In-Depth Review

Blood Purif 2018;45:61–70 Received: January 13, 2017

Accepted: August 10, 2017
DOI: 10.1159/000480221
Published online: November 23, 2017

Sodium Prescription in the Prevention of

Intradialytic Hypotension: New Insights
into an Old Concept?
Gabriele Donati a Mauro Ursino b Alessandra Spazzoli a Nicolò Natali a
       

Roberto Schillaci a Diletta Conte a Andrea Angeletti a Anna Laura Croci Chiocchini a

       

Irene Capelli a Olga Baraldi a Gaetano La Manna a 

     

a Nephrology, Dialysis and Renal Transplantation Unit, S. Orsola University Hospital, and b Department of Electrical,
 

Electronic and Information Engineering University of Bologna, Bologna, Italy

Keywords Introduction
Hemodialysis · Sodium mass balance · Intradialytic
hypotension · Techniques An excessive sodium load is associated with a high mor-
tality in patients with end-stage renal disease on chronic
hemodialysis (HD) [1]. A post hoc analysis from the HEMO
Abstract study considering 1,800 chronic dialysis patients showed a
Background: Sodium prescription in patients with intradia- significantly increased risk of death with a dietary sodium
lytic hypotension remains a challenge for the attending ne- load >2.5 g/die. In addition to dietary sodium intake, sodi-
phrologist, as it increases dialysate conductivity in hypoten- um loading in dialysis patients is due to the diffusive gradi-
sion-prone patients, thereby adding to dietary sodium lev- ent from dialysate to blood [1]. Keen and Gotch [2] found
els. Methods: New sodium prescription strategies are now that a 2–10 mEq rise in sodium gradient from dialysate to
available, including the use of a mathematical model to com- blood increases the patient’s sodium load due to an increase
pute the sodium mass to be removed during dialysis as a in sodium gained from the dialysate in comparison to that
physiological controller. Results: This review describes the gained from the daily diet. Flanigan [3] found a positive so-
sodium load of patients with end-stage renal disease on dium gradient from dialysate to blood in more than 75% of
chronic hemodialysis (HD) and discusses 2 strategies to re- 120 patients with a predialytic natremia of 137 ± 4 mEq/L
move excess sodium in patients prone to intradialytic hypo- and a sodium dialysate concentration of 140 mEq/L. Studies
tension, namely, Profiled HD and the hemodiafiltration Ae- on behalf of the Renal Research Institute undertook a 3-year
quilibrium System. Conclusion: The Profiled HD and Aequi- follow-up of 4,000 HD patients finding a predialytic natre-
librium System trial both proved effective in counteracting mia between 139 and 140 mEq/L related to a positive sodi-
intradialytic hypotension. © 2017 S. Karger AG, Basel um gradient between dialysate and blood in more than 40%

© 2017 S. Karger AG, Basel Prof. Gaetano La Manna

Nephrology Dialysis and Renal Transplantation Unit
S. Orsola University Hospital
E-Mail [email protected]
Via Massarenti 9, IT–40138 Bologna (Italy)
www.karger.com/bpu
E-Mail gaetano.lamanna @ unibo.it
of the patients when dialysate sodium was 140 mEq/L and Dialysate Sodium and Hypotension
in more than 20% when the dialysate sodium was 138 mEq/L
[4, 5]. The extracellular volume may increase during exces- Reducing the diffusive sodium gradient of sodium
sive sodium load due to both the water shift from the inter- from dialysate to blood and decreasing sodium gain
cellular space and thirst which leads to high interdialytic with the diet will diminish thirst and lead to negative
weight gain and arterial hypertension [6]. Hypertension, in sodium and water balance. This favors the normaliza-
turn, can have a strong impact on patients’ morbidity and tion of arterial pressure and cardiac remodelling, but
mortality [7]. The weight gain raises the ultrafiltration rate triggers intradialytic hypotension, presumably, as blood
during dialysis, which is associated with myocardial stun- is dialyzed, plasma osmolarity drops from approximate-
ning and increased mortality [8]. Penne and Sergeyeva [5] ly 310 mOsm/L to approximately 290 mOsm/L. When
showed an increased odds ratio for intradialytic morbidity dialyzed blood is reinfused into the patient, whose plas-
in patients with positive sodium gradient (>6 mEq/L) from ma osmolarity is 310 mOsm/L, the osmotic gap is dis-
blood to dialysate. Mc Causland et al. [1] enrolled 2200 HD sipated when water moves out of the plasma into the
patients during a 30-month follow-up finding that a >140 interstitial and intracellular space (ICV) [11]. This pro-
mEq/L sodium concentration in the dialysate increases cess reduces plasma volume and fosters edema even in
mortality in patients with predialytic natremia >140 mEq/L. the absence of ultrafiltration. The different mass trans-
fer coefficients yield the following times for equilibrium
to take place between the extracellular space (ECV) and
Avoiding Sodium Loading: Isonatric Dialysis the ICV: 30 s for osmotic equilibrium (because of the
high cell wall permeability to water), 20 min for urea
It is plain from the previous excursus that a diffusive equilibrium and over 10 h for equilibrium of the ICV-
sodium gradient from dialysate to blood should be avoid- ECV sodium concentrations. A mathematical model
ed. To prevent intradialytic patient hypotension, excessive devised by Mann and Stiller [12] calculates the volume
sodium removal by diffusion should also be avoided using shift as a function of eliminated quantities of solutes; in
isonatric dialysis in which sodium is removed by convec- particular, it considers sodium to be the very effective
tion alone. A large amount of sodium can be removed osmole: if the extracellular sodium is decreased by
simply by ultrafiltration, with the great benefit of avoiding 5  mmol/L and osmotic equilibrium is established, the
any alteration in plasma osmolarity. For example, if 3 L ECV decreases by 6%. These events cause intradialytic
are removed by ultrafiltration during a session, and plas- hypotension that involves 20–50% of HD sessions and
ma sodium concentration is 137 mEq/L, the total sodium can significantly increase the risk of death in the short
mass removed is as high as 411 mEq. This quantity cor- and long term [13].
responds to a sodium intake of up to approximately 205
Eq/day considering the 2 previous interdialytic days.
However, to achieve isonatric dialysis, the dialysate so- Managing Hypotension-Prone Patients
dium can also be aligned to the patient’s sodium “setpoint.”
Indeed, individual dialysis patients have their own predi- The European Dialysis and Transplant Association
alysis sodium values that change very little over time and K-DOQI defines hypotension as either a fall in sys-
(1.6%). This value is the so-called sodium “setpoint” and is tolic blood pressure (SBP) ≥20 mm Hg or a 10 mm Hg
generally computed by calculating the monthly mean of decrease in mean arterial pressure in combination with
the patient’s sodium values [3]. Dialysis patients tend to clinical symptoms requiring intervention [14, 15]. Re-
maintain their own sodium setpoint increasing the water peated episodes of intradialytic hypotension have been
gain to balance the excess in dietary sodium that cannot be associated with increased mortality in maintenance HD
decreased by urine output. For example, a sodium intake patients, particularly when an absolute nadir SBP <90
of 8 g per day needs the intake of 1 L of water to maintain mm Hg was reached [16, 17]. During a hypotension epi-
the sodium setpoint [9]. Nonetheless, the use of the sodium sode, the diastolic blood pressure (DBP) falls and as the
setpoint has its drawbacks: the correlation between salt in- myocardium is perfused during diastole, cardiac isch-
take and thirst is not a constant in a dialysis patient because emia can result due to the drop in perfusion pressure.
osmoreceptors function may be impaired and because the Repeated episodes of cardiac hypoperfusion may lead to
setpoint does not consider the hypotonic hyperhydration increased cardiac fibrosis and myocardial stunning [18,
due to the osmotic burden unrelated to sodium [10]. 19]. The commonest cause of intradialytic hypotension is

62 Blood Purif 2018;45:61–70 Donati  et al.

 

DOI: 10.1159/000480221
 can improve the intradialytic tolerance of chronic dialysis
CNa,d QF MNa,inf Qin
patients because a serum sodium change of 1 mEq/L is the
osmotic equivalent of a 6 mg/dL change in blood urea ni-
Ve 1 Sodium MNa,e trogen (2 mmol urea) or the oncotic gradient produced
extracellular by 10 g/dL of serum protein [11]. Brummelhuis et al. [24]
demonstrated that sodium profiling gradually declining
Vi 2 Sodium MNa,i from 150 to 140 mmol/L improves the plasma refill rate,
intracellular
whereas a positive effect of cool dialysate 1 ° C below core
QF Qinf
   

temperature could not be established. During profiled

Ve
MU,i Ve HD, the sodium or conductivity dialysate values must not
3 Urea 5 Fluid
Vi intracellular balance be maintained at the same high levels throughout the di-
Vi alysis session. To avoid the risk of an elevated sodium
level or high dialysate conductivity causing an increase in
K+ CI–H+ HCO–3 thirst and hence a higher interdialytic weight gain, dialy-
4 Urea
sis machines are currently equipped with different physi-
Ve extracellular ological controllers. A mathematical model can be em-
MU,e
Vi
ployed as a physiological controller to reach any clinical
QF
target, namely, end-dialysis sodium, blood volume de-
crease, arterial pressure decrease, and weight loss. The
Fig. 1. Block diagram describing the main mathematical relation- model needs to receive real-time signals of the patient’s
ships between solute masses and volumes used in the “Profiler” clinical status from specific sensors. This ability to mea-
model. Block 1 computes the sodium mass in the extracellular pool sure the patient’s status and automatically control the
(MNa,e) starting from the sodium concentration in the dialysate clinical targets is called “biofeedback” [25, 26]. As a result,
(CNa,d), the ultrafiltration rate (QF), the sodium mass in the rein-
fusion fluid (MNa,inf), the infusion rate (Q,inf) and the extracel- conductivity and ultrafiltration profiling during dialysis
lular volume (Ve). Block 2 computes the sodium mass in the intra- need (a) a mathematical model to reach the neutral so-
cellular pool (MNa,i) starting from intracellular volume (Vi) and dium mass balance automatically; (b) a biofeedback sys-
sodium mass in the other compartment. Blocks 3 and 4 compute tem for real-time modulation of the conductivity and ul-
the urea mass in the intracellular and extracellular pools (MU,i and trafiltration profiles.
MU,e respectively) starting from intracellular volume (Vi), extra-
cellular volume, ultrafiltration rate, and urea mass in the other
compartment. Lastly, Block 5 computes the intracellular and ex-
tracellular volumes from the solute masses and the ultrafiltration Mathematical Model for Profiled Dialysis
rate.
The sodium mass to be removed can be determined
from a nomogram in which the mass is the result of the
Table 1. Different techniques to counteract intradialytic
­hypotension
difference between dietary sodium intake and physiolog-
ical loss [27]. Alternatively, the sodium mass can be cal-
Techniques References culated using the so-called sodium target, which is the
average blood sodium value at the end of the last 12 di-
Sodium profiling [12, 19] alysis sessions when the patient is at his/her dry weight
Dialysate temperature balance [20, 21]
Ultrafiltration profiling [22]
[28, 29]. After calculating the sodium mass, the best strat-
Relative blood volume monitoring [23] egy must be devised for its removal.

The “Profiler” Mathematical Model

Colì et al. [27] and Ursino et al. [30] have developed
an ultrafiltration rate exceeding the corresponding plas- the “Profiler,” an algorithm that makes use of a mathe-
ma refilling rate long enough to reduce the plasma vol- matical model comprising a 2-compartment description
ume to a critical level [18]. A number of advances in di- (intracellular and interstitial) of sodium and urea kinetics
alysis machine technology have reduced the risk of intra- (Fig. 1). The model is applied to calculate sodium and ul-
dialytic hypotension (Table  1) [20–23]. Nonetheless, trafiltration profiles as concave downward curves whose
sodium prescription is the main modifiable factor that apices correspond to 60 min after the start of the dialysis

Sodium Prescription and Intradialytic Blood Purif 2018;45:61–70 63

Hypotension DOI: 10.1159/000480221
 session [31]. These profiles are computed from the pa-

§ Student t test; ^ linear mixed models; * ANOVA test, difference 150 min after dialysis start; ° ANOVA test, difference in blood pressure between HFR-Aeq and HFR
tient’s initial data: session timing, body weight to be lost,

319±19 vs. 347±19,

298±61 vs. 317±69,

238±43 vs. 238±43
Sodium removal

predialysis concentration of sodium and urea, and the

No increase in
(mEq/session)

end-dialysis sodium target. In particular, model equa-

interdialytic
weight gain
tions are used to simulate the time pattern of sodium con-

p = ns#

p = ns*
centration, starting from predefined profiles of dialysate
sodium and ultrafiltration rate. These profiles are then
modified with an iterative procedure to establish the so-
by hypotension, %

dium mass removal (or the required sodium target) and

the dry weight needed. This strategy has been adopted to
complicated

p = 0.04# achieve a neutral sodium balance (interdialytic dietary in-

p < 0.05
Dialysis

take = dialytic removal) and counteract the drop in plas-

p < 0.05§ NA
NA

ma osmolarity occurring during the first hour of dialysis

following the rapid clearance of low molecular weight sol-
Cardiac

utes. This implies a reduced sodium extraction and great-

output

er ultrafiltration during the first half of the dialysis session

NA

NA

NA

followed by reduced ultrafiltration and increased sodium

removal during the second half. During the first half of
p value variation, %

<0.001§ <0.001§ <0.001§ p < 0.001§

the dialysis session, the sodium profile prevents a sharp

volume
Blood

fall in plasma osmolarity and increases the plasma refill-

NA

NA

NA

ing rate. The excess fluid is drained from the intracellular

SBP, systolic blood pressure; DBP, diastolic blood pressure; NA, not assessed; ns, nonsignificant.

compartment and can be removed by means of a high

<0.001^
Heart

ultrafiltration rate, thereby achieving most of the weight

p value p value rate,

ns

ns

loss required. During the second half of the dialysis ses-

sion, the ultrafiltration rate is automatically reduced to-
<0.05*
DBP,

0.04^

gether with the sodium profile to allow excess sodium

ns

removal [31]. The Profiler was successfully validated in

<0.05*
<0.01^

<0.05°

experiments and proved to give accurate descriptions of

SBP,

solute kinetics during the dialysis session, maintaining

the strategy to increase the ECV/ICV ratio [31]. Consid-
144 vs. 1,728 Non controlled

ering that there are osmotic sodium and non-osmotic

controlled trial
Randomized

body sodium stores, the Profiler mathematical model was

Cross-over

controlled

revised and the intracellular sodium compartment was

design
Study

included in the model with a detailed description of in-

642 vs. 2,376 Non

trial

trial

terstitial elastance and interstitial fluid pressure [32, 33].

The model forecasts the sodium mass balance during the
923 vs. 988

4-h dialysis. It is up to the physician to check the patient’s

20 vs. 20
sessions
Dialysis

clinical status and modify the sodium target to maintain

standard at dialysis end; # Wilcoxon test.

the sodium mass balance in the long term. Plasma osmo-

Table 2. Summary of clinical outcome

larity time pattern prediction will be further improved

when the model will be integrated with the glucose kinet-
Patients,

ics. For the time being, the model takes the intradialytic
20
55

43

24

plasma glucose mass as approximately constant because

n

a glucose-containing dialysate fluid is currently used, and

this counteracts the diffusive loss of glucose across the
Locatelli et al. [40]
HFR vs. HFR-Aeq

dialyzer membrane.
Nacca et al. [41]
HD standard vs.

Colì et al. [34]

Colì et al. [35]

The Profiler system was then validated in the clinical

setting enrolling 20 hypotension-prone dialysis patients
Profiler
Studies

(Table 2). Blood volume and cardiac output during Pro-

filer HD showed a lower decrease than on standard HD,

64 Blood Purif 2018;45:61–70 Donati  et al.

 

DOI: 10.1159/000480221
a more stable intradialytic mean blood pressure and a A Biofeedback System Combined with the
lower heart rate increase than the values obtained during Mathematical Model for Online Computation of the
standard HD [34]. The Profiler was then used extensively Conductivity and Ultrafiltration Profiles
in a multicenter study involving 15 institutions enrolling
55 patients (Table  2). A 6-month follow-up comparing A limitation of the Profiler mathematical model is that
642 dialysis sessions using the usual technique and 2,376 the initial plasma sodium concentration is not known or
dialysis sessions implementing the Profiler system showed can only be partially inferred from the patient’s history.
(a) a significant improvement in SBP, DBP and heart rate This technique requires the use of a sodium sensor to
during dialysis, (b) a neutral sodium balance (no signifi- evaluate plasma sodium concentration during the indi-
cant increase in predialysis blood sodium level or inter- vidual session (Fig. 2). The sodium sensor yields continu-
dialytic weight gain), and (c) an improvement in disequi- ous real-time measurements of serum sodium, and pass-
librium syndrome symptoms [35]. As to hypotension- es this information to the mathematical model.
prone diabetic patients, Colì et al. [35] enrolled 18 patients
with diabetes out of 55 (33%), the patients were on strict The Sodium Sensor
antidiabetic therapy and differences between diabetic and The sodium sensor, known as Natrium®, comprises a
non-diabetic patients were not reported. probe with 2 conductive elements. Each element has a
The Profiler system was then adapted to hemodiafil- first contact surface facing the inside of the probe and de-
tration (HFR) with reinfusion of the endogenous ultra- signed to be in contact with the endogenous ultrafiltrate,
filtrate, a technique indicated for the treatment of di- and a second contact surface facing the outside of the
alysis patients with inflammatory syndrome and mal- probe in connection with the device for measuring con-
nutrition [36]. HFR is obtained by means of the HFR ductivity [38]. The sensor is applied on the endogenous
double chamber filter (Bellco, Mirandola, Italy). The ultrafiltrate circuit and reads the endogenous ultrafiltrate
first part of the filter consists in a polyphenylene high conductivity before the resin and before the second
flux hemofilter. The ultrafiltrate is driven from the he- HFR17 filter. The sensor measures the conductivity on
mofilter to a 40 g neutral styrene resin with an adsorb- the endogenous ultrafiltrate (or plasma water) obtained
ing area of 28,000 m2. The resin does not adsorb either by mechanical ultrafiltration. This conductivity measure-
sodium and electrolytes or urea [37]. After adsorption, ment was experimentally validated during HFR treat-
the ultrafiltrate is added to the whole blood that then ments [39]: the sensor measurements showed a signifi-
passes into the second part of the filter, a polyphenylene cant correlation with the corresponding serum sodium
low flux filter where the weight loss and diffusive depu- measurements by indirect potentiometry (Fig.  3). The
ration take place. The mathematical model is applied in differences observed between the mean of the sodium val-
the second filter to compute the sodium concentration ues obtained by Natrium and those obtained by the cur-
and ultrafiltration profiles in the dialysate. The mathe- rent laboratory methods are 0.5 mEq/L. The accuracy of
matical model called Profiler takes into account the Natrium is 1.2%. The difference observed between the
Gibbs-Donnan effect as reported by Ursino et al. [36] mean sodium values obtained by Natrium at dialysis end
during the Profiler validation in HFR. Using 9 HFR ses- and the values of the sodium target is 1.0 mEq/L [39]. An
sions on 9 chronic HD patients (one for each patient), equation ([Na+] = 13.95* Cuf – 53.48) is currently used to
the time course of plasma solutes and osmolarity mea- correlate endogenous ultrafiltrate conductivity and plas-
sured every 30 min during HFR was compared with ma sodium [40]. In turn, the correlation equation calcu-
those predicted by the model. The average deviations lates the plasma sodium to be given in real time to the
between model and real data (sodium: 1.9 mEq/L; po- mathematical model [40], which then recalculates the pa-
tassium: 0.32 mEq/L; urea: 1.04 mmol/L; osmolarity: tient’s predialysis sodium profile by considering the value
5.02 mosm/L) are of the same order as measurement at 15 min and at 60 min from dialysis start (Fig. 4, 5). Sub-
errors and similar to those obtained using our previous sequently, some model parameters are adjusted on the
models in standard and profiled HD. Sodium concen- basis of the discrepancy between the initial model predic-
tration prediction only slightly worsens (from 1.9 to tions and the real-time sodium sensor measurement, and
2.02 mEq/L) if default values are used for the initial the profiles recalculated to ensure the desired sodium tar-
value of other solutes in blood (i.e., if the algorithm uses get. This produces biofeedback that permits ongoing ad-
only initial body weight and initial sodium concentra- justment of the model to the individual patient. This HFR
tion in plasma) [36]. system is called HFR Aequilibrium (HFR-Aeq).

Sodium Prescription and Intradialytic Blood Purif 2018;45:61–70 65

Hypotension DOI: 10.1159/000480221
 Sodium mass
Sodium sensor balance
[Na]pl

Quf
+ -ΔMmol/kg weight
Target [Na]pl

QR

Na
Qdo
Uf

Kinetic
model

Na
Qdi
Uf

Sodium balance: yes

Clinical effect: yes

Fig. 2. Schematic diagram of HFR Aequilibrium.

15.0

14.8

14.6

14.4

14.2
Cuf, mS/cm

14.0

13.8

13.6
y =0.0717x + 3.8347
R2 = 0.8821
13.4
n = 120

13.2

13.0
132 134 136 138 140 142 144 146 148 150
[Na]pl, mEq/L

Fig. 3. Correlation between conductivity measured by the Natrium sodium sensor (Cuf) and plasma sodium (Na pl) measured by indi-
rect potentiometry.

66 Blood Purif 2018;45:61–70 Donati  et al.

 

DOI: 10.1159/000480221
 16.0 16.0

Conductivity profile, mS/cm

15.5 15.5

Conductivity profile,
15.0 15.0

adpated, mS/cm
Natrium
14.5 14.5
14.0 14.0
13.5 13.5
13.0 13.0
12.5 12.5
12.0 12.0
0 60 120 180 240 0 60 120 180 240
a Time, min b Time, min

15.5
[Na+] during HFR aequilibrium,

15.0

14.5
[Na+], mEq/L

14.0

13.5

Natrium
13.0
0 15 60 120 180 240
c Time, min

Fig. 4. Theoretical graph of conductivity profiles and plasma so- ing on the conductivity profile set-up off-line; solid line = [Na+] in
dium over time. a Dialysate conductivity profile set-up off-line. plasma predicted by the model during HFR depending on the con-
b Dialysate conductivity profile adapted on-line after sodium de- ductivity profile adapted online. Note that the different plasma
termination by Natrium sensor at 15 min from HFR start. c Dashed sodium patterns are imputable to a wrong offline knowledge of the
line = [Na+] in plasma predicted by the model during HFR depend- initial plasma [Na+].

Clinical Use of HFR-Aeq plicated by hypotension using HFR-Aeq; (b) a signifi-

HFR-Aeq was compared with traditional HFR in an cant reduction of symptomatic hypotension cases (23 ±
international multicenter randomized study (the AIMS 3% in HFR-Aeq vs. 31 ± 4% in HFR, p = 0.03); (c) a re-
study) that assessed the efficacy of the HFR-Aeq system duced onset of intradialytic morbid events requiring
on intradialytic hypotension (Table 2). The study com- nursing interventions (17 ± 3% of sessions with at least
pared 923 HFR sessions with 988 HFR-Aeq sessions in one intervention in HFR-Aeq vs. 22 ± 1% of sessions
43 patients prone to intradialytic hypotension. Intradia- with at least one intervention in HFR, p < 0.01) [40]. SBP
lytic hypotension was defined according to Colì et al. significantly increased in HFR-Aeq 60 min after the start
[35]: (i) an SBP value ≤90 mm Hg in patients with a pre- of dialysis with respect to values measured in HFR,
dialysis SBP value >100 mm Hg, even if not accompa- whereas DBP values rose significantly in the second half
nied by symptoms and therapeutic interventions; (ii) of the dialysis session with HFR-Aeq compared to HFR.
any SBP reduction ≥25 mm Hg compared to the predi- Dividing patients into quartiles according to the per-
alysis value in the presence of symptoms and therapeutic centage of dialysis sessions complicated by hypotension,
maneuvers; (iii) an SBP reduction of at least 10% accom- a significant reduction in the number of hypotension
panied by typical symptoms (nausea, vomiting, head- events was found in patients presenting arterial hypo-
ache, dizziness) in patients with a predialysis SBP value tension in more than 75% of dialysis sessions [40]. In
<90 mm Hg. The results showed the following indica- addition, HFR-Aeq treatment maintained hemodynam-
tions: (a) a significant reduction of dialysis sessions com- ic stability during dialysis with preservation of patients’

Sodium Prescription and Intradialytic Blood Purif 2018;45:61–70 67

Hypotension DOI: 10.1159/000480221
 Patient 1: NA target 140 mEq/L Patient 2: NA target 138 mEq/L Patient 3: NA target 139 mEq/L Patient 4: NA target 137 mEq/L
15.5

15.0

14.5
mS/cm2

14.0 Conductivity profile offline

13.5 Conductivity profile at 15’
Conductivity profile at 60’
13.0
15 45 75 105 135 165 195 15 45 75 105 135 165 195 225 15 45 75 105 135 165 195 225 15 45 75 105 135 165 195

144
143
142
Sodemia, mEq/L

141
140
139
138 Natrium
137 Laboratory
136
15 45 75 105 135 165 195 15 45 75 105 135 165 195 225 15 45 75 105 135 165 195 225 15 45 75 105 135 165 195

1.2

1.0

0.8
UF rate, L/h

0.6

0.4

0.2

0
15 45 75 105 135 165 195 15 45 75 105 135 165 195 225 15 45 75 105 135 165 195 225 15 45 75 105 135 165 195
Time, min Time, min Time, min Time, min

Fig. 5. In vivo conductivity and ultrafiltration profiles and plasma time with the Natrium sensor. Note that the light blue line is cov-
sodium over time. The figure represents the conductivity and ul- ered by the red and the green lines except for the peak conductiv-
trafiltration profiles during HFR Aequilibrium in 4 different ity profile curve. The Natrium sensor can also make a second cor-
chronic hemodialysis patients. The top row shows the conductiv- rection of the conductivity profile at 60 min: the slope of the green
ity profiles. Each graph in the top row represents the following: (a) curve becomes lower than that of the red curve. The central row
the light blue line represents the conductivity profile set-up off-line represents the sodium values measured by Natrium (blue line) and
before starting dialysis, (b) the red line represents the conductivity by the current laboratory method (indirect potentiometry, red
profile corrected at 15 min by sodium values measured in real time squares). The bottom row represents the concomitant ultrafiltra-
with the Natrium sensor; (c) the green line represents the conduc- tion rate profile during HFR Aequilibrium.
tivity profile corrected at 60 min by sodium values measured in real

sodium balance: no differences were found between Conclusion

HFR and HFR-Aeq serum sodium concentrations pre-
dialysis (138.6 ± 0.5 vs. 139.4 ± 0.5 mEq/L) and post- Maintaining a correct sodium balance and a controlled
dialysis (139.2 ± 0.2 vs. 139.7 ± 0.52 mEq/L). End-dialy- reduction of osmolarity during dialysis is challenging but
sis serum sodium in HFR-Aeq was equal to the sodium not impossible. Sodium and ultrafiltration profiles com-
target (139.7 ± 0.2 vs. 139.0 ± 0.1 mEq/L) [40]. Nonethe- bined with a correct sodium balance have a positive effect
less, Locatelli et al. [40] considered 13 chronic HD pa- on intradialytic hemodynamic stability. This strategy can
tients with diabetes out of 50 (26%); they were on strict be optimized by monitoring intradialytic systems and ad-
anti-diabetic therapy. Differences between diabetic and justing the profiles in real time on the basis of sodium and
non-diabetic patients were not reported to be the aims ultrafiltration kinetics.
of the trial. The findings of the AIMS study were also Nonetheless, the Profiler HD procedure described in
confirmed by a multicenter study on HFR-Aeq and in- this work involves several possible errors, which should
tradialytic cardiovascular stability carried out in one be clearly recognized, and may be the target of future
Italian region (Lazio), Table 2 [41]. technical and theoretical improvements. These can be

68 Blood Purif 2018;45:61–70 Donati  et al.

 

DOI: 10.1159/000480221
classified into errors in the dialysis procedure, errors in in a clinical set up, a model should be as simple as possi-
data measurements, and errors induced by model limita- ble, in order to favor direct implementation in a dialysis
tions. machine, allow real time computation, and permit a more
The first aspect includes possible inaccuracies in the straightforward analysis of results. However, each simpli-
dialysate composition and in the delivered acid-base bal- fication involves some unavoidable errors compared with
ance, and errors in the determination of the patient so- the complexity of a real physiological system. Among the
dium intake. With regard to sodium intake, Maduell and main points deserving future study, we can mention the
Lambie, considering small caseloads of HD patients, work of active ionic transport pumps (in particular, the
found that the daily salt load varied between 170 and 250 Na+-K+ pump) and the effect of cardiovascular regulation
mmol/die [42, 43]. These may affect the actual final so- mechanisms on fluid pools [44]. Finally, accounting for
dium target, which can differ from that presumed by the the large individual variability requires implementation
procedure. of ad hoc procedures for personalized parameter esti-
Data used to validate the model are generally achieved mates, which in turn are influenced by data inaccuracy.
with the potentiometry technique, which is quite inaccu- All these aspects are challenges for future improvements.
rate in terms of sodium concentration: indirect potenti-
ometry (ion selective electron potentiometry, Beckman
Coulter®, Rome, Italy) is currently used to determine so- Acknowledgments
dium concentration. The coefficient of variation of labo-
ratory sodium determination is 0.64%, while the standard This research was supported by a grant from the University of
deviation is 0.84 mEq/L. These errors can be reflected in- Bologna. Project entitled: “Ricerca fondamentale orientata.” Prin-
cipal investigator: Gaetano La Manna. Anne Collins edited the
accurately in the model validation, especially when some English text.
parameters are estimated directly from the data set (we
remind that the higher the inaccuracy in the measure-
ment, the higher the variance of parameter estimates).
Disclosure Statement
Finally, all physiological models include some simpli-
fications and limitations, since they represent a compro- The authors declare that there are no conflicts of interest to
mise between simplicity and completeness. To be useful disclose.

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70 Blood Purif 2018;45:61–70 Donati  et al.

 

DOI: 10.1159/000480221