[On-line sequential hemodiafiltration (HDF-OL-S): a new therapeutic option].

Abstract

on line haemodiafiltration provides the greatest clearance for low and high-molecular weight uremic toxins, which is associated with a lower risk of mortality in our patients. Nowadays, there's increasing evidence about the need of achieving at least 20 litters ultrafiltration in postdilution mode and 70% reduction of beta-2-Microglobulin (B2M), however it requires a vascular access's high blood flow. Unfortunately, we do not succeed in these objectives because of our patients being older, diabetic and with poor vascular access; in this situation high blood flows are more difficult to get at the expense of lower post-dilution exchange volumes. The aim of this study was to assess the efficiency of OL-S-HDF to obtain an equivalent ultrafiltration volume as 20 L in OL-postdilution-HDF (OL-P-HDF). OL-S-HDF initially begins in postdilution mode changing to predilution once the transmembrane pressure (TMP) reached 250 mmHg.
we performed one high-flux HD session (HF-HD), one OL-P-HDF session and one OL-S-HDF session in each of the 16 adult patients who participated during 3 consecutive weeks. We compared the clearance rates of low and middle molecules such as urea, creatinine, B2M, myoglobulin and levels of albumin and haematocrit between the 3 different techniques. We measured the pre-filter pressure (PFP) by a manometer set before the dialyzer.
The main characteristics of the sessions are described in table N1. There wasn't significant difference in Kt/V, urea and creatinine removal between the three techniques. B2M and myoglobulin's clearance rates were significantly higher in both hemodiafiltration modes than in HF-HD (p=0.000), however we didn't find differences between OL-P-HDF and OL-S-HDF. There was a direct correlation between PFP and TMP along the sessions in every technique (p<0.05). We found that PFP was better than TMP to correlate with pre-dialysis levels of albumin and haematocrit and also with the haemoconcentration percentage at the end of the sessions.
This study confirms that OL-S-HDF is as good as OL-P-HDF and it could be a useful technique to treat patients with suboptimal access's blood flow to get to achieve ultrafiltration volumes within the objectives. PFP could offer extra information than TMP.

