136] M. Tijink, J. Kooman, M. Wester, J. Sun, S. Saiful, J. Joles, Z. Borneman,
M. Wessling, D. Stamatialis, Mixed matrix membranes: a new asset for blood
purification therapies, Blood Purif. 37 (2014) 1–3.
[137] M.S.L. Tijink, M. Wester, G. Glorieux, K.G.F. Gerritsen, J.F. Sun, P.C. Swart,
Z. Borneman, M. Wessling, R. Vanholder, J.A. Joles, D. Stamatialis, Mixed matrix
hollow fiber membranes for removal of protein-bound toxins from human plasma,
Biomaterials 34 (2013) 7819–7828.
[138] D. Pavlenko, E. van Geffen, M.J. van Steenbergen, G. Glorieux, R. Vanholder, K.G.
F. Gerritsen, D. Stamatialis, New low-flux mixed matrix membranes that offer
superior removal of protein-bound toxins from human plasma, Sci. Rep. 6 (2016).
[139] D. Kim, D. Stamatialis, High flux mixed matrix membrane with low albumin
leakage for blood plasma detoxification, J. Membr. Sci. 609 (2020).
[140] C.C. Fu, Y.S. Hsiao, J.W. Ke, W.L. Syu, T.Y. Liu, S.H. Liu, R.S. Juang, Adsorptive
removal of p-cresol and creatinine from simulated serum using porous
polyethersulfone mixed-matrix membranes, Separ. Purif. Technol. (2020) 245.
[141] G. Selvolini, G. Marrazza, MIP-based sensors: promising new tools for cancer
biomarker determination, Sensors 17 (2017) 718.
[142] C. Baggiani, L. Anfossi, C. Giovannoli, Molecular imprinted polymers as synthetic
receptors for the analysis of myco-and phyco-toxins, Analyst 133 (2008) 719–730.
[143] X. Zhou, W.Y. Li, X.W. He, L.X. Chen, Y.K. Zhang, Recent advances in the study of
protein imprinting, Separ. Purif. Rev. 36 (2007) 257–283.
[144] A. Bossi, F. Bonini, A.P.F. Turner, S.A. Piletsky, Molecularly imprinted polymers
for the recognition of proteins: the state of the art, Biosens. Bioelectron. 22 (2007)
1131–1137.
[145] P.S. Malchesky, W. Varnes, W. Piatkiewicz, Y. Nose, Membranes containing
sorbents for blood detoxification, T Am Soc Art Int Org 23 (1977) 659–666.
[146] E. Denti, J.M. Walker, D. Brancaccio, V. Tessore, Evaluation of novel sorbent
systems for joint hemodialysis and hemoperfusion, Med. Instrum. 11 (1977)
212–216.
[147] P.S. Malchesky, W. Piatkiewicz, W.G. Varnes, L. Ondercin, Y. Nose, Sorbent
membranes - device designs, evaluations and potential applications, Artif. Organs
2 (1978) 367–371.
[148] E. Klein, F.F. Holland, K. Eberle, F.C. Morton, I. Cabasso, Sorbent-filled hollow
fibers for hemopurification, T Am Soc Art Int Org 24 (1978) 127–130.
[149] H.J. Gurland, L.A. Castro, W. Samtleben, J.C. Fernandez, Combination of
hemodialysis and hemoperfusion in a single unit for treatment of uremia, Clin.
Nephrol. 11 (1979) 167–172.
[150] G.V. Chapman, P.W.E. Hone, W. Bolton, A. Blogg, C. Stokoe, T. Cahill, J.
F. Mahony, P.C. Farrell, Evaluation of hemodiafiltration and sorbent membrane
dialysis .1. Invivo and invitro dialyzer performance, Dial. Transplant. 11 (1982)
758.
[151] G.V. Chapman, P.W.E. Hone, M.J. Shirlow, W. Bolton, A. Blogg, C. Stokoe,
T. Cahill, J.F. Mahony, P.C. Farrell, Evaluation of hemodiafiltration and sorbent
membrane dialysis .2. Clinical, nutritional, and middle molecule assessment, Dial.
Transplant. 11 (1982) 871.
Y. Ma et al.
[152] M.S.L. Tijink, M. Wester, J.F. Sun, A. Saris, L.A.M. Bolhuis-Versteeg, S. Saiful, J.
A. Joles, Z. Borneman, M. Wessling, D.F. Stamatialis, A novel approach for blood
purification: mixed-matrix membranes combining diffusion and adsorption in one
step, Acta Biomater. 8 (2012) 2279–2287.
[153] S. Saiful, Mixed Matrix Membrane Adsorbers for Protein and Blood Purification,
University of Twente, Enschede, 2007.
[154] S. Ito, M. Yoshida, Protein-bound uremic toxins: new culprits of cardiovascular
events in chronic kidney disease patients, Toxins 6 (2014) 665–678.
[155] G. Lesaffer, R. De Smet, N. Lameire, A. Dhondt, P. Duym, R. Vanholder,
Intradialytic removal of protein-bound uraemic toxins: role of solute
characteristics and of dialyser membrane, Nephrol. Dial. Transplant. 15 (2000)
50–57.
[156] D.H. Krieter, A. Hackl, A. Rodriguez, L. Chenine, H.L. Moragues, H.D. Lemke,
C. Wanner, B. Canaud, Protein-bound uraemic toxin removal in haemodialysis
and post-dilution haemodiafiltration, Nephrol. Dial. Transplant. 25 (2010)
212–218.
[157] Y. Yoshida, T. Sakai, M. Ise, Effects of oral adsorbent in the rat model of chronic-
renal-failure, Nephron 62 (1992) 305–314.
[158] P. Owada, M. Nakao, J. Koike, K. Ujiie, K. Tomita, T. Shiigai, Effects of oral
adsorbent AST-120 on the progression of chronic renal failure: a randomized
controlled study, Kidney Int. (1997) S188–S190.
[159] T. Miyazaki, I. Aoyama, M. Ise, H. Seo, T. Niwa, An oral sorbent reduces overload
of indoxyl sulphate and gene expression of TGF-beta 1 in uraemic rat kidneys,
Nephrol. Dial. Transplant. 15 (2000) 1773–1781.
[160] J.-F. Marier, J. Lee, S.R.P. Kambhampati, L. Galitz, R. Vargas, J. Moberly, D.
E. Salazar, Effect of repeated oral administrations of the oral adsorbent AST-120
on serum creatinine and other markers of renal function, Am. J. Nephrol. 26
(2006) 136–141.
[161] K. Shimoishi, M. Anraku, K. Kitamura, Y. Tasaki, K. Taguchi, M. Hashimoto,
E. Fukunaga, T. Maruyama, M. Otagiri, An oral adsorbent, AST-120 protects
against the progression of oxidative stress by reducing the accumulation of
indoxyl sulfate in the systemic circulation in renal failure, Pharmaceut. Res. 24
(2007) 1283–1289.
[162] Y. Iwasaki, H. Yamato, T. Nii-Kono, A. Fujieda, M. Uchida, A. Hosokawa,
M. Motojima, M. Fukagawa, Administration of oral charcoal adsorbent (AST-120)
suppresses low-turnover bone progression in uraemic rats, Nephrol. Dial.
Transplant. 21 (2006) 2768–2774.
[163] Y. Nakada, K. Onoue, T. Nakano, S. Ishihara, T. Kumazawa, H. Nakagawa,
T. Ueda, T. Nishida, T. Soeda, S. Okayama, M. Watanabe, R. Kawakami, Y. Saito,
AST-120, an oral carbon absorbent, protects against the progression of
atherosclerosis in a mouse chronic renal failure model by preserving sFlt-1
expression levels, Sci. Rep. 9 (2019).
[164] M. Asai, S. Kumakura, M. Kikuchi, Review of the efficacy of AST-120 (KREMEZIN
((R))) on renal function in chronic kidney disease patients, Ren. Fail. 41 (2019)
47–56.
15
Microporous and Mesoporous Materials 319 (2021) 111035
[165] G. Schulman, R. Vanholder, T. Niwa, AST-120 for the management of progression
of chronic kidney disease, Int. J. Nephrol. Renovascular Dis. 7 (2014) 49–56.
[166] D. Falkenhagen, W. Strobl, G. Vogt, A. Schrefl, I. Linsberger, F.J. Gerner,
M. Schoenhofen, Fractionated plasma separation and adsorption system: a novel
system for blood purification to remove albumin bound substances, Artif. Organs
23 (1999) 81–86.
[167] W. Laleman, A. Wilmer, P. Evenepoel, C. Verslype, J. Fevery, F. Nevens, Review
article: non-biological liver support in liver failure, Aliment. Pharmacol. Ther. 23
(2006) 351–363.
[168] H. Geiger, J. Klepper, P. Lux, A. Heidland, Biochemical assessment and clinical
evaluation of a bilirubin adsorbent column, Br-350) in Critically ILL Patients with
Intractable Jaundice 15 (1992) 35–39.
[169] B.K. Meijers, V. Weber, B. Bammens, W. Dehaen, K. Verbeke, D. Falkenhagen,
P. Evenepoel, Removal of the uremic retention solute p-Cresol using fractionated
plasma separation and adsorption, Artif. Organs 32 (2008) 214–219.
[170] F. Brettschneider, M. Tolle, M. von der Giet, J. Passlick-Deetjen, S. Steppan,
M. Peter, V. Jankowski, A. Krause, S. Kuhne, W. Zidek, J. Jankowski, Removal of
protein-bound, hydrophobic uremic toxins by a combined fractionated plasma
separation and adsorption technique, Artif. Organs 37 (2013) 409–416.
[171] J.J. de Vries, C.J.M. Snoek, D.C. Rijken, M.P.M. de Maat, Effects of post-
translational modifications of fibrinogen on clot formation, clot structure, and
fibrinolysis A systematic review, Arterioscl Throm Vas 40 (2020) 554–569.
[172] V. Binder, B. Bergum, S. Jaisson, P. Gillery, C. Scavenius, E. Spriet, A.K. Nyhaug,
H.M. Roberts, I.L.C. Chapple, A. Hellvard, N. Delaleu, P. Mydel, Impact of
fibrinogen carbamylation on fibrin clot formation and stability, Thromb.
Haemostasis 117 (2017) 899–910.
[173] V.V. Sarnatskaya, A.I. Ivanov, V.G. Nikolaev, E. Rotellar, K. von Appen,
M. Haspar, V.N. Maslenny, H. Klinkmann, Structure and binding properties of
serum albumin in uremic patients at different periods of hemodialysis, Artif.
Organs 22 (1998) 107–115.
[174] V.V. Sarnatskaya, W.E. Lindup, P. Walther, V.N. Maslenny, L.A. Yushko, A.
S. Sidorenko, A.V. Nikolaev, V.G. Nikolaev, Albumin, bilirubin, and activated
carbon: new edges of an old triangle, Artif. Cells Blood Substit. Immobil.
Biotechno. 30 (2002) 113–126.
[175] V.G. Nikolaev, V.V. Sarnatskaya, A.N. Sidorenko, K.I. Bardakhivskaya, E.
A. Snezhkova, L.A. Yushko, V.N. Maslenny, L.A. Sakhno, S.V. Mikhalovsky, O.
P. Kozynchenko, A.V. Nikolaev, Deliganding Carbonic Adsorbents for
Simultaneous Removal of Protein-Bound Toxins, Bacterial Toxins and
Inflammatory Cytokines, Nato Sci Peace Sec A, 2011, p. 289.
[176] V.V. Sarnatskaya, L.A. Yushko, L.A. Sakhno, V.G. Nikolaev, A.V. Nikolaev, D.
V. Grinenko, S.V. Mikhalovsky, New approaches to the removal of protein-bound
toxins from blood plasma of uremic patients, Artif Cell Blood Sub 35 (2007)
287–308.