DESIGN OF ARTIFICIAL KIDNEYS

5. DESIGN OF ARTIFICIAL KIDNEYS

5.1. INTRODUCTION

The human kidney constitutes one of the most vital and sensitive organs, and
represents the most complex mass transfer and excretory mechanisms of the
body. In addition to excreting urea and other metabolic waste products, the
kidneys regulate the body fluid volume, the ionic content (Na +, C –, K +), and
the acid base balance through the excretion of water, excess ions, and
elimination of H + and HCO 3. Also, the kidney performs several nonexcretory
functions, including the production of numerous hormones. 1 Significant
failure of the kidney function often results in quick buildup of urea and other
metabolic waste, which in turn leads to cessation of vital metabolic reactions.
In acute renal failure, complete recovery is expected in few days or weeks.
Chronic renal failure, on the other hand, can lead to irrevocable loss of
2
kidney function. Chronic renal failure can result from a number of
etiologies, including chronic infection, glomerular nephritis, renal ischemia
(inhibition of blood flow), reflex nephropathy, diabetes mellitus, etc. Renal
failure leads to uremia, and uremia leads to weakness, lethargy, fuzzy
consciousness, vomiting, and may sometimes lead to seizure and coma. The
artificial kidney device presents a life-saving opportunity for patients with
chronic renal failure.

In the natural kidney, most components of the blood, except blood cells and
proteins, are first filtered out using ultrafiltration, and then the essential
nutrients (glucose, amino acids, etc.) and the required amounts of
electrolytes (Na, K, Cl, HCO 3, Ca, Mg, etc.) and water are reabsorbed through
either passive, active, or facilitated transport. The waste products are not
reabsorbed and therefore are excreted in the urine. This complex process of
filtration and reabsorption may be difficult to duplicate in the artificial kidney
device.

The artificial kidney device removes excess waste from the blood using the
principle of dialysis. Dialysis represents the movement of solute and water
through a semipermeable membrane separating the two solutions. These
artificial kidney devices are also called hemodialyzers . The word “heme”
refers to blood. In the hemodialyzers, blood flows on one side of the
semipermeable membrane and dialysate fluid flows on the other side of the
membrane. The membrane in these devices is usually chosen such that all
species, except proteins and blood cells, can potentially transfer. The
dialysate fluid is an aqueous make-up solution consisting of glucose and
electrolytes in water, and does not contain any waste products such as urea,
3
creatinine, uric acid, phenols, sulfates, etc. As the blood flows through the
dialyzer, these waste products diffuse, out of the blood, across the membrane
into the dialysate fluid. In the patient with chronic renal failure, in addition to
the waste product buildup, usually there is a buildup of certain solutes such
as NaCl, NaHCO 3, etc. The dialysis process should also remove the excess
concentration of these solutes. Moreover, excess water must also be removed
by the dialyzer. This is achieved by creating a slight pressure gradient across
the semipermeable membrane. The removal of middle waste molecules can
be effectively achieved by convection and adsorption. High flux dialyzers use
4
membranes with large pores for removal of uremic toxins and fluid. The
high flux dialysis is also referred to as high efficiency dialysis.
Figure 5.1. Hemodialysis. (a) The principle of dialysis: blood flows
through the inside of the hollow fiber and dialysate fluid flows on
the outside of the hollow fiber. The hollow fiber wall acts as a
semipermeable membrane. The toxic waste products are removed by
either diffusion (low flux dialysis) or by convection (high flux
dialysis). (b) Blood from the patient’s artery flows into the hollow
fibers in the dialysis membrane, and the cleaned blood is returned
back to the patient’s vein.

Most of the artificial kidney devices are hollow-fiber–type devices with blood
flowing inside of the hollow fibers and dialysis fluid flowing on the outside of
the fibers (Fig. 5.1a ). Blood from the patient’s artery is connected through
tubing to the artificial kidney device and is returned to the patient’s vein
through tubing from the artificial kidney (Fig. 5.1b ). There are several
requirements in the design of a hemodialyzer device.