Full text

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Nefrología (2008) 4, 433-438
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http://www.senefro.org
© 2008 Órgano Oficial de la Sociedad Española de Nefrología
originals
On-line sequential hemodiafiltration (OL-S-HDF):
a new therapeutic option
J. Kanter, M. Puerta Carretero, R. Pérez García, J. M. López Gómez, R. Jofré and P. Rodríguez Benítez
Servicio de Nefrología. Unidad de Hemodiálisis. Hospital G. U. Gregorio Marañón. Madrid. España.
Nefrología 2008; 28 (4) 433-438
Correspondence: Julia Kanter
Hospital Universitario Dr. Peset
Av. Gaspar Aguilar, 90
46017 Valencia. España
jkanter@senefro.org
SUMMARY
Background: On line haemodiafiltration provides the greatest
clearance for low and high-molecular weight uremic toxins,
which is associated with a lower risk of mortality in our patients.
Nowadays, there’s increasing evidence about the need of achie-
ving at least 20 litters ultrafiltration in postdilution mode and
70% reduction of beta-2-microglobulin (B2M), however it requi-
res a vascular access’s high blood flow. Unfortunately, we do not
succeed in these objectives because of our patients being older,
diabetic and with poor vascular access; in this situation high
blood flows are more difficult to get at the expense of lower
postdilution exchange volumes. The aim of this study was to as-
sess the efficiency of OL-S-HDF to obtain an equivalent ultrafil-
tration volume as 20 L in OL-postdilution-HDF (OL-P-HDF). OL-S-
HDF initially begins in postdilution mode changing to predilution
once the transmembrane pressure (TMP) reached 250 mmHg.
Methods: We performed one high-flux HD session (HF-HD), one
OL-P-HDF session and one OL-S-HDF session in each of the 16
adult patients who participated during 3 consecutive weeks. We
compared the clearance rates of low and middle molecules such as
urea, creatinine, B2M, myoglobulin and levels of albumin and hae-
matocrit between the 3 different techniques. We measured the
pre-filter pressure (PFP) by a manometer set before the dialyzer.
Results: The main characteristics of the sessions are described in
table Nº1. There wasn’t significant difference in Kt/V, urea and crea-
tinine removal between the three techniques. B2M and myoglobu-
lin’s clearance rates were significantly higher in both hemodiafiltra-
tion modes than in HF-HD (p = 0.000), however we didn’t find
differences between OL-P-HDF and OL-S-HDF. There was a direct co-
rrelation between PFP and TMP along the sessions in every techni-
que (p < 0.05). We found that PFP was better than TMP to correlate
with pre-dialysis levels of albumin and haematocrit and also with the
haemoconcentration percentage at the end of the sessions.
Conclusions: This study confirms that OL-S-HDF is as good as
OL-P-HDF and it could be a useful technique to treat patients
with suboptimal access’s blood flow to get to achieve ultrafiltra-
tion volumes within the objectives. PFP could offer extra infor-
mation than TMP.
Key words: On line haemodiafiltration. Transmembrane pressu-
re. Blood flow. B2-microglobulin. Myoglobulin.
RESUMEN
La hemodiafiltración en línea proporciona una alta eficacia
depurativa de moléculas de mediano y gran peso molecu-
lar. Existe consenso sobre la necesidad de conseguir al
menos 20 L de ultrafiltración en postdilución y tasas de re-
ducción de B2-microglobulina mayores del 70%. Desafor-
tunadamente muchos pacientes tienen un acceso vascular
inadecuado siendo muy difícil lograr esos volúmenes de
ultrafiltración sin complicaciones clínicas. El objetivo de
este trabajo fue conseguir un volumen de ultrafiltración
equivalente a 20 L en postdilucional, mediante la técnica
«Secuencial» (HDF-OL-S) que comienza siendo postdilucio-
nal y cuando la PTM alcanza los 250 mmHg se trasforma
en predilucional. Se realizó una sesión de hemodiálisis de
alto flujo (HD-HF), una de hemodiafiltración postdilucional
(HDF-OL-P) y otra sesión en modo secuencial a 16 pacien-
tes durante 3 semanas consecutivas, en la sesión de mitad
de semana. Se compararon los rendimientos de elimina-
ción de pequeñas y medianas moléculas entre las diferen-
tes técnicas. Se midió la presión prefiltro (PPF) mediante
manómetro predializador. No encontramos diferencias en
el Kt/V, tasa de reducción de urea y de creatinina entre las
3 técnicas. La tasa de reducción de B2-microglobulina y
mioglobina fue significativamente mayor tanto en HDF-
OL-P como en HDF-OL-S con respecto a la HD-HF, no ha-
biendo diferencias entre ambas técnicas de HDF. Existió
una correlación directa entre PTM y PPF a lo largo de la se-
sión en todas las técnicas. La PPF horaria se correlacionaba
mejor que PTM con los niveles basales de albúmina sérica,
hematocrito y porcentaje de hemoconcentración al final
de la diálisis. La HDF-OL-S es una técnica de hemodiálisis
con los mismos beneficios de la postdilucional que permite
lograr volúmenes de ultrafiltración dentro de los objetivos
planteados. Creemos podría ser útil en pacientes con flu-
jos sanguíneos limitados para lo cual habría que diseñar
nuevos estudios. La PPF aporta información complementa-
ria a la PTM.
Palabras clave: Hemodiafiltración en línea. Presión transmembra-
na. Flujo sanguíneo. B2-microglobulina. Mioglobina.
INTRODUCTION
On-line hemodiafiltration (OL-HDF) is a dialysis procedure
that adds to diffusive transport characteristic of standard he-
modialysis (HD) a significant amount of convective transport.
Convective transport allows for an increased clearance of me-

