review
org
Achieving more frequent and longer dialysis for the
majority: wearable dialysis and implantable artificial
kidney devices
William H. Fissell1, Shuvo Roy2 and Andrew Davenport3
1
Nephrology and Hypertension, Vanderbilt University, Nashville, Tennessee, USA; 2Bioengineering and Therapeutic Sciences, University of
California, San Francisco, San Francisco, California, USA and 3UCL Center for Nephrology, Royal Free Hospital, University College London
Medical School, London, UK
The long-term survival for many chronic kidney failure
patients who remain treated by dialysis in economically
advanced countries remains similar to that of those with
solid-organ malignancy, despite a disproportionate amount
of health-care expenditure. As such, the current paradigm of
three times weekly in-center hemodialysis for 4 h or shorter
sessions needs to change to improve patient outcomes.
Although more frequent and longer dialysis sessions have
been reported to improve cardiovascular risk surrogates and
short-term outcomes, these options are only practically
available to a very small fraction of the total dialysis
population. As such, radically new approaches are required
to improve patient outcomes and quality of life for the
majority of dialysis patients. Currently, two different
approaches are being developed, wearable devices based on
current dialysis techniques and more futuristic implantable
devices modeled on the natural nephron.
Kidney International (2013) 84, 256–264; doi:10.1038/ki.2012.466;
published online 13 February 2013
KEYWORDS: continuous dialysis; daily dialysis sorbent; implantable dialysis;
middle molecule; protein bound toxins; wearable dialysis
Correspondence: William H. Fissell, Nephrology and Hypertension, Vander-
bilt University, Nashville, Tennessee, USA.
E-mail: william.fissell@vanderbilt.edu
Received 24 August 2012; revised 19 October 2012; accepted 26
October 2012; published online 13 February 2013
256
http://www.kidney-international.
& 2013 International Society of Nephrology
Once hemodialysis had become established as a treatment for
chronic kidney disease (CKD), the early pioneers realized the
limitations of the treatment, particularly in terms of the
impact the intermittent three times weekly hemodialysis had
on patients’ quality of life—not only in terms of time spent
on dialysis and the time traveling to and from treatment but
also dietary and fluid restrictions. In addition, many patients
lose employment as a direct consequence of starting dialysis,
and not surprisingly, as with many chronic illnesses,
depression is well recognized among dialysis patients. This
motivated a search for the holy grail—a wearable dialysis
device that would allow patients to receive continuous
treatment while going on with the normal activities of daily
life. Such a device would not only provide adequate solute
clearances and control both electrolyte and acid–base status,
but also improve blood pressure control—all while allowing a
liberal diet and fluid intake. Despite many attempts to
develop such a wearable artificial kidney, it is only recently,
with the advent of micro-technologies, that it has been
possible to construct a truly wearable device that can
accurately regulate ultrafiltration and achieve adequate solute
clearances.1
Peritoneal dialysis (PD), as we know it today, can be
described as a portable or wearable mode of dialysis.
However, when first introduced in the 1960s, PD was limited
to patients with acute renal failure, through hard catheters
inserted percutaneusly using a sharp metal trochar and
dialyzed with sterile dialysate supplied in 1-liter glass bottles,
with treatments typically lasting for more than 24 h. Over the
next decade, PD started to be introduced as a treatment for
CKD, which was initially similar to that used for treating
acute renal failure but then progressed to patients being
admitted to hospital three times weekly for overnight PD
treatment sessions requiring a new catheter insertion for
each treatment. As such, in many centers PD was a temporary
treatment modality until patients could be established on
intermittent hemodialysis. However, a number of key
technical advances, including the introduction of indwelling
silicone catheters and commercially available sterile dialysate
in plastic bags, have allowed the development of a wearable
Kidney International (2013) 84, 256–264
WH Fissell et al.: Wearable and implantable dialysis devices
dialysis system by the late 1970s,2 with patients being
dialyzed at home using simple mechanical devices, which
regulated dialysate inflow, dwell, and out-flow. However, it
was only with the advent of continuous ambulatory PD,
pioneered by Montcrief and Popovich,3 that PD truly became
the major mode of renal replacement therapy we recognize
today, with now more than 230,000 patients being treated
worldwide.
CONTINUOUS WEARABLE PD DEVICES
PD is a wearable and portable dialysis therapy. However,
continuous ambulatory PD typically requires three or four
daily exchanges, which often limits the patient’s lifestyle
flexibility. Although treatment with cycler PD allows daytime
freedom, the patient is connected to the machine overnight,
and treatment requires transport and storage of relatively
large volumes of fresh dialysate. Currently, two new designs
have been proposed to increase patient freedom from
additional dialysate fluid exchanges. First, the Vicenza
wearable artificial kidney (ViWAK)4 utilizes a dual lumen
catheter, allowing continuous flow PD powered by a small
lightweight battery-powered pump. After an initial 2-h dwell
with standard glucose-based dialysate, peritoneal dialysate is
then continuously recycled by the passage of spent dialysate
through a series of sorbents. Sorbents have traditionally
contained microporous carbon, zirconium, or polystyrene.
However, as neither of these readily absorbs urea, most
sorbent designs have additionally incorporated urease to clear
urea, by metabolism to ammonium and carbon dioxide. As
ammonium is rapidly absorbed by zirconium phosphate,
ammonium generated by urease can be readily removed by
placing zirconium phosphate adjacent to or in series with a
urease sorbent. Even so, ammonia levels must be checked in
the dialysate before return to the patient, for safety to ensure
that the zirconium phosphate sorbent has not become
exhausted. Carbon dioxide micro- and macro-bubbles can
form in the extracorporeal circuit predominantly from the
metabolism of urea, but also potentially from bicarbonate,
which requires removal with a deaerating chamber, typically
made of gas-permeable plastic polymers.5 Whereas
microporous carbons absorb a wide range of azotaemic
toxins, including creatinine, uric acid, chloramines, oxidants,
other organic compounds, heavy metals, middle molecules,
including beta 2 microglobulin, and protein-bound solutes,
other sorbents act largely as ion exchangers. Although
zirconium phosphate absorbs ammonium, calcium,
magnesium, potassium, other cations, and metals, it
releases hydrogen and, to a lesser extent, sodium ions, and
zirconium oxide and zirconium carbonate, which absorb
phosphate, fluoride, and heavy metals, release sodium and
bicarbonate, as well as, to a lesser extent, acetate.6 As such,
changes in dialysate electrolyte, bicarbonate, and glucose
composition occur over time. The proposed ViWAK system
uses a combination of microporous carbon and polystyrene
resin in a series of absorption columns, but does not have any
specific system to correct electrolyte changes; however, it
Kidney International (2013) 84, 256–264
review
relies on using a fresh glucose-based dialysate each morning
and an overnight 7.5% icodextrin exchange to maintain
electrolyte homeostasis. In addition, there is no specific
ultrafiltration control, but ultrafiltration can be achieved by
adding additional glucose supplements to the regenerated
dialysate during the last 2 h of daytime cycling therapy to
augment any ultrafiltration achieved from the nocturnal
7.5% icodextrin exchange.4
Spent peritoneal dialysate effluent contains proteins in low
concentration, including fibrin, but with reuse this protein
content may well increase over time, and as such additional
filters are required to prevent protein coating of the sorbents,
thus reducing their efficiency.
Currently, the ViWAK has not been formally tested in
animal or human clinical trials.
The automated wearable artificial kidney (AWAK) is
another continuous PD device designed for continued use,
which differs from the ViWAK in having single catheter
lumen access, and as such dialysate flow is discontinuous,
depending upon a tidal regimen requiring a reservoir for
refreshed dialysate7 (Figure 1). Whereas the ViWAK is
proposed to use two conventional peritoneal dialysate
exchanges each day, the AWAK system is designed to
continuously regenerate dialysate, so that a single conven-
tional glucose-based peritoneal dialysate solution may be
continuously reused for up to a month or even longer. As
such, this system has an additional chamber containing
electrolytes, lactate, and glucose to refresh regenerated
dialysate, and an ammonia sensor to monitor sorbent
saturation. Around 750 ml of fresh dialysate is initially
infused into the peritoneal cavity, and then recirculated in a
tidal manner at 4 l/h using a battery-powered pump and any
ultrafiltrate generated over an 8–10-h period drained into a
separate bag attached to the module. As recycled dialysate has
lower glucose and changed electrolyte composition, it must
be continuously regenerated, and as such the recycled
dialysate is reinfused with glucose and electrolyte solutions.
Thus, the AWAK is designed to have both daily and monthly
disposable sections, designed for ease of replacement
(Figure 2). The rechargeable battery life is estimated to be
around 18 h and requires recharging overnight.
A 70-kg hemodialysis patient with a dietary protein intake
of 1 g/kg could be expected to generate around 9–10 gm of
urea nitrogen per day.8 Although urease and 250 g of
zirconium can readily catalyze and absorb 2 g urea/h, this
amount of urea clearance would typically exhaust the
currently available sorbent cartridges for wearable
peritoneal devices, potentially necessitating more than one
daily cartridge exchange. To overcome this problem, the
AWAK device has produced two different sorbent cartridges,
one designed to extract 3.5 g of urea nitrogen and a larger
heavier cartridge to remove 10 g of urea nitrogen.9 During
tidal PD, urea nitrogen clearance also depends upon
individual transporter status, and thus short-term 5-h
studies simulating the AWAK tidal exchanges ranged from
12.9 to 17.1, which, based on the AWAK providing continual
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Cycler Cartridge
Non-disposables Daily disposables
Controller Gas
remover
Enrichment
solution
Monthly disposables
Sorbent
Pump Storage
cartridge
module

Ammonia
Pressure
sensor Pump sensor
Fibrin
filter Filter
UF bag

Catheter
Peritoneal
cavity
Connector

Figure 1 | The artificial wearable ambulatory kidney (AWAK) consists of two main components: a daily replaceable sorbent cartridge
containing electrolyte and glucose solution to regenerate spent dialysate, and a second assembly comprising ammonia detector,
protein, and bacterial filters designed to be changed monthly.

Cycler Cartridge
Non-disposables Daily disposables
Controller
Gas
remover
Enrichment
solution
Monthly disposables
Sorbent
Pump cartridge
Storage module
Ammonia
Pressure
sensor Pump sensor
Fibrin
filter Filter
UF bag

Catheter
Peritoneal
cavity
Connector

Cycler Cartridge
Non-disposables Daily disposables
Controller Gas
remover
Enrichment
solution
Monthly disposables
Storage Sorbent
Pump cartridge
module

Ammonia
Pump Pressure
sensor
sensor
Fibrin
Filter
filter
UF bag

Catheter
Peritoneal
cavity
Connector

Figure 2 | The artificial wearable ambulatory kidney (AWAK) uses a single lumen peritoneal dialysis access catheter, and therefore
peritoneal effluent is either pumped into the AWAK (upper panel) or returned to the patient (lower panel).

dialysis, extrapolates to a weekly Kt/Vurea of 3.4–6.5. terms of dietary protein intake, physical activity, and urea
However, the duration of effectiveness for any sorbent will generation rate, and the renewed interest in sorbent
depend markedly on individual patient characteristics in technology may well lead to the development of newer,

258 Kidney International (2013) 84, 256–264

WH Fissell et al.: Wearable and implantable dialysis devices
more effective sorbents. The AWAK device is currently
undergoing clinical trials, and the results are eagerly awaited.
CONTINUOUS WEARABLE HEMODIALYSIS DEVICES
The challenges to design and produce a wearable continuous
hemodialysis treatment are similar to those for PD, but are
complicated by the requirement for blood access. Although
continuous renal replacement therapy (CRRT) can deliver
significantly higher solute clearances than conventional three
times weekly standard hemodialysis, simple miniaturization
of the CRRT circuit is not without technical challenges.
Standard hemodialysis machines use roller pumps to
generate countercurrent blood and dialysate flows. To be
truly portable, an energy-efficient dual-chamber pump,
capable of being powered by long-life lightweight batteries
without generating excess heat is required. As such, several
different pump designs have been suggested to provide
adequate flows, but also to reduce protein fouling of the
dialyzer membrane and mechanical activation of platelets
and leukocytes. As with the AWAK and ViWAK, the system is
primed with a small volume of sterile dialysate, which is then
regenerated by sorbents.10 After passage through the ion-
exchange sorbents, electrolytes, including bicarbonate, have
to be returned to ‘refresh’ the regenerated dialysate. As with
standard extracorporeal circuits, anticoagulation is required
to prevent clotting, and ultrafiltration needs to be regulated.
The control and monitoring of electrolytes, anticoagulation,
and ultrafiltration volumes all add complexity to the circuit,
but can be overcome using small lightweight minipumps,
with servo-controlled safety feedback loops, supported with
point-of-care testing just as a diabetic would check blood
glucose. The traditional hemodialysis circuit encompasses a
venous blood chamber, which acts as a safety device to
prevent air emboli returning to the patient. As blood–air
interfaces increase the risk of clot formation in the
extracorporeal circuit, this standard design has to be changed
for wearable devices, by utilizing developments in gas-
permeable, water-impermeable plastics to remove micro-
bubbles, typically carbon dioxide, which can develop in the
blood circuit depending on the pressure and temperature.
Similarly, gas-permeable plastics are also required in the
dialysate circuit again to remove carbon dioxide generated by
the metabolism of urea by urease in the sorbents. As a
wearable hemodialysis device requires blood access, addi-
tional safety features are required to prevent air emboli and
blood loss, using a protective bubble detector sensor placed
after the blood pump, designed to stop blood flow if gas
bubbles are detected in the blood circuit, and a second
servomechanism to halt the ultrafiltration pump if the blood
flow stopped for any reason. In addition, by using a pulsatile
blood pump with self-limited capacity to generate negative
pressure for suction from the arterial side of the vascular
access, any disconnection on the arterial side would stop the
blood pump.11
Currently, a wearable hemodialysis device has been
extensively trialed in pig models of acute kidney injury, and
Kidney International (2013) 84, 256–264
review
also used in two proof-of-concept human clinical trials, first
as an ultrafiltration device, and second for hemodialysis.12
These trials were of relatively short duration, and as such the
sorbents were not tested to exhaustion. Laboratory studies
have suggested that they would be expected to last for at least
24 h, allowing a simple daily exchange. Similarly, ex vivo
experiments suggested a battery life in excess of 24 h. Clotting
of the extracorporeal circuit did occur in some patients when
heparin anticoagulation was withdrawn; however, the circuit
used contained many additional temporary ‘T’ connectors to
allow for detailed blood sampling and pressure monitoring.1
As such, these additional connectors added areas of blood
stagnation and increased the presence of air–blood interfaces,
and as such circuit clotting would be expected to be reduced
by careful design of the circuit tubing to minimize pressure
drops and areas of stagnation,13 and this device has recently
been fast-tracked by the US FDA for further clinical trials
(Figure 3). Other devices designed to use an external blood
access and to be worn externally on a belt, again using
nanosorbent technology using a mixture of clay and
biopolymer, nanoporous carbon, and a catalytic adsorbent
with ultrafiltration control, are also being developed at an
experimental stage (Nanodialysis, Oirschot, Netherlands).
THE IMPLANTABLE ARTIFICIAL KIDNEY
Although wearable options for both PD and hemodialysis are
now potentially therapeutic options on the horizon for
patients with CKD, the question arises as to whether these
treatments will be suitable for all patients or just a minority,
as with current home hemodialysis programs. Previous
studies looking at the barriers to self-care dialysis have
shown that the major reasons given by patients were for the
most part related to achieving competence with the
technology used for the treatments,14 and concerns over
vascular access ranging from needle phobia to undetected
venous needle dislodgement. Even new dialysis machine
developments designed for the home market, such
as the NxStage System 1 (NxStage Medical, Lawrence,
Massachusetts), have not managed to recruit large numbers
of in-center patients to adopt home therapies, and similarly
the more frequent hemodialysis trials had difficulty recruiting
sufficient patients willing to accept more frequent and/or
longer dialysis sessions.15
Home-based therapies certainly have advantages over
center-based dialysis; however, they also tend to place a large
burden on the caregivers of the dialysis patient, in terms of
adopting responsibility for the treatment and maintaining
vigilance for complications of therapy. In addition, home-
based therapies require space not only for dialysis equipment
but also storage for consumables, increased energy costs, and
water usage for home hemodialysis. As dialysis typically
remains to be a disease of the disadvantaged, many of these
patients lack the financial and housing requirements nece-
ssary for successful home hemodialysis. Thus, a truly implan-
table artificial kidney could have both greater patient appeal
and applicability, in addition to reduced complications from
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Blood-leak/bubble detector
and pump power-up and
alarm/shut-off system
Shuttle pump Battery
Mini
pump
Mini
pump
External flowmeter
Probe measures Dialyzer
blood and dialysate flow rate
Figure 3 | Circuit diagram of version 1.0 of the wearable artificial kidney (WAK) showing micro-shuttle pump for countercurrent blood
and dialysate flows, a series of sorbent cartridges, and minipumps for refreshing electrolyte solution, bicarbonate, heparin, and
ultrafiltration control.
an extracorporeal blood loop, which must be repeatedly
opened and reclosed, thus reducing the risks of access-
associated infection and accidental disconnection.
DESIGN SPECIFICATION FOR AN IMPLANTABLE ARTIFICIAL
KIDNEY
The operational requirements for an implanted renal device
are shown in Table 1. Medications and dietary modification
can help compensate for the loss of some of the physiological
functions of the mammalian kidney, and several studies of
elderly patients starting dialysis have reported that symptom
control, survival, and quality of life are similar for those
treated by dialysis and those managed conservatively with
drugs, including erythropoietin, activated vitamin D analogs,
phosphate binders, bicarbonate, and dietary modifica-
tion.16,17 As such, any implantable kidney would
predominantly have to achieve two key goals: waste
elimination and homeostasis of extracellular fluid volume.
Whereas typical vascular access devices for hemodialysis,
including catheters, needles, and tubing sets, have significant
flow resistance such that peristaltic pumps are required not
just to circulate blood through the hollow-fiber dialyzer, but
also to overcome viscous flow resistance in the access device,
an implantable device anastomosed to the iliac vessels would
potentially have very low flow resistance, obviating the need
for energy-intensive blood pumps.
The three dominant considerations in the design en-
gineering of an implantable device for treating CKD
(CKD5d) are device lifetime, power requirements, and waste
removal. Several other classes of implantable devices are now
in common clinical use, including orthopedic and dental
implants, pacemakers, implantable defibrillators, and left-
ventricular assist devices. Service lifetimes for these devices
260
WH Fissell et al.: Wearable and implantable dialysis devices
Dialysate
Mini regenerating
pump system
Mini
pump
Blood-leak-detecting probe
Bubble-detecting probe
Ultrafiltrate
range from decades (dental implants) to months (implanted
continuous glucose sensors). The risk, cost, and effort
associated with medical devices that have either failed or
worn out vary considerably; generator exchanges for pace-
makers are generally low-risk uneventful outpatient proce-
dures, whereas on the other hand an left-ventricular assist
device replacement for driveline fracture, hemolysis, or
increased power consumption from bearing wear may not
even be feasible for the patient. The lifetime of any
implantable artificial kidney device anastomosed to the iliac
vessels and connected to the bladder would have to be long
enough to overcome the disadvantage of subsequent removal
or replacement of the whole device or parts of the device.
Vascular access is the first hurdle to overcome in terms of
device lifetime, whereas synthetic arterial grafts have been
clinically successful; those used as arterio–venous dialysis
access grafts have often suffered venous clotting problems.
Animal studies have shown that, whereas noticeable adherent
clot and mural thrombus develops over time using custom-
engineered silicon darts inserted into the femoral vein,
surface modification of the darts with polyethylene glycol
appeared to prevent both clot adherence (Figure 4) and
mural thrombi (Figure 5).18
Clotting of dialyzer fibers often occurs during a standard
4-h hemodialysis treatment session because of fiber protein
deposition and clot formation due to the activation of
inflammatory cells and the extrinsic coagulation pathway.19
The hydrostatic pressure drop from blood inlet to blood
outlet along the length of a hollow-fiber dialyzer leads to
significant internal filtration within the proximal portion of
the hollow fiber, and these blood–membrane interactions
actually dominate solute clearance, rather than the prescribed
modality.20,21 The concentration polarization of plasma
Kidney International (2013) 84, 256–264
WH Fissell et al.: Wearable and implantable dialysis devices review

Table 1 | Replacement of native renal function by dialysis versus miniaturized renal assist device
Physiologic function Native kidney Conventional dialysis Miniaturized RAD
Toxin clearance High-volume convective ultrafiltration, Predominantly diffusive clearance of small High-volume convective ultrafiltration by
followed by active tubular electrolyte, water-soluble solutes from plasma water silicon nanoporous membrane, followed
water, organic anion, and small protein to dialysate, with some convective by selective reabsorption of electrolytes
reabsorption from the ultrafiltrate with clearance of middle-sized molecules, and water by tubule cell bioreactor or
fine tuning by subsequent cellular depending on dialyzer flux and design synthetic ‘tubular’-like membrane
secretion
Volume homeostasis Active distant and intra-renal neuro- Ultrafiltration volume determined Computerized synthesis of physiologic
humoral feedback systems controlling clinically by assessment of dry weight and data and patient-entered weight data to
glomerular blood flow, perfusion pres- ultrafiltration rate by dialysis session time control balance between ultrafiltration
sure, filtration, and tubular reabsorption and reabsorption rates
Calcium–phosphorus Calcium and phosphorus are filtered by As dialysis does not adequately remove Calcium and phosphorus are filtered by
metabolism the glomerulus and differentially reab- sufficient phosphate, patients are the silicon nanoporous membrane, some
sorbed by the tubule under hormonal required to avoid phosphate-rich food- calcium and phosphate is reabsorbed,
and phosphatonin control and tubular stuffs, and require phosphate-binding and any deficiencies will be supplemen-
flow rate medications. Additional active vitamin D ted by oral medications
sterols are required. Dialysate calcium is
adjusted to maintain serum calcium
concentration
Potassium regulation Potassium is filtered by the glomerulus, Patients require a potassium-restricted Patient will self-monitor blood potassium
then reabsorbed by the tubule, and then diet, and then dialysate potassium is at home by finger stick blood sampling,
secreted under hormone control and adjusted to maintain a target pre-dialysis and adjust diet, and if necessary adjust
exchanged to maintain acid–base home- concentration ion exchange resin dose, accordingly
ostasis
Red blood cell mass Renal tubular cells in renal interstitium Require exogenous erythropoiesis-stimu- Require exogenous erythropoiesis-
cells secrete erythropoeitin in an oxygen lating agents, or HIF receptor blockers. stimulating agents, or HIF receptor
delivery–dependent manner regulated Iron supplementation required for blood blockers
by HIF lost in the dialyzer
Acid–base balance The kidney reabsorbs bicarbonate and Patients adhere to a protein-restricted A renal tubular cell bioreactor will excrete
excretes acid by an ammonium-based diet to reduce acid generation, and some acid, but oral bicarbonate will be
buffering system and hydrogen ion dialysate bicarbonate concentration is necessary to completely buffer dietary
exchange for other cations adjusted to control pH acid load, and certainly for a synthetic
‘tubular’ membrane
Abbreviations: HIF, hypoxia inhibitory factor; RAD, renal assist device.

Figure 4 | Scanning electron microscopy images showing explanted darts taken from rat femoral vein showing debris on the uncoated
(left) and clean surfaces on polyethylene glycol–coated (right) darts (adapted from ref. 18).

proteins at the dialyzer membrane surface effectively
increases the protein concentration, which may cause some
proteins to come out of solution as a gel, or may allow
progression of the coagulation cascade to thrombin
deposition and fiber clotting. Protein fouling of a
biomaterial is a complex sequence of events driven by very
high–frequency contact interactions between solutes and
surface, followed by reversible binding and then a conforma-
tional change in the protein with exposure of hydrophobic
epitopes and irreversible loss of solubility.22,23 As such,
to achieve adequate device longevity, a different approach
to dialyzer design is required for a long-term implanted
device.
The mammalian nephron accomplishes the majority of
metabolic waste excretion through a two-stage tandem
process of nonspecific size-based filtration in the glomerulus,
followed by transcellular and paracellular transport of water
and a small number of solutes (primarily electrolytes, urea,
glucose, amino acids, and small proteins), so that waste
products present in about 100–140 l of filtered blood each day
are concentrated into a fluid volume small enough (1–2 l)
that it can be balanced by oral intake. In contrast, standard

Kidney International (2013) 84, 256–264 261

review
intermittent hemodialysis requires B240 l of ultrapure water
for each treatment, a volume and mass that is impractical for
implanted or portable therapies. Dialysate regeneration by
sorbents has long been used to minimize water requirements,
but requires fresh reagents for each treatment as they become
saturated, thus limiting the applicability of sorbent technol-
ogy to implantation devices.
Therefore, a new type of dialyzer membrane was required
for an implantable device with a resistance low enough to
allow 300 ml/min of well-mixed blood to flow from the
arterial side of the device through to the venous return, yet
only driven by a native cardiac perfusion of 80–100 mm Hg.
At the same time, the dialyzer membrane also had to have
sufficient hydraulic permeability such that lower hydrostatic
pressures of 30–50 mm Hg within the dialyzer could drive
30 ml/min of small solute clearance by convection. It would
appear that nature, as well as man, has chosen elongated pore
structures for filtration in many settings, from the baleen
plates of filter-feeding whales to the slots in storm drains in
city streets, elongated structures provide steric hindrance to
large objects without blocking fluid flow. This would also
appear to hold true in the kidney, where the glomerular slit
diaphragm appears to consist of elongated slots of at least
two very different length scales,24,25 whereas the standard
dialyzer polymer membranes have irregular, round pore
structures with considerable variability in individual pore
100 µm
Figure 5 | Light microscopy of vein removed from a rat that had
an uncoated silicon dart inserted showing thrombus formation
(adapted from ref. 18).
a b
Figure 6 | Scanning electron microscope images showing silicon nanopore membranes. (a) Low magnification showing an array of
rectangular membranes; (b) higher magnification showing the pores on a single membrane; and (c) tilted, high magnification showing
a close-up of the slit pore.
262
WH Fissell et al.: Wearable and implantable dialysis devices
size.26 Although in typical log-normal pore size distributions
large pores are relatively few in number, the largest pores
contribute significantly to the water volume flux through the
dialyzer membrane and thus disproportionately increase the
leakage of plasma proteins into the ultrafiltrate. For standard
dialysis membranes, this effect is ameliorated by shifting the
entire distribution of pores toward smaller pore sizes, and
thus reducing the number of large pores sufficiently to limit
protein leakage. This then reduces hydraulic permeability and
compromises clearance of so-called ‘middle molecules’
between 5 and 25 kD.
Silicon micromachining is a technological development
capable of producing very high numbers of miniaturized
electromechanical devices with extraordinary repeatability
with low unit cost,27 and adaptation of this technology to
filtration allows nearly complete control over pore size and
shape within Angstrom-level fidelity across several centimeters
of silicon wafer, to produce flat-sheet membranes of highly
regular elongated slit-shaped pores of 5–10 nm (Figure 6).
In vitro and in vivo testing of these prototype membranes
showed that their performance matched predicted hydraulic
permeability and steric and electrostatic hindrances,28 and
outperformed conventional polymer membranes with round
pores.29 Blood–materials interactions were examined both
in vitro and in vivo. Polyethylene glycol surface-modified
silicon nanopore membranes were tested in an ultrafiltration
cell using citrated bovine blood, and hydraulic permeability
and sieving curves remained stable over 96 h of filtration, with
no detectable change from the initial first hour to that during
the 96th hour of the study.
For a successful implantable artificial kidney, the ‘glo-
merular’ membrane has to be linked to a ‘tubule’ membrane
designed to reabsorb ultrafiltrate, so that patients only pass
2 l of urine daily, yet excrete an adequate amount of waste
products. Although a ‘tubule’ membrane that can reabsorb
water and solutes could be engineered similarly, in some
ways, to the membranes used in reverse osmosis water
systems, one that could differentiate which solutes to
reabsorb and which to excrete has not yet been developed.
One option would be to consider using a bioreactor to solve
problems that engineering alone could not resolve. Renal
tubule cell bioreactors have been maintained in perfused
tissue culture for extended periods of time before clinical use.
c
7 nm pore
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During and after deployment in an extracorporeal circuit,

when cell nutrition and respiratory gas exchange was entirely
dependent on a combination of ultrafiltrate flow from a
hemofilter through the hollow fibers coated with renal
tubular cells, harvested from renal transplant discards, and
blood flow outside the hollow fibers of the bioreactor, human
renal tubular cells not only maintained their viability but
also demonstrated their epithelial integrity by low-inulin
leak rates.30–34 Similarly, when grown to confluence on
silicon nanopore membranes,35 indirect immunofluorescence
imaging showed localization of zona occludens-1 to cell–cell
junctions and acetylated tubulin in cilia, suggesting a
differentiated phenotype (Figure 7). In addition, the transe-
pithelial resistance of these tubular epithelial monolayers grown
on silicon membranes was similar to that of monolayers grown Figure 7 | Fluorescent microscopy image of human renal
proximal tubule cells cultured from discarded renal transplant
on conventional tissue culture inserts. More importantly, when kidneys on silicon nanopore membranes. Blue stain refers to
grown in a calibrated shear-stress bioreactor, these renal cell nuclei, green refers to tight junctions, and red refers to cilia
proximal tubule cells showed shear-dependent rearrangement (adapted from ref. 34).
of cytoskeletal proteins and shear-dependent solute trans-
port.36,37 The question arises, as with other bioartifical devices,
as to what cell mass is required to achieve required function.
As such, mass balance considerations dictate the operating
characteristics of the renal cell bioreactor. A target small solute
clearance of 30 ml/min implies that a very similar volume must
be reabsorbed in the bioreactor. Isolated perfused tubules have
been shown to reabsorb filtrate between 20 and 40 ml/min/m2,
suggesting that a bioreactor surface area of less than a square
meter should suffice to match reabsorption to filtration.38,39
Further work is needed to determine the interplay between
bioreactor geometry and the minimum fractional excretion of
sodium required.
As such, a renal tubular–based bioreactor linked to a
synthetic ‘glomerular’ membrane could potentially provide a
reabsorptive capacity for the ultrafiltrate, as well as providing
some additional tubular metabolic control. This would be
surgically implanted using iliac vessel access (Figure 8).
However, as the device would not be able to replace normal Figure 8 | Schematic design for an implantable artificial kidney
device, using iliac vessels for arterial blood inflow and venous
renal function, patients would still rely on medications return, with ultrafiltratate draining into the bladder.
(table 1) to maintain homeostasis.
proof-of-concept experiments have demonstrated the feasi-
SUMMARY bility of each component of an implanted artificial kidney
Although it has taken more than 50 years to develop a comprising a novel ‘glomerular’ membrane technology,
prototype of a truly wearable artificial kidney for the optimizing membrane separation process coupled with a
treatment of patients with CKD5d, two devices based on bioreactor of living cells harvesting energy, and solute
current hemodialysis and PD paradigms are currently reabsorption from the ‘glomerular’ membrane’s plasma
embarking on clinical trials. How successful these devices ultrafiltrate, recapitulating nephron anatomy.
are will depend not only on their efficacy in terms of solute We are therefore potentially at a crossroads for new
removal but also their ability to maintain electrolyte, paradigms for the treatment of CKD5d patients with
acid–base and volume homeostasis, patient acceptance, and wearable and implantable devices on the near and far
costs. It may well be that these treatments are not suitable for horizon, respectively, that could in the future not only
all patients, but could potentially offer more patients the improve patient survival but also the quality of life.
advantages of both more frequent and longer dialysis
treatments than current in-center-based hemodialysis pro-
DISCLOSURE
grams, with improved quality of life for patients. Implantable Drs Fissell and Roy are primary inventors on one or more patents
devices on the other hand potentially offer a treatment related to implantable artificial kidneys, and principals of Silicon
solution for the majority, and over the past few years key Kidney, LLC.

Kidney International (2013) 84, 256–264 263

review
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Kidney International (2013) 84, 256–264
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