5.2. REQUIREMENTS OF AN ARTIFICIAL KIDNEY

1. The device should be safe. Safety is the most important consideration in

the design of any medical device. Biological Safety. The device should have
high biocompatibility and blood compatibility. 5 The device should not cause
hemolysis. Hemolysis is the destruction of red blood cells. The device should
not adsorb or filter vital blood components. Also, the device should not
introduce any foreign materials or toxic materials into the blood. The device
should efficiently remove toxic material. While most toxic substances are in
the low molecular weight, certain toxins are in the middle molecular weight.
At the same time, the membrane should not remove essential proteins such
as blood serum albumin. Accumulation of β 2-microglobulin leads to a

clinical condition called amyloidosis. 6 The molecular weight of β 2-

7
microglobulin is around 11,800 Da. The molecular weight of albumin is
66,400 Da. Simply increasing the membrane size to remove the β 2-
microglobulin can lead to the removal of essential molecules like the blood
serum albumin, which is close in molecular weight to the toxic molecules.
Removal of β 2-microglobulin has been shown to reduce morbidity in end-
8
state renal disease (ESRD) patients. In addition, the interaction of blood
9
with the dialyzer membrane often results in human complement activation.
This immunological reaction may result in undesirable effects or even in
 10
morbidity in ESRD patients. In high flux dialysis, although a positive
pressure gradient exists across the hollow fiber tube, the large axial
pressure drop may result in lower pressure in certain portion of the distal
(venous) end of the fiber. Thus in these regions of the fiber, the pressure
could be lesser than that in the dialysate fluid causing back filtration of
dialysate fluid in these high flux dialyzers. 11 , 12 This may result in
complement-activating factors (cytokine-inducing substances) to be back
transported into the blood, causing significant complement activation and
the associated immunological reactions. 11 Reliable vascular access is
essential for repeated hemodialysis. 12 A fistula is constructed by joining a
major artery in the wrist (e.g., radial artery) with an adjacent vein such that a
portion of the arterial blood takes a shortcut directly into the vein. Woven
tubes of synthetic materials such as Dacron, and expanded
polyterofluoroethylene (PTFE, Gortex, Impra) as synthetic grafts should be
biocompatible and blood compatible and should not cause clotting.
Transcutaneous vascular access device should also be blood compatible and
biocompatible and should not cause clotting. The transcutaneous access
device should allow easy and quick connections. These access devices should
not cause infection. The National Kidney Foundation has issued clinical
guidelines for vascular access. 13 Chemical Safety. Water quality, for
dialysate fluid, is a major safety concern. 14 The patient’s blood is exposed to
approximately 20,000 L of dialysate fluid each year. Consequently, impurities
which are considered insignificant for drinking water may be potentially
harmful for the dialysis patient and can create long-term toxic effects.
Substances present in the dialysate fluid, even in low concentrations, can
enter the blood stream and cause damage. For example, chloramine can
cause hemolytic anemia. Special attention should be paid to substances that
bind to the plasma proteins. For example, aluminum in small quantities can
cause severe brain and bone damage in long-term dialysis patients. Lead,
cadmium, mercury, and selenium, etc., have similar toxic effects. The
Association for the Advancement of Medical Instrumentation (AAMI) has set
up standards for hemodialyzers and water quality for hemodialysis (Table
5.1). In addition, the water used to makeup the dialysate fluid should not
have excess microbial content. Improper water treatment or inadequate
design can lead to biofilm growth on various conduits of the artificial kidney
machine. Bacteria at these biofilm sites may release pyrogen or cytokine-
inducing substances and other endotoxins into the dialysate fluid. Although
the microorganisms cannot cross the dialysis membrane, the pyrogen lipids
and cytokine-inducing substances produced by these organisms can cross
the dialysis membrane and can lead to infection. 15 – 17 Proper sterilization of
the device (cartridge, etc.) is important. All membranes are not compatible
with all types of sterilization. For instance, ethylene oxide (EtO), when
conjugated with human blood serum albumin, may lead to anaphylactic
reactions observed in some patients on EtO-sterilized
hemodialyzers. Mechanical Safety. The dialysis membrane should have high
shear strength (resistance to tearing) and high ultimate strength. The
membrane should maintain adequate strength and dimensional stability
while wet. The membrane often loses water-soluble components and often
adsorbs components of the surrounding medium, which can lead to changes
in dimensions and mechanical properties.The blood side flow resistance
should be low enough to maintain adequate blood flow with minimal
pumping. Artificial pumping of blood may cause hemolysis (destruction of
red blood cells). Therefore, pressure developed by patient’s own heart
should be able to pump the blood through the dialyzer machine back to the
heart. The normal blood pressure in the adult is pulsatile with 120 mmHg
systolic (upper peak of the wave) and 70 mmHg diastolic (lower peak of the
waveform), with an average pressure of 100 mmHg. Blood pressure in
children is even lower. Usually, a roller-type blood pump is used to pump
blood. This blood pump is placed in between the arterial access line and the
blood inlet manifold of the artificial kidney device.

Table 5.1. Allowed Limits for Impurities in ppm

Contaminant EP New AAMI (Draft RD-

62a)

Aluminum 0.01 0.01

Ammonium 0.2

Antimony 0.005

Arsenic 0.005

Barium 0.1

Beryllium 0.0004

Cadmium 0.001
 Calcium 2 (0.05 mmol/L) 2

Chloramines 0.1 0.1

Total chlorine 0.1

Free chlorine 0.5

Chlorides 50

Chromium 0.014

Copper 0.1

Cyanide 0.002

Fluorides 0.2 0.2

Heavy metals 0.1

Lead 0.005

Magnesium 2 (0.07 mmol/L) 4

Mercury 0.001 0.0002

Nitrates 2 2

Potassium 2 (0.1 mmol/L) 8

Sodium 50 (2.2 mmol/L) 70

Selenium 0.09

Silver 0.005

Sulfates 50 100

Thallium 0.002

Zinc 0.1 0.1

Bacteria 100 CFU/mL 200 CFU/mL (action at

100)

Endotoxin 0.25 EU/mL 2.0 EU/mL (action at

1.0)

Source: Reproduced from Ref. 14 with permission.

Human Factors Safety. The device should be easy to operate and should be
fool-proof. The blood inlet and outlet connections and the dialysate inlet and
outlet connections should be such that they permit only error-free operation.
The part of the device which contains the hollow fibers should be
preassembled and prepackaged into a cartridge, and presterilized.Size and
color coding of various connections will ensure safety. For example, the blood
inlet manifold should be of the size such that only the inlet tubing bringing
the arterial blood should be able to connect. The arterial (access) pressure
and the return venous pressure should be monitored. Air leak into the
arterial and the venous lines should be detected automatically. Air in the
blood causes blood embolism and clotting. In addition, blood leak into the
dialysate fluid should be detected automatically. The device should be
designed to avoid error-prone stage.Alarms should be incorporated into the
dialysis machine to signal system malfunction. There should be alarms for (1)
low arterial pressure, (2) high arterial pressure, (3) low venous pressure, (4)
high venous pressure, (5) air leaks (air in the blood lines), (6) transmembrane
pressure, and (7) blood pump torque. These alarms should be easily audible
(70 dB) and visible from 2 to 3 m distance. The dialyzer should be designed
such that system malfunction should be able to automatically shut off the
blood pump and clamp the blood lines such that the patient is isolated.

2. The device should be efficient in removing nitrogen, and other waste

material and toxic products of metabolism. It should also remove excess ionic
species. The device should efficiently remove toxic middle molecules.
3. The device should have small priming volume. The priming volume is the
volume of the artificial-kidney–occupied blood. This amount of blood is lost in
every dialysis session. Therefore, the priming volume should be small. The
normal blood volume in adult is approximately 5 L. Therefore, the priming
volume should not exceed 250 mL corresponding to 5 percent of the blood
volume. It should be noted that the blood volume in children is much lower.
4. The device should be reliable.

5.3. LOW FLUX VERSUS HIGH FLUX DIALYSIS

Hemodialysis involves the transfer of solutes and water from the blood to the
dialysate fluid through a semipermeable membrane. In the conventional or
low flux dialysis, the solutes are removed by diffusion across the
semipermeable membrane, and minute quantity of water is removed by using
slight pressure across the membrane. The membrane in low flux dialysis
usually has low water permeability such that an ultrafiltration controller is
not needed to prevent excess water loss from the patient. On the other hand,
membranes used in high flux dialysis have high water permeability, and the
solutes are removed by diffusion and convection. While diffusion depends on
the concentration gradient and the solute permeability of the membrane,
convection depends on the membrane sieving coefficient, water permeability,
and the transmural pressure gradient. 7 Solute transfer flux (dW ) for a
differential length can be expressed as

(5.1)

where dA = the membrane surface area for a differential length along the
membrane
C = the concentration of the solute in the blood
Δ C = the concentration difference across the membrane
k D = the solute permeability for the membrane
k U = the ultrafiltration coefficient
Δ P = the pressure drop across the membrane
Δπ = the osmotic pressure gradient
S = the sieving coefficient

The ultrafiltration coefficient (k U) for high flux dialyzers is typically in the

range of 20 to 50 mL/h/mmHg. With convective removal of the middle
molecules, there is a significant water loss. Saline (make-up solution of water
and essential nutrients) is infused into the patient along with the cleaned
(dialyzed) blood. Therefore, these high flux dialyzers require precise
ultrafiltration control. The ultrafiltration coefficient is generally in the range
of 15 to 30 mL/h/mmHg. 18 – 20 The U.S. FDA defines high flux hemodialyzers
as those with an ultrafiltration coefficient k U greater than 12 mL/h/mmHg.

The sieving coefficient (S ) and the solute permeability ( k D) depend on the

ratio of solute radius to pore radius. The solute permeability (k D) drastically
decreases with increasing solute radius. The sieving coefficient (S ) also
decreases with increasing solute diameter (molecular weight). 7 , 21 Figure
5.2 shows the relationship between sieving coefficient (S ) and solute
molecular weight for various pore sizes. The removal of middle molecules by
diffusion is very limited. Middle molecules are defined as uremic toxins that
have intermediate molecular weight between conventional small molecules
and serum albumin. In particular, β 2-microglobulins have a molecular weight
of 11,800 Da and present a major problem. The diffusion coefficient for β 2-
microglobulin is 13.7 × 10 –7 cm 2/s, whereas for serum albumin the diffusion
coefficient is 6.3 × 10 –7 cm 2/s. 7 Moreover, the blood concentration of β 2-
microglobulins is 0.06 g/L, whereas the blood concentration of serum albumin
is very high 50 g/L. Therefore, it is difficult to separate the β 2-microglobulin
from serum albumin using diffusion. The middle molecules are removed by
convective transport in high flux dialysis. Although the conventional
membranes used in low flux dialysis with 15- to 30-Å pore size will not leak
albumin, the extraction of β 2-microglobulin is not sufficient. More than 50-Å
pore size is required to achieve a 60 percent removal of β 2-microglobulin.
This large pore size leads to significant leakage of albumin. Also, adsorption
of blood serum albumin to the dialysis membrane is a major problem. 22

Therefore, the challenge in the design and selection of the membrane is to

achieve an effective removal of middle molecules without the loss of serum
albumin.

Figure 5.2. The relationship between sieving coefficient and solute

molecular weight. (Reproduced from Ref. 7 with permission.)

Extraction (E ) is a dimension less parameter that can be used to compare the

performance of various dialyzers 23 :

(5.2)
Concentration of waste products in the dialysate fluid C DI is zero as the
dialysate fluid enters the dialyzer. Therefore,

(5.3)

Although engineers prefer extraction, clinical preference is the use of

clearance (K ) to compare various dialyzers:

(5.4)

where Q B is the blood flow rate to the artificial kidney. For the artificial
kidney device, the clearance

(5.5)

The extraction coefficient for countercurrent flow dialysis without significant

ultrafiltration can be expressed as 23

(5.6)

The term (k D A /Q B) is a dimension-less quantity and is referred to as the

number of mass transfer units N T. Therefore,

(5.7)

where Z is the ratio of blood flow rate ( Q B) to the dialysate flow rate (Q D ):

(5.8)

The extraction coefficient E increases with decreasing Z . When Z = 0,

regardless of the dialyzer (countercurrent, cocurrent, or mixed flow), the
extraction coefficient can be expressed as

(5.9)
The clearance for countercurrent flow low flux dialysis can be expressed as

(5.10)

In the conventional or low flux dialysis, the blood flow rates are in the range
of 200 to 250 mL/min. In the high flux dialysis, the blood flow rates are above
400 mL/min. For low flux as well as high flux dialysis, clearance depends on
extraction and therefore on k D and k U. These parameters in turn depend
on the type of membrane used.

5.4. MEMBRANES FOR DIALYSIS

The properties of the semipermeable membrane play a major role in dialysis.

The membrane should have high permeability to water and organic
metabolites and at the same time should be able to retain plasma proteins. In
particular, the membrane should be able to remove middle molecules such as
β 2-microglobulins and advanced glycation end products (AGE), and at the
same time should not cause any depletion of serum albumin and other
proteins. 7 , 24 In addition, the membrane should be biocompatible and blood
compatible. An ideal membrane does not adsorb blood proteins or hormones.
C. P. Sharma 25 provides an excellent review of membranes for hemodialysis.

Cellulose, modified cellulose, and synthetic polymers are the three types of
membranes used in dialysis. Cellulose membranes were used initially as they
have good permeability with uniform pore size and are hydrophilic. 25 Protein
adsorption decreases with increasing hydrophilicity. However, cellulose
membranes are known for biocompatibility and hemocompatibility problems.
25 – 27 Cellulose and regenerated cellulose membranes lead to the release of
thromboxane, histamine, interleukin-1, and tumor necrosis factor, etc. 26 In
addition, significant transient leucopenia has been observed with these
membranes. Cellulose is a long-chain molecule containing hydroxyl (OH)
groups. The free hydroxyl groups have been associated with the complement
activation and leucopenia observed when using cellulose or regenerated
cellulose membranes. 27

Substituted cellulose has been developed to reduce the hemocompatibility

problems associated with cellulose. 25 Cellulose acetate (diacetate and
triacetate) membranes are formed by bonding acetate to the hydroxyl
groups. This modified cellulose membranes have tertiary amino compounds
bound to the hydroxyl groups. This modified cellulose is marketed under the
trade name Hemophan. While cellulose acetate membranes induce significant
platelet activation, platelet activation with Hemophan membranes is not as
pronounced. 25 , 26 , 28

Synthetically modified cellulose is produced by replacing some hydroxyl

groups with benzyl groups by ether bonds. These membranes offer a
combination of hydrophobic (benzyl groups) to reduce complement activation
and hydrophilic (hydroxyl groups) to reduce protein adsorption. In another
type of synthetic modification, the surface hydroxyl groups are replaced by
grafting polyethelene glycol. 29 Although there is an improved compatibility
with the modified cellulose membranes, the improvement is far from the
desired.

Advantages of cellulose and it’s derivatives include uniform pore size, ability
to form thin membranes of the order of 5 to 15 µm, high mechanical strength,
chemical stability and high tenacity even in the wet state, reduced tendency
for protein adsorption, and excellent permeability to small molecules.
Disadvantages of the cellulose and modified cellulose membranes include
complement activation, leucopenia, and inability to eliminate toxic middle
molecules such as β 2-microglobulin. Vitamin E–bonded cellulose available
under the trade name Excebrane has improved blood compatibility and
microglobulin clearance when compared to cellulose. 30 , 31 In addition,
oxidative DNA damage has been less pronounced when compared to cellulose
membranes. However, more pronounced leukopenia was observed with
vitamin E–modified cellulose when compared to synthetic polysulfone
membranes. 32

Synthetic membranes offer superior blood compatibility and middle molecule

clearance. Synthetic membranes, in general, are more hydrophobic than
cellulose-based membranes. Polysulfone is the most widely used synthetic
membrane. Polysulfone membranes have high water permeability and
33
significantly improved biocompatibility. Polysulfone is used for both low
flux and high flux dialysis. Helixone is a commercially available polysulfone
high flux membrane which efficiently removes middle molecules, such as β 2-
microglobulin, in a narrow range without the loss of albumin. This is achieved
by uniform pore in Helixone membranes, which are produced by
nanocontrolled spinning techniques. Polyethersulfone membranes available
under the trade name Diapes are thin (30 m) and have higher water
permeability with increased middle molecule (β 2-microglobulins and AGE)
clearance. 25 , 34 , 35

Polymethylmethacrylate (PMMA) membranes have good middle molecule

clearance, and have excellent biocompatibility. Both polysulfone membranes
and PMMA membranes effectively eliminate several immunogenic products,
including neutrophil elastase. Immunoglobulin light chains are uremic toxins
which are effectively eliminated by PMMA membranes. 25 , 36 – 38

Polyacrylonitrile-based membranes have very good biocompatibility and

enhanced permeability. AN69 is a commercially available high flux membrane
made from copolymer of acrylonitrile and sodium methyl sulfonate. 39 AN69
has excellent blood compatibility due to its negative surface charge, and has
high permeability with pores in the range of 25 to 55 Å. AN69 membrane
effectively removes β 2-microglobulin AGE peptides by convection (high flux)
and adsorption. In addition AN69 eliminates immunogenic substances such
as C3a and C5a, and factor D, etc., by adsorption. However, AN69 membranes
lead to severe adverse reaction in patients who are on medical treatment
with angiotensin-converting enzyme (ACE) inhibitors. 40 , 41

In general, high flux synthetic membranes have increased biocompatibility,

blood compatibility, and increased middle molecule clearance when compared
to membranes made of cellulose and its derivatives. Clinical studies have
revealed lower mortality, lower microglobulin and triglyceride values, and
lower incidence of amyloid disease in synthetic high flux membranes
(polysulfone, AN69, and PMMA, etc.) when compared to cellulose-derived
membranes. 25 However, the clearance of these middle molecule toxins, even
with the high flux dialysis, using synthetic membranes is much lower when
compared to the clearance in the natural kidney.

5.4.1. The Dialysis System

Blood flows through hollow fibers and dialysate fluid flows outside the hollow
fibers, and the hollow fiber wall acts as a membrane separating the blood
and the dialysate fluid. Therefore, there are three distinct circulation
components: the dialysis circuit; the blood circuit, and the hollow fiber which
interfaces both. Figure 5.3 describes the dialysis system for low flux dialysis.
The basics of hemodialysis machine are well described by Misra. 42 The
dialysis fluid forms a major component of the dialysis system. The stringent
requirements for the water quality demand several levels of water
purification, including ion exchange and distillation. The required nutrients
(Na +, K +, Cl −, glucose, etc.) are proportioned and mixed with water. The
mixture is then heated to body temperature to avoid heat transfer between
the dialysate fluid and the blood. The heated dialysate fluid is now deaerated
to trap bubbles. The mixing and heating, etc., are performed in the dialysis
machine (Fig. 5.4). The dialysis fluid usually flows counterclockwise outside
the hollow fiber (semipermeable membrane) carrying the blood. The hollow
fibers are preassembled and prepackaged into a cartridge with blood and
dialysis fluid inlet and outlet manifolds. These cartridges come in various
sizes having different number of fibers and therefore different surface area
(Fig. 5.5). In low flux dialysis, the transmural (transmembrane) pressure
gradient across the hollow fiber is negligible; however, a slight negative
pressure is used to remove some water. On the other hand, for high flux
dialysis, the negative pressure has to be precisely controlled. Since there is a
significant rate of fluid removal from the blood, a make-up solution is
introduced into the blood stream before it is returned to the vein (Fig. 5.6).
This fluid replacement has to be regulated precisely. Other components of
the dialysate circuit include a blood leak detector in the dialysate output line
(Fig. 5.3). The blood leak detector detects for any blood in the dialysate fluid
that might have leaked from the hollow fiber (across the membrane) into the
dialysate fluid using a photo detector. While the dialysate fluid does not
absorb red or infrared light, the red blood cell absorbs red and infrared light.
The dialysate fluid is then pumped into the drain. The pressure in the
dialysate fluid is precisely regulated. 42
Figure 5.3. The dialysis system for low flux dialysis.

There is a roller blood pump in the arterial line between the arterial access
and the blood inflow manifold of the artificial kidney machine. Blood pressure
is measured in the arterial line between the access and the blood pump. Also,
blood pressure is measured in the return venous line. An air leak detector in
the return blood line (downstream of the exhaust blood manifold) detects any
air in the blood line. In addition, there is a heparin pump placed before the
blood enters the venous return access to prevent clotting. Heparin is an
anticlotting hormone. The treatment regimes vary from clinic to clinic and
from patient to patient.
Figure 5.4. The Baxter hemodialyzer machine. (Photograph Courtesy
of Baxter Inc., reproduced with permission.)

Figure 5.5. Hemodialysis cartridges come in various sizes with

different surface areas. (Courtesy of Baxter Inc., reproduced with
permission.)
Figure 5.6. The hemodialysis system for high flux dialysis.
Replacement fluid is added to the blood before returning to the
patient’s vein.

5.5. TREATMENT PROTOCOL AND ADEQUACY OF DIALYSIS

Let us consider a simple one-compartmental model for the prescription of

treatment protocols for dialysis using an artificial kidney device (Fig. 5.7).
While the blood urea concentration (BUN) in the normal individual is usually
15 mg% (mg% = milligrams of the substance per 100 mL of blood), the BUN in
uremic patients could reach 50 mg%. The purpose of the dialysis is to bring
the BUN level closer to the normal. During the dialysis, some hormones also
diffuse out of the dialyzer membrane along with the urea molecule. Too rapid
dialysis often may lead to depression in the individual due to the rapid loss of
23
hormones. On the other hand, too slow dialysis may lead to unreasonable
time required at the hospital. Simple modeling can be used to calculate the
treatment protocols. Let us consider a one-compartmental model of the
tissue where we assume that the blood and tissue are well mixed, and that
the concentration of urea is uniform throughout the body. 43 Let C be the
Bi
concentration of urea at the inlet of the dialyzer in the arterial line which
takes blood into the dialyzer, that is, at the outlet of the body. Let C Bo be the
concentration of urea at the exit of the dialyzer in the venous line which
brings the blood back to the body, that is, at the inlet of the body
compartment. Mass balance demands that the rate of change of mass in the
body be equal to the net rate of mass coming into the body from the dialyzer,
plus the metabolic production rate G :

(5.11)

Figure 5.7. Patient-dialyzer interaction modeling using one-

compartmental model of the body.

where V = the tissue volume plus the blood volume

Q = the blood flow rate to the kidney
G = the metabolic production rate of urea in the body

Extraction ratio for low flux dialysis can be further expressed in terms of the
concentrations as follows:

(5.12)

where A is the interfacial membrane surface area for mass transfer and k is
the permeability of the membrane for that particular solute (urea in the
present context).
Since Q does not change during dialysis, and since k and A are design
parameters, extraction ratio E remains a constant for low flux dialysis.

It should be pointed out that C Bi is the concentration at the outlet of the

body and therefore at the inlet of the dialyzer, and C Bo is the concentration
in the blood coming into the body and therefore going out of the dialyzer
(Fig. 5.7). Also, it should be noted that the concentration in the blood going
out of the body C Bi is the same as the concentration in the body ( C ) since
we assumed that the entire body (tissue and blood) constitutes a
homogeneous well-mixed compartment. Therefore, Eq. (5.11) can be
rewritten as follows upon substitution of Eq. (5.12):

(5.13)

For low flux dialysis, the volume does not change significantly:

(5.14)

When the dialyzer is turned on, metabolic production rate G can be assumed
to be negligible when compared to the other term in the equation, and upon
integration will result in

(5.15)

where C 0 is the initial concentration of urea in the tissue and K is clearance

(K = Q B E ).

When the patient is not on dialysis, then the blood flow to the dialyzer Q is
zero, and therefore,

(5.16)
Figure 5.8. Concentration of urea as a function of time.
Concentration decreases exponentially when the patient is on
dialysis during the dialysis session, and slowly rises when the
patient is off-dialysis.

When the patient is not on dialysis, the concentration of urea would increase
linearly if the metabolic production rate is constant or will increase
exponentially if the metabolic production rate is a linear function of the
concentration (first-order reaction). When the patient is on dialysis, the
concentration would decrease exponentially. This way, the treatment protocol
can be prescribed after simulating different on and off times (e.g., turn on
the dialyzer for 2 hours every 2 days) to bring the BUN under control (Fig.
5.8).

Now, let us examine the limitations of the one-compartmental model. First,

the entire blood and tissue are assumed to be in equilibrium. However, it is
well known that intracellular urea concentration may be significantly
different from the extracellular compartment. Moreover, urea may be
preferentially produced in certain organs like brain, heart, muscle, etc. An
accurate treatment requires a multicompartmental model.

Let us consider a two-compartmental model (Fig. 5.9) consisting of an

intracellular pool (compartment 1) and an extracellular pool (compartment 2).
Urea is produced by intracellular pool and is transported across the cell
membrane into the interstitial fluids and then into the blood stream. Mass
balance for these two compartments can be expressed as follows:

(5.17)

where B (C 1 − C 2) = the interfacial transfer from compartment 1 to

compartment 2
(from intracellular to extracellular pool)
C 1, C 2 = concentrations of urea in compartments 1 and
compartment 2
B = constant

The constant B is a product of permeability of the cellular membrane for urea

and the interfacial surface area:

(5.18)

Blood flow to the dialyzer (Q ) is zero when the patient is not on dialysis
machine. However, the two-compartmental model may not be sufficient if one
wants to find the concentration of urea in the brain tissue. A
multicompartmental model involving separate compartments for brain, heart,
kidney, lean tissue, etc., may be needed to accurately determine the
concentration of urea in critical organs.

Figure 5.9. Patient-dialysis interaction modeling using two-

compartmental model of the body consisting of an extracellular
compartment (blood and interstitial fluid), and an intracellular
compartment.

From the single-compartmental model Eq. (5.15),

(5.19)

The quantity Kt /V provides a measure of the delivered dialysis dose, and has
44 – 46
been used in the clinic in the management of dialysis patients. As a
rough estimation, the quantity Kt /V can be calculated by taking the inverse
logarithm of the ratio of postdialysis to predialysis BUN. However, an
accurate method would be to solve the multicompartmental model equations
taking into account the metabolic production rate of urea G. 44 Computer
programs exist for solving the urea kinetic modeling differential equations
taking into account the postdialysis urea rebound often observed in patients.
47 The National Kidney Foundation (NKF) has issued guidelines on calculating
the Kt /V value. 48 Daugirdas 49 has derived an empirical relationship which
takes into account the amount of urea removed via ultrafiltration and urea
generated in the tissue:

(5.20)

where R = the ratio of postdialysis to predialysis BUN

T = the time in hours (h)
U = the ultrafiltration volume in liters (L)
W = the patient’s postdialysis weight in kilograms (kg)

Equation (5.20) is referred to as Daugirdas II formula and has been endorsed

44 , 45
by the NKF as a measure of dialysis adequacy. The NKF has established
Dialysis Outcome Quality Initiative (DOQI) clinical practice guidelines. For a
thrice-a-week-dialysis program, NKF guidelines require a Kt /V value of 1.2 or
44 , 45
larger. It should be noted that the minimum Kt /V value required for
clinically adequate dialysis depends on the frequency of dialysis.

The above guidelines for Kt /V are for urea clearance. There are numerous
45 , 50
other uremic toxins that have to be removed. Inadequate removal of
middle molecules, such as β 2-microglobulin, and a loss of blood serum
albumin are major problems. The Clinical Performance Measures Project has
set blood serum albumin >4 g/dL as a target for incenter dialysis patients.

In addition to removing the toxic waste materials, the natural kidney

reabsorbs many essential nutrients and amino acids from the filtrate. In the
natural kidney, the filtrate from the glomerulus in the Bowman’s capsule
passes through the proximal tubule and the distal tubule before it is rejected
as urine. In the proximal tubule, salt, essential ions, glucose, water, amino
acids, small protein, peptides,

glutathione, and other substances are reabsorbed through active, passive,

and facilitated transport mechanisms. The artificial kidney does not reabsorb
some of the essential nutrients, such as the amino acids, small protein, and
peptides, etc. Activated charcoal microcapsules have been suggested for use
in the artificial kidney. 51 However, there are numerous drawbacks with the
charcoal kidney. There continues to be a need for replacing the other
functions of the natural kidney, such the amino acid and peptide
reabsorption. Humes et al. 52 are developing a bioengineered artificial kidney
device.

5.6. BIOENGINEERED ARTIFICIAL KIDNEY

Recent advances in tissue engineering and tissue culture have created

opportunities for the development of bioengineered artificial kidney devices.
52 , 53
Humes et al. have successfully developed a bioengineered renal tubule
assist device (RAD) by seeding proximal tubule cells on the inner surface of
hollow fibers made of polysulfone. The inner luminal surface of polysulfone
was first coated with a synthetic protein, Pro-Nectin-L, to promote cellular
attachment to the surface. Tubule cells were then seeded onto this surface.
For preclinical trials, investigators have extracted tubule cells from pigs.
However, for further studies and clinical trials, they have extracted proximal
tubule cells from human postmortem kidney specimens and transplant
discards. After seeding, the bioreactors (tubule-cell–seeded hollow fibers)
were perfused with culture media initially through diffusion and later with
convective flow. The bioreactors were then evaluated for reabsorption
protein, amino acids, glucose, etc. Initial experiments were conducted with
tubule cells seeded onto single hollow fibers and then with tubule cells
seeded onto commercially available polysulfone catridges. In preclinical
anesthetized dog experiments, a commercial high flux hollow fiber artificial
kidney was used to remove waste materials, and the ultrafiltrate from this
artificial kidney was then perfused through the RAD bioreactor cartridge as
shown in Fig. 5.10.

Figure 5.10. The bio-artificial kidney being developed by Humes et

al. Renal tubule assist device (RAD) is in series with a hemofilter.
Renal tubule cells are grown on the inside wall of a synthetic
hollow fiber. The renal tubule cells produce and/or reabsorb
essential hormones. The RAD cartridge consists of the bio-hollow
tubes. The waste from the hemofilter flows through the inside of
the bio-hollow tubes and the blood flows on the outside of these
tubes in the RAD cartridge, absorbing the essential hormones
produced by the renal tubule cells in the wall of the bio-hollow
tube.

The investigators have found that the RAD bioreactor was able to reabsorb
glucose, glutathione, 1-25 dihydroxy-vitamin D 3, etc. In addition, the RAD
bioreactors were able to generate ammonia in a quantity comparable to the
natural kidney. Clinical trials are currently ongoing.

The bioengineered artificial kidney with real tubular cells from the kidney
seeded onto synthetic polymeric hollow fibers is promising. These RAD
bioreactors form the beginning of bioengineered artificial kidney devices and
provide a foundation for the development of artificial devices for full
restoration of the kidney function. Perhaps, one day, the renal glomerular
cells can also be grown on hollow fiber polymer cartridges to form a
bioengineered glomerulus and Bowman’s capsule, which, together with the
RAD, could form a total bioengineered artificial kidney device.

5.7. CONCLUSION

The purpose of the artificial kidney device is to remove urea and other toxic
waste molecules. Blood flows on one side of a semipermeable membrane and
dialysate solution flows on the other side of the membrane. The toxic waste
molecules are removed by either diffusion, or convection, or both. Diffusion is
the primary mechanism of waste product removal in the conventional low flux
dialysis. High flux dialysis involves solute removal by convection and
diffusion, but convection is the primary mechanism. Toxic middle molecules
(e.g., β 2-microglobulin) are effectively eliminated in the high flux dialysis.
However, high flux dialysis may lead to the loss of blood serum albumin,
which is closer in molecular weight to the toxic middle molecules.
Biocompatibility is a major requirement of hemodialysis membranes. The
conventional cellulose base membranes are associated with biocompatibility
problems, including complement activation and lucopenia. Substituted
cellulose and synthetic membranes have significantly improved
biocompatibility. Polyacrylonitrile based and polysulfone membranes have
excellent biocompatibility. There are stringent water quality requirements for
use in dialysis fluid. Quantitative measures such as Kt /V are clinically useful
for the prescription and assessment of adequacy of dialysis. Designing a
membrane to effectively remove toxic middle molecules without the loss of
blood serum albumin presents continuing challenge. The present artificial
kidney systems do not duplicate all the functions of the kidney. The future
direction is toward tissue-engineered renal assistive devices in series with
hemodialysis cartridges.

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