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Nefrología (2008) 4, 433-438
434
dium and large-sized molecules, difficult to remove by diffu-
sion.1Retention of these uremic molecules has traditionally
been associated to various chronic complications in patients
on hemodialysis. Several studies have shown decreases in
these complication when procedures with greater convective
transport are used.2-6The disparity in the clinical results of
HDF procedures reported in the literature may be accounted
for by the different convective component. Hemodiafiltra-
tions of 6-8 Lof ultrafiltrate per session are often compared to
HDs greater than 20 L. It was recently reported that the relati-
ve mortality risk could be decreased in patients treated with
HDF with a high convective transport, as compared to either
low or high-flux HD.7,8
On-line postdilutional HDF (OL-P-HDF) is the most effi-
cient renal clearance procedure in clinical practice, being
more efficient, the higher the infusion rate is. In this regard,
agreement begins to exist about the need for achieving at
least 20 L of ultrafiltration (UF)9and B2-M clearance rates
higher than 70%.4,10However, postdilutional infusion is limi-
ted by the progressive plasma hemoconcentration in the
dialyzer.11
When a filtration coefficient of 25% of real Qb is exceeded
in the OL-P-HDF procedure, a hemoconcentration will be in-
duced in the dialyzer that will interfere with diffusion, with a
subsequent decrease in clearance of small molecules and a
trend to coagulability in capillaries, which may further decre-
ase clearance.12Coagulation of the whole blood circuit may
sometimes occur. TMP increases, and extreme values (> 300
mmHg) are associated to protein denaturation and hemolysis,
with irreversible reduction in dialyzer efficacy.13
To solve these problems, systems combining the advanta-
ges of both modalities (pre and postdilution) and attempting
to minimize their disadvantages have been devised. Such sys-
tems include the mixed OL-HDF14and mid-dilutional15,16pro-
cedures, but are not still available or require special materials
that increase the costs. There are also sequential convective
procedures combining hemofiltration and hemodiafiltration
which have been shown to improve the hemodynamic tole-
rance of patients, as well as the clearance rates of molecules
of medium molecular weight.17
Patients whose vascular access allows for a real blood flow
(Qb) of 400 mL/min in OL-P-HDF will have no problems for
maintaining 100 mL/min of UF without technical problems,
thus achieving 24 L of convective transport in a 4-hour ses-
sion. Many patients currently have an inadequate vascular ac-
cess, particularly those with indwelling catheters. UF would
therefore have to be reduced to 60 mL/min or to be converted
into predilutional. Since predilutional OL-HDF has a 1/2 to
1/3 lower performance than postdilutional OL-HDF for me-
dium-sized molecules,9UF rates as high as 300 mL/min (18
L/h) and commensurate infusions, which cannot be achieved
by all machines, would be required.
In an attempt to achieve ultrafiltrations equivalent to 20 L
in postdilution for potential future application to patients with
limited Qbs, we developed a procedure called «on-line se-
quential HDF» (OL-S-HDF). OL-S-HDF starts with infusion
in postdilution, at an approximate rate of 100 mL/min, and
once TMP reaches 250 mmHg, infusion is manually changed
to predilution, increasing the infusion rate by 50% until the
end of the session (fig. 1). Hence the term «sequential», be-
cause infusion would not be simultaneous, but sequential over
time, not requiring any filters or monitors different from the
usual ones. Our purpose was to analyze the performance of
the OL-S-HDF procedure in the clearance of small and me-
dium-sized molecules, and to compare it to high-flux hemo-
dialysis (HD-HF) and OL-P-HDF.
STUDY DESIGN
This was a controlled, prospective study where 16 patients in
a chronic hemodialysis program were randomly dialyzed
using HD-HF, OL-P-HDF, and OL-S-HDF. Patients conti-
nued on their standard dialysis technique three times weekly,
and the above procedures were performed in each patient in
the mid-week session for three consecutive weeks. Procedu-
res were analyzed and compared to each other.
J. Kanter et al. Hemodiafiltración en línea secuencial
originals
Figure 1. Scheme depicting the mo-
dified on-line hemodiafiltration (HDF)
procedure from Fresenius Medical
Care®(FMC). UF pump: Ultrafiltration
pump.
On-line HDF scheme (FMC®)

