Kidney International, Vol. 24 (1983), pp.
143—151
Kinetic modeling of hemodialysis, hemofiltration,
and hemodiafiltration
The principle underlying all methods of blood purification for
the treatment of uremia is based on the assumption that most
symptoms of uremia depend on the concentrations of dialysable
substances which are the end products of metabolism normally
eliminated by the kidney. Therefore, dialysis therapy can only
be effective if the concentrations of these endogenous sub-
stances remain below toxic limits.
In the last 10 years, diverse guidelines have been suggested
for optimal treatment of uremic patients [1—6]. Common to
them all is the endeavor to standardize dialysis therapy by
systematically establishing the connection between the concen-
trations of certain substances and the length of treatment.
Concentrations of urea or creatinine in plasma or urine of the
calculated clearance of certain marker substances are used to
indicate the adequacy of treatment. The treatment schedule is
chosen so that concentrations remain within a given range, or
so that a particular volume of blood is cleared of toxin each
week [7—1 11. The best known models are the "dialysis index"
[2, 3] and the so-called kinetic or pooi models. We will focus our
attention on the latter models.
Kinetic models allow the prediction and control of the
concentrations of substances during and between treatments.
Moreover, multiple pool models can predict changes in body
compartments normally inaccessible to the clinician but none-
theless may be relevant to clinical side effects. However, the
compartment volumes and intercompartmental transfer and
distribution coefficients vary from one patient to another and
between treatments and are not readily accessible, thus detract-
ing from the routine use of such models for the estimation of
required treatment times. If clinical symptoms are caused by
"disequilibrium" between body compartments, they are unlike-
ly to be alleviated without the use of multiple pool models.
The mathematical definition and the ability to measure the
variables which influence solute concentrations and distribution
are essential requirements for the use of kinetic models. These
include: (1) dialyser clearance; (2) residual renal clearance; (3)
the rate and location of generation of the substance in question;
(4) compartment volumes, intercompartmental transfer and
distribution coefficients. Each of these variables will be treated
separately.
Variables in kinetic modeling
Dialyzer clearance (K). The dialyzer clearance determines
the removal rate of a substance from blood and does not only
depend on the characteristics of the dialyzer but also on the
nature of the treatment method.
In all methods (hemodialysis, hemofiltration, or hemodiafil-
tration), dialysis clearance K can be calculated by means of the
mass balance equation:
KC8, = Qth CBI — Qs0 CBO. (1)
143
EDITORIAL REVIEW
Here, K represents clearance (mllmin), QBI and QB0 repre-
sent blood flow at the inlet and outlet of the dialyzer, and CBI
and CBO corresponding concentrations of the substance in
question (mmoles/liter). If QF is the ultrafiltration rate, then
QB0 = QBI
QF. (2)
Henceforth, blood flow will be defined by QB = QBI, and QBO
is eliminated from equation (1) by substitution of equation (2).
This leads to a general clearance formula which can be applied
to all three methods (hemodialysis, hemofiltration, and
hemodiafiltration):
CBI — CB0
CB0
KKHDFKHDKHFQB
L.Bi
CBI—CBO
(QB — QF) _________
+ QF. (3)
It is often assumed, particularly in hemodiafiltration, that the
first terms of equation (3) describe the effect of diffusion and the
second that of convection [12]. We find that this division into
components is incorrect, because CB0 depends on both the
diffusion and convection components, which occur
simultaneously.
In hemofiltration (pure), the removal rate of substance
through the filter can be measured in the filtrate. Thus equation
(1) can be replaced by KHF CB = QF CF, C representing the
concentration in the filtrate (mmoles/liter). This results in a
special clearance equation for hemofiltration:
KHF = Qi. (4)
In hemodialysis we have (approximately) QF = 0, and
equation (3) reduces to the familiar formula [9, 13]:
KHD = QB CBI (5)
CBI
This dialyzer clearance is considered to be constant during
hemodialysis under unchanged operating conditions (blood and
dialysate flow). This assumption is approximately true only for
high flux dialyzers and machines with controlled ultrafiltration.
But these conditions are not always fulfilled in the literature.
Received for publication January 27, 1982
and in revised form September 1, 1982
© 1983 by the International Society of Nephrology
144 Sprenger et a!

100 Table l.a

80 . Filtration rate, mi/mm
Time
E 4 5 6
a) 60 mm (1) (2) (3)
Co

40
0 84.09 83.46 83.31 80.27 85.89 84.97
•0
Co
20 30 71.30 70.90 70.80 65.02 75.49 76.42
LJ
60 68.49 67.73 66.84 60.29 72.94 70.63
20 40 60 80 100 120 140 160 180'2O0'20 240
90 66.90 66.95 65.21 56.96 71.02 66.03
Time, mm
Fig. 1. Progress of average filtration rates (QF) during hemodiafiltra- 120 66.07 65.52 62.09 53.89 68.84 62.49
tion treatments lasting 3 to 4 hr in three of six patients. The measured
filtration rates of the six patients are summarized in Table 1. In all 150 65.22 64.05 59.62 51.28 68.64 58.74
patients the filtration rate changes substantially, particularly in the first
30 mm. It decreased on an average by 30.6%, from 84 mI/mm in the first 180 63.48 61.46 59.90 50.62 66.90 57.13
5 mm to 58 mI/mm after 3.5 hr. The points of measurement lie on an
exponential curve described by a function of the type y = A + i3e". 210 62.68 58.33 50.02 64.50 54.82
Differences in the rate of decrease of filtration rate between patients
(curves I to 3) may be attributed to differences in blood composition 240 61.40
(hematocrit, concentration of fat, albumen, and fibrinogen). Symbols are:
A, markers of curve 1; •, markers of curve 2; •, markers of curve 3.
y=A+ l3e'
a —5.6 —4.5 —2.8 —4.6 —4.4 —1.6
In hemodiafiltration (HDF), that is, a simultaneous hemofil- 3 20.8 22.0 30.7 30.2 19.8 41.4
A 84.09 83.46 83.31 80.27 85.89 84.97
tration/hemodialysis [14, 15], however, the clearance decreases
significantly during treatment, as our own in vivo measure- a These numbers represent the mean values SD of N = 50 measured
ments have shown. This is caused by a decrease of the filtration data; Table I supplements Figure 1.
rate and of the sieving coefficient. The observed decrease in
filtration rate during hemodiafiltration (Fig. 1, Table 1)' is
probably caused by a protein gel layer of "secondary mem- recommended that dialyzer clearance should be determined
brane" forming on the surface of the dialyzer membrane at a again for each patient, because the changes in plasma concen-
rate dependent upon the filtration rate and in turn causing an trations can be predicted only for an individual dialysis treat-
increasing resistance to filtration [16]. A steady state may occur ment if the clearance is known as a function of time.
when the rate of deposition is balanced by the rate of removal These results imply that even in hemodialysis the ultrafiltra-
by diffusion and penetration through the membrane [17]. How- tion rate may influence dialyzer clearance. As a rule, only low
ever, the sieving coefficient also decreases with protein deposi- ultrafiltration rates (5 to 15 mllmin) are necessary to attain the
tion and mass transport is further reduced. This was investigat- required weight loss and this increases the clearance of small
ed for several substances at the beginning and at the end (after 4 molecules such as urea only slightly (3 to 10%) but can increase
hr) of six hemodiafiltration treatments for the RP 6 dialyzer the clearances of middle molecules such as inulin by 30 to 40%.
under standard conditions (QB = 200 mllmin, TMP = 500 mm A small drop in the ultrafiltration rate during hemodialysis may
Hg, QD = 0 mllmin). The decrease of sieving coefficient was therefore cause a significant reduction in middle molecule
significant for creatinine (15%), glucose (9%), phosphate (17%), clearance. This effect may be diminished by devices that
and inulin (22%) but not for urea (unpublished data). The maintain a constant ultrafiltration rate rather than a constant
reduction of filtrate flow and sieving coefficient causes a transmembrane pressure.
patient-specific reduction of the total clearance of urea and Residual renal clearance (KR). The effects of even very low
creatinine by about 10 to 15% in HDF (Figs. 2 and 3, Table 2). residual renal clearances (1 to 2 mllmin) should not be underes-
For the kinetic modeling of hemodiafiltration, it is therefore timated for the calculation of substance concentrations in
dialysis patients because the natural kidney functions continu-
ously and can significantly affect blood concentrations [18],
'Six patients were hemodiafiltered in postdilution mode 50 times particularly in the middle molecular weight range (500 to 5000
each; filtrate was collected continuously in 30-mm periods. The average daltons). Care should be exercised because an error of 1/2
volume of substitution solution was 10.5 2 liters per treatment. Blood ml/min when measuring a clearance of 1 ml/min can lead to
flow (250 mI/mm), dialysate flow (500 mI/mm), and transmembrane errors of 10 to 12% in the weekly middle molecule clearance if
pressure (513 12 mm Hg) were maintained at constant levels during
all treatments. At the beginning, after 30 mm, 30 mm before the end, the clearance during dialysis is 20 mllmin [23]. The main
and at the end of six consecutive treatments heparinized blood samples sources of error are: the difficulty in passing small volumes of
were taken at the arterial and venous parts of the dialyzer (RP6). Urea urine and the change in plasma creatinine concentration be-
and creatinine concentrations were determined by routine methods. tween dialysis treatments.
Also, urea and creatinine concentrations were measured 45 and 90 mm Errors can be minimized by the collection of urine over a
after the end of three consecutive HDF and in the intertreatment
interval to cover the course of the concentration during the interval. See period substantially longer than the usual 24 hr and taking blood
the legend of Figure 1 for the progress of average filtration rates during samples at the beginning and the end of urine collection and
hemodiafiltration treatments in three of the six patients. using the average.
 Kinetic modeling of artificial kidney 145

200 200

160 E 160
E
a)
C
a) 120 C 120

a)
0
C
80 80
'a
a)
a) 40 40
0
0 0 0
0 20 40 60 80 100 120 140 160 180 200 220 240 0 20 40 60 80 100 120 140 160 180 200 220 240
Time,min Time,min
Figs. 2 (left) and urea and creatinine clearance (N = 6) of three patients (Table 2) plotted against time during hemodiafiltration
3 (right). Average
treatments lasting 4 hr. Urea and creatinine clearance of the four sample points were calculated by means of equation [3]. Then clearance as a
function of time was calculated connecting these points by a spline function.

A convenient method is to collect urine samples during an Table 2.a

entire interdialytic interval so that arterial blood samples post- Time, mm
and predialysis can be used. Urine collection begins immediate- Patient
ly following dialysis after the emptying of the bladder and ends 0b Substance 0 30 150 180 210 240
with the collection of the urine at the final emptying of the 1 U 167 162 155 155
bladder before the subsequent treatment. The volume of urine
(Va) and urine concentration (Ce) are measured, and residual C 148 142 135 134
renal clearance is calculated using
2CxV0 2 U 162 156 150 148
—
KR — (6)
(C0 + C) X t C 143 137 129 127

where t is the duration of collection (that is, interdialytic

interval) and C0 and C refer to plasma concentrations at the 3 U 152 146 138 139

beginning and end of collection.

C 136 129 121 121
We assume that plasma concentrations increase linearly and
the small nonlinear "rebound" which occurs after dialysis is
negligible. 4 U 152 140 130 129
Generation rate. The synthesis of toxic substances can in
C 136 127 118 117
effect take place in either the intra- or extracellular compart-
ments [13, 19]. For example urea is the end product of protein
catabolism in the liver which represents a small proportion of 5 U 166 156 ISO 147
body tissue and can therefore be considered extracellular with
respect to the majority of cells. Nevertheless, an intracellular C 152 147 141 138

pool generation is generally assumed in the literature [21, 22].

Creatinine, on the other hand, is produced intracellularly in 6 U 170 158 145 141
muscle which represents the bulk of body mass and therefore is
considered to be generated in the intracellular compartment [19, C 146 140 129 125
20]. If a single pooi model is assumed and the volume, residual
renal clearance, and generation rate are assumed to be con- Abbreviations: U, urea; C, creatinine,
a The data represent mean values sn of six measurements; dialyzer
stant, the latter can be estimated from the rise in plasma
concentration between treatments: clearance (K) has been measured in milliliters per minute.
b The curves of Figures 2 and 3 are calculated with the data of
Cb(t) — Cb(0) patients 1 to 3 shown here.
G=Vx t +KRXc:b (7)

where Cb is the mean value of Cb (T) during the period from 0 to
t, and a good estimate of Cb is given by 1/2 [Cb (0) + Cb (t)].
In this formula V represents the distribution volume in
milliliters; Cb (0) and Cb (t) are plasma concentrations at the
beginning and end of the measurement period (t). To prevent
rebound from affecting the measurement of G the first blood
sample can be taken a few hours after the end of dialysis.
Compartment volumes, mass transfer, and distribution coef-
ficients: Compartment volumes (V). Various multiple pool models
have been constructed in accordance with physiological
measurements of body compartment volumes usually in pa-
tients with normally functioning kidneys [21, 23—30]. Popovich
Ct al [30] estimated the volumes of the intracellular, intravascu-
lar, and interstitial compartments and the coefficients of mass
transfer between these compartments by using a three-pool
model to analyze the dilution curves after bolus injection of
radioisotope labelled substances in an anephric patient between
dialysis treatments. The results show mass transfer coefficients
146 Sprenger et a!

and interstitial volumes which decrease when molecular weight tions of urea and creatinine, so that their distribution coeffi-
increases. Popovich et al [301 attributes the latter to the cients may be ignored in pool calculations.
omission from the model of "flow limitations." Schindhelm and
Farrell [24] repeated this method using fixed volumes from Kinetic modeling
physiological literature rather than attempting to fit both vol- Compartmental kinetic models may be used with differential
umes and mass transfer coefficients to one set of data. This equations to simulate the rates of changes in concentrations of
resulted in a much higher estimate of transcellular mass transfer solutes in the various compartments (or fluid pools) of dialysis
coefficients. It is not yet clear from available data whether the patients. Given a starting point ("infinitral condition") the
use of a multiple pool model with variable volume comes closer differential equations can be solved, such as on a computer
to reality for the prediction of mass transport than those with using numerical methods, for example, the Runge-Kutta meth-
fixed volume. od, to predict changes in the variables, for example, concentra-
Mass transfer coefficients (T). A series of measurements of tions. Reliable prediction of the probable course and results of
blood concentrations during dialysis or immediately after dialy- therapy is, however, only possible when sufficient information
sis can be used to determine the distribution of a substance in on the past and present condition of the patient is available. If
the body and the concomitant transfer resistance to transport this is the case, the model can, for example, be used to obtain
between the compartments [30]. "optimal therapy."
During treatment the high dialyzer clearance causes an im- To our present knowledge, a pool model that supplies long-
balance between concentrations in the intra- and extracellular term predictions does not exist [1, 9, 13, 19, 21, 22, 24—27, 29—
compartments. The rapid decrease in plasma concentration 31, 35—40]. It is doubtful whether a suitable model can be
leads to a considerably slower drop in intracellular concentra- developed for such a diverse group as that of dialysis patients.
tion, since only a small proportion of substance passes over Human physiology is complex and the more realistic models
from the intracellular to the extracellular space during dialysis. require too many data for general application to individual
This results in an accelerated renewed increase of plasma patients. Furthermore, small errors in the received data of the
concentration after dialysis. This increase is referred to as variables can generate accumulative errors in long-term predic-
"rebound" and can be used to calculate the cell membrane tions. Thus, models should be divided into at least two distinct
mass transfer coefficient [21, 30]. The magnitude of disequilibri- types depending on the desired application namely: (I) models
um and rebound are higher when the mass transfer coefficient is which are used primarily as research tools to check the quanti-
low (as is the case for middle molecules). Measurements of tative validity of proposed physiological mechanisms and (2)
transcellular transfer coefficients for urea, creatinine, and vita- models which can be applied in routine clinical practice or for
min B12 have been reported by several authors [19, 21, 22, 24— designing protocols to test new techniques or equipment. The
26, 28—31]. However the urea rebound may not be caused latter requires particularly simple models with a minimum of
exclusively by transcellular disequilibrium but may be affected variables to be measured and processed, but a reasonable
by an increase in protein catabolism induced by loss of glucose degree of accuracy is necessary to predict overall mass balance
and aminoacids [24]. This would make the transfer resistance (that is, pre- and postdialysis concentrations). The research
seem larger than it actually is. models, on the other hand, can be considerably more complex
For all the solutes studied the transcapillary transfer coeffi- and may be valid as broad generalizations of the system rather
cients are at least an order of magnitude higher than the than being applied quantitatively to individual patients. It is,
transcellular transfer coefficients. The latter must therefore be however, often necessary to limit the number of variables
the limiting factor in mass transport. because of the difficulty in making measurements, unless ex-
Distribution coefficients (x). The distribution coefficient (x) is trapolation from minimal data is considered acceptable. This is
the ratio of concentrations of the substance in two compart- often a necessary expedient.
ments at equilibrium. Dombeck, Klein, and Wendt [29] report- The single pooi model. In the past, the one-pool model has
ed the best fit of calculated to measured creatinine data using x been applied most frequently to dialysis-related techniques, not
= 1.63 between the intracellular and extracellular compart- only to simulate the overall mass balance of small molecules,
ment, which was the value previously measured by Giovanetti but also for middle molecules such as inulin [1, 38].
and Barsotti [32]. Although reduction of x to 1.0, which is In the single pool model, the body of the patient is conceived
usually assumed in the literature for distribution of all sub- as a homogenous compartment or "pool" of fluid in which all
stances between the intracellular volume (ICV) and extracellu- substances are uniformly distributed. The distribution volume
lar volume (ECV), had little effect on the mass transfer coeffi- should correspond to the total body water [24—28].
cient, it affected the generation rate and the dialyzer clearance The rate of change of the quantity of a substance in the pool
substantially. The latter is thereby diminished to values which
clearly lie under the measured in vivo clearance values [29].
(V), that is, !. Cb (t), during treatment can then be calculated
Distribution coefficients for urea, creatinine, and inulin be- from the dialyzer clearance (K), substance concentration (Cb),
tween red cells and plasma have been reported as 0.86, 0.73, residual renal clearance (KR), and the generation rate (G) of the
and 0.0, respectively [33]. The distribution coefficient is equal substance according to the following general model equation [41]:
to 0 for substances which cannot penetrate into the red cells,
while the distribution coefficient is equal to 1 if the concentra- [V (t) x Cb (t)] = —K(t) Cb(t) — KR Cb(t) + G. (8)
tion is equal in both compartments. However, more recent
measurements [34] on uremic erythrocytes could not detect a If the initial concentration and time intervals [and, of course,
significant difference between plasma and red cell concentra- the variables V(t), K(t), KR, G] are known, then this equation
 Kinetic modeling of artificial kidney 147

C,

Q.1 1.2 Curve A

0
Curve B
E 1.1
Curve C
0
E
C,
Curve A
Curve B
: tO
C, 0.9
0
0 C 0.8
0
0
C, 0.7
C
C 0C
C,
0
C 0 0.6
0
C)
C)

5 10 15 20 25 30 35 40 45 50 55

Time, hours Time, hours

Figs. 4 (left) and 5 (right). Kinetics of urea and creatinine during hemodiafiltration and in the following interval, simulated by the one pooi model
(curve C) and two pooi model (curve B, intravascular compartment; curve A, intracellular compartment). The measured plasma concentrations of
urea and creatinine are marked.

Table 3. Table 4. Patient no. 1: Hemodiafiltration (HDF): 3 x 240 mm/week

residual renal clearance: 0 mI/mm: dry body weight, 62.0 kg
Variable factors Fig. 4 Figs. 5 and 6
Filtration
Dialyzer clearance K, ml/min Time Urea Creatinine rate
0 mm 154 140 Day HDF mm mmoleslliter mmoles/liter mI/mm
30 mm 148 134
180 mm 140 125 1 1 0 29.5 1.45 84
210 mm 137 122 1 30 25.0 1.17 71
1 210 13.3 0.83 60
Residual renal clearance KR, mI/mm 0 0 1 240 12.8 0.70 57
285 13.2 0.84
Total body volume V (L) = 0.57 x kg [24, 25] 42.75 34.8 330 14.3 0.85
Intracellular V1 = ¾ V [29]
Extracellular V2 = 1/3 V [29] 2 1390 17.1 1.09

Mass transfer coefficient T, ml/minb 3 2 2870 23.3 1.30 85

Urea 700 2 2900 19.5 1.08 68
Creatinine 150 2 3080 12.5 0.73 63
2 3110 12.0 0.71 55
Distribution coefficient X 1 1 3155 12.2 0.76
3200 12.5 0.81
Generation rate G, p.moleslminc 136 5.01
Extracellular G2 = 0 4 4350 16.9 1.04
Intracellular G, = G
5 3 5745 23.6 1.23 90
a From these data K was calculated as a function of time (spline- 3 5775 21.2 1.02 68
function) as mentioned earlier. 3 5955 11.2 0.65 58
b T was chosen, such that the theoretical curve, calculated from the 3 5985 10.3 0.64 54
model, fits the measured data. (They correlate with values from [19, 22, 6030 11.7 0.72
28—301.) 6075 13.2 0.76
For the
calculation of G the rebound effect was eliminated by using
the measurements 1.5 and 3 hr after HDF, respectively, as the initial 6 7525 16.5 1.01
concentration.
7 8620 23.3 1.24

8 4 10110 28.2 1.34 88

can be used to predict the actual time course of the concentra- 4 10140 25.0 1.20 68
tion changes, for example, pre- and postdialysis concentrations
in plasma [3, 7—11, 13, 20, 23, 35, 37, 39, 421. But this model
does not simulate the interdialytic period precisely. Before the
beginning of the next treatment a clear difference exists be- data. Such a model is capable of predicting concentration
tween measured and calculated values. This discrepancy is changes over several treatments, but the results presented here
caused by the rebound of urea and creatinine after treatment illustrate that fitted values of G may not be physiologically
(as, for example, after hemodiafiltration in Figs. 4 and 5, Tables realistic. That is particularly true for creatinine where the
4 to 9). In the clinical application of the single pool model it is rebound shown by the two pool model (see below) is large.
normal practice to adjust G until the model fits the observed Although the error caused by rebound when a single pooi model
148 Sprenger et a!

Table 5. Patient no. 2: Hemodiafiltration (HDF): 3 X 210 mm/week Table 6. Patient no. 3: Hemodiafiltration (HDF): 3 >< 180 mm/week
residual renal clearance: 1.0 ml/min; dry body weight, 62.5 kg residual renal clearance: 2.9 mI/mm; dry body weight, 86.0 kg
Filtration Filtration
Time Urea Creatinine rate Time Urea Creatinine rate
Day HDF mm mmoleslliter mmo/es//iter mi/mm Day HDF mm mmoles/iiter mmoies/iiter mi/mm

1 1 0 30.6 1.48 92 1 1 0 31.3 1.35 87

1 30 25.2 1.18 70 1 30 26.6 1.17 72
1 170 18.9 0.88 62 1 130 20.8 0.97 62
1 210 17.8 0.85 58 1 180 19.8 0.94 58
255 18.5 0.92 225 20.4 1.00
300 18.9 0.96 270 20.7 1.02

2 1250 20.3 1.16 2 1270 23.1 1.12

3 2 2875 25.3 1.32 90 3 2 2865 25.0 1.25 90

2 2905 22.6 1.11 70 2 2895 21.8 1.03 88
2 3045 15.2 0.80 60 2 2995 16.3 0.84 62
2 3075 14.3 0.76 60 2 3025 15.5 0.83 59
3120 14.5 0.86 3070 16.8 0.89
3165 15.0 0.87 3115 17.8 0.90

4 3890 19.2 LOS 4 3965 19.3 1.07

5 3 5760 24.4 1.25 89 5 3 5750 23.4 1.20 90

3 5790 20.6 1.08 68 3 5780 21.2 1.07 71
3 5930 14.4 0.77 61 3 5880 15.9 0.86 62
3 5960 14.0 0.72 60 3 5910 14.8 0.80 56
6005 14.2 0.80 5955 15.4 0.84
6050 14.7 0.92 6000 15.8 0.89

6 6970 18.7 1.00 6 6965 18.0 1.02

7 8495 24.5 1.19 7 8375 23.7 1.13

8 4 10195 30.5 1.42 88 8 4 10115 31.1 1.25 90

4 10215 25.9 1.13 71 4 10145 29.9 1.06 83

is used for urea is relatively small [13, 20, 21]; it can be as high • Mass transfer of solutes between compartments (in accord-
as 50% for middle molecules [30]. ance with coefficients T and X) is linear
The two pooi model. In the two pool model, the total body • Solute generation only takes place in the intracellular pool.
water volume (V) is divided into two homogeneous compart- Errors may result if any of these assumptions are incorrect. The
ments: the intracellular volume (ICY V1) and the extracellu- equations for the two pool model can be solved explicitly [41] if
lar volume (ECV = V2). The concentrations in these compart- the variables are constant or, as in the instance cited below on a
ments are denoted by Cb and Cb2, respectively, and the intra- to computer using numerical methods, using, for example, the
extracellular mass transfer coefficient (T) and the distribution Runge-Kutta method [41]. The interdialytic interval, including
coefficient (X) must also be known. The general differential the rebound, is of course simulated by using K = 0. The initial
equations describing the two pool model with constant volumes plasma concentration is easily measured but the intracellular
are: concentration must be estimated from the distribution coeffi-
cient Cb = XCb2. As the one pooi model simulations had only
Cb(t) = -(—TCb(t) + XTCb,(t) + G1) (9) given an imprecise description of urea and creatinine kinetics in
hemodiafiltration patients, we attempted a better evaluation of
the measurements obtained with a two pool model. In the
C2(t) = +(TCb(t) — (XI + K(t) + application of the one and two pool models the following data
for the variable factors were used (Table 3).
It can be seen in our Figures 4 and 5 that the two pool model
KR) Cb2(t) + G2) (10) simulates the observed data more accurately than the single
pool model, particularly with regard to the creatinine rebound.
where G1 and G2 are the generation rates in compartments V1 This becomes especially clear if the process is followed over
and V2. Usually the following assumptions are made: two treatment intervals such as creatinine concentration in
• V1, V2, T, X, KR, G1, and G2 are constant Figure 6 (Tables 4 to 9). The urea rebound is smaller and of
• No significant protein binding occurs shorter duration and so the difference between the two models
• Pools are homogenous — even during dialysis is less significant.
 Kinetic modeling of artificial kidney 149

Table 7. Patient no. 4: Hemodiafiltration (HDF): 3 x 210 mm/week Table 8. Patient no. 5: Hemodiafiltration (HDF): 3 x 210 mm/week
residual renal clearance: 0.4 mI/mm; dry body weight, 64.5 kg residual renal clearance: 0 mI/mm; dry body weight, 75.0 kg
Filtration Filtration
Time Urea Creatinine rate Time Urea Creatinine rate
Day HDF mm mmoles/liter mmoles/liter mi/mm Day HDF mm mmoles/liter mmoles/liter mi/mm Fig.
1 1 0 31.6 1.59 87 1 1 0 30.3 1.28 80
1 30 26.1 1.34 66 1 30 28.2 1.05 75
1 170 18.5 0.99 50 1 120 21.6 0.91
1 210 17.5 0.93 48 1 180 19.1 0.82 65
255 18.0 1.00 210 15.7 0.73 62
300 18.3 1.05 390 19.4 0.88
570 20.5 0.89
2 1330 22.6 1.25 730 20.7 0.90

3 2 2915 28.5 1.42 85 2 1525 22.1 1.02

2 2945 24.8 1.21 72 2170 28.2 1.11
2 3085 16.0 0.85 50
2 3115 15.5 0.80 50 3 2 2870 28.7 1.15 80 1'
3160 15.8 0.88 2 2900 23.7 0.96 74
3205 16.3 0.90 2 2990 18.9 0.78
2 3050 15.9 0.75 64
4 4005 18.2 1.08 2 3080 13.6 0.63 60
3260 14.4 0.74
5 3 5705 24.2 1.23 89 3440 15.5 0.78
3 5735 19.2 1.02 65 3620 16.9 0.83
3 5875 12.5 0.75 48
3 5905 12.2 0.73 48 4 4310 17.6 0.92
5950 12.8 0.78 5090 21.2 0.98
5995 13.2 0.83
5 3 5770 23.0 1.05 82
6 7095 18.0 1.05 3 5800 20.1 0.98 77
3 5890 18.0 0.74
7 8545 21.8 1.22 3 5950 13.2 0.68 67
3 5980 11.4 0.60 63
8 4 10085 28.7 1.39 88 6160 12.5 0.69
4 10115 23.7 1.19 65 6340 13.9 0.74
6520 14.8 0.78

6 7280 16.2 0.88

7935 21.0 1.03

7 8720 22.8 1.05

Multiple pooi models. Some authors have checked the valid- 9365 24.2 1.12
ity of the two pool model by looking for further improvements
after subdividing the intra- and extracellular compartments [24, 8 4 10100 29.7 1.25 81
25, 30, 31]. Multiple pool models attempt to reproduce as 4 10130 25.2 1.02 75
realistically as possible the kinetics of solute transport during
and between treatments. To do this, as many kinetic data as are
available are used. However, the requirement for data limits the
usefulness of multiple pool models because most of the new
variables cannot be measured directly in humans and with Conclusions
every additional compartment several new variables and con- The object of our work has been to review existing models
stants are introduced. While the single pool model has disad- and collect the parameters which have been measured to help
vantages caused by the omission of transport across cell the reader choose a simple but adequate model for the desired
membranes, the addition of this factor requires the estimation application.
of the mass transfer coefficient, Further extension requires the Most of the models clinically employed at present are single
extraction of more information from essentially the same data pool models based on the assumptions that toxins are uniformly
and this becomes susceptible to experimental error. Further- distributed throughout body tissues [9, 39], and that mass
more, it is difficult to determine whether these subtle differ- transport between body compartments is fast compared with
ences in the raw data actually represent the physiological the rate of removal by dialysis-related techniques [301. The
processes built into the models. single pool model suffices for the description of urea kinetics
These problems have prevented the widespread use of mull i- and has in this role proved its worth in practice [35J.
ple pool models. In practice one must therefore choose between The two pool model is appropriate and necessary for the
simple models, which only define reality in a limited fashion, simulation of creatinine kinetics. It is also suitable for describ-
and complex models which demand the collection of large ing the kinetics during dialysis of uric acid, vitamin B12, and
quantities of precise data with corresponding expense in effort. inulin, as their transcapillary transfer coefficients are very high,
150 Sprenger et al

Table 9. Patient no. 6: Hemodiafiltration (HDF): 3 x 210 mm/week a)

1.
residual renal clearance: 0 mI/mm; dry body weight, 61.0 kg (a
a)
Filtration E
Time Urea Creatinine rate Figs. 5 Curve A
HDF mmoles/liter mmoles/liter mi/mm and 6 a) Curve B
Day mm
C
C Curve C
1 1 0 42.0 1.27 82 a)
a)
1 30 30.3 0.92 72 0
1 190 18.2 0.61 61 0
1 210 15.0 0.57 57 C
0
275 15.3 0.65
320 16.7 0.72 C
a)
0C
2 1760 25.6 0.97 00
3 2 2820 32.0 1.08 80 Time, hours
2 2850 23.1 0.80 74 Fig. 6. Creatinine concentration (according to Fig. 5) over two treat-
2 3010 13.0 0.53 56 ment intervals.
2 3040 11.3 0.50 54
2 3085 12.2 0.55
3130 12.3 0.63
• Control of electrolyte concentrations [45]
4 3860 20.3 0.91 • Influence of sodium balance on the volumes of fluid com-
5 3 5520 27.2 1.03 88 partments [45]
3 5550 21.9 0.81 83 • Modeling of urea and protein catabolism [46]
3 5710 11.2 0.49 59 • Heparin model [461
3 5740 10.4 0.47 59 • Acetate model and acetate metabolism [46]
5785 11.9 0.54
5830 12.2 0.58 • Carbon dioxide mass balance [461
• Body base model [46]
6 7250 19.2 0.83 Thus, models afford a basis for obtaining optimal treatment
by dialysis-related procedures.
7 8675 25.9 1.00 KUNO BERNT GERHARD SPRENGER
33.7 1.18 87 WERNER KRATZ
8 4 9885
4 9915 24.1 1.04 75 ANTHONY EVAN LEWIS
ULRICH STADTMULLER
Ulm, West Germany
but their transcellular transfer coefficients are relatively low Acknowledgments
compared to the dialyser clearance. It is therefore valid to
This review is dedicated to Prof. H. F. Franz, Head, Section of
combine the interstitial and plasma volume pools into a single Nephrology, University of Ulm, on the occasion of his 55th birthday.
extracellular pool [30], but the division between extra- and
intracellular pools is, however, essential. Reprint requests to Dr. K. B. G. Sprenger, Department of Internal
Although Popovich et al [30] found that a three pool model is Medicine, University of U/rn, Steinhovelstraj3e 9, 7900 U/m/Donau,
necessary to describe rapid dilution kinetics following the West Germany
injection of a radioactive-labelled bolus of middle molecules, it
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