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Nefrología (2008) 4, 433-438
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PATIENTS
Sixteen stable adult patients diagnosed of chronic kidney di-
sease undergoing dialysis three times a week at the Hemo-
dialysis Unit of Hospital G. U. «Gregorio Marañón» partici-
pated in the study.
Inclusion criteria were: age ranging from 18 and 80 years;
hemoglobin levels within normal ranges according to Europe-
an guidelines for anemia management;18vascular access with
a Qb3300 mL/min; and urea recirculation within normal li-
mits (less than 12%, measured at low flow). Patients provided
consent for the study. Poor dialysis tolerance was an exclu-
sion criterion.
MATERIALS
A Fresenius®model H400-S equipment fitted with an OCM
device (online clearance monitor, ionic dialysance) and BVM
(blood volume monitor), and a HF80S dialyzer (polysulfone,
1.8 m2; Fresenius®, Hamburg, Germany) were used in all ses-
sions. Aportable digital pressure gauge (Nagano®) was placed
between the blood pump and dialyzer to measure pre-filter
pressure (PFP).
METHODS
In all sessions studied, the theoretical blood flow rate adequa-
te for achieving an real Qb (calculated by the equipment from
pre-pump negative pressure) of 400 mL/min was kept. If this
figure was not achieved, Qb was increased until a pressure –
200 mmHg was induced in the pre-pump arterial line. A bath
flow rate (Qd) of 800 mL/min, a dialysis fluid with a calcium
concentration of 3 mEq/L, and a total conductivity of 14
mS/cm were used. Session duration was as usual for each pa-
tient.
In OL-P-HDF sessions, an infusion rate of 25% of real Qb
was used. OL-S-HDF sessions started in postdilutional phase,
programming an infusion rate of 100 mL/min without excee-
ding 30% of Qb, and when TMP reached 250 mmHg, the in-
fusion fluid was transferred to predilution at an infusion rate
50% higher than the previous one (fig. 2).
The following laboratory parameters were measured before
and after dialysis: urea, creatinine, B2-microglobulin, myo-
globin, albumin, and hematocrit (Hct). The post-dialysis sam-
ple was taken from the arterial line after reducing pump speed
to 50 mL/min for 2 minutes.
DATA COLLECTION
The following were measured and recorded during each ses-
sion: calculated real Qb, arterial line pressure (AP), venous
line pressure (VP), TMP, PFP, and changes in plasma volume
(by BVM) every hour. To measure the efficacy of the diffe-
rent procedures, clearance rates of urea, creatinine, B2-micro-
globulin, and myoglobin were calculated. The final Kt was
measured in all sessions using the OCM (ionic dialysance)
and Kt/V was estimated, calculating V by the Watson formu-
la. Kt/V was calculated from pre- and post-session urea levels
using the Daugirdas (1993) and Maduell formulas.
Percent hemoconcentration (HC) was calculated at the end
of session using the following equation: [(Post-dialysis Hct x
100)/Pre-dialysis Hct]-100. To use this formula, hematocrit
was measured before dialysis in the arterial line and at the end
of dialysis at dialyzer outlet.
STATISTICS
Normal values were expressed as the mean (± standard devia-
tion). The value interval was sometimes recorded. A Chi-
square test or a Fisher’s exact test when appropriate were
used to compare qualitative variables. Differences between
means were tested using an analysis of variance (ANOVA).
Normalized variables were correlated to each other (Pear-
son’s correlation coefficient). A value of p < 0.05 was consi-
dered statistically significant. Data were analyzed using SPSS
software version 12 for Windows.
RESULTS
The 16 patients, 9 females and 7 males, had a mean age of 62
(± 14) years, a mean dry weight of 67 (± 9) kg, and a mean
J. Kanter et al. Hemodiafiltración en línea secuencial
originals
Figure 2. Temporal representation of
change from post to predilution infu-
sion and its relationship to transmem-
brane pressure (TMP) in the on-line
sequential hemodiafiltration (OL-S-
HDF) procedure. Values are given as
mean and standard deviation.
250
240
230
220
210
200
190
180
170
160
150
155
145
135
125
115
105
95
85
TMP mmHg
Infusion rante mL/min
1º hour 2º hour3º hour4º hour
TMP Infusión rate mL/min
Change from post to predilution
150 150
231
192
100100 175
181
Relationship between infusion rate and TMP in OL-S-HDF

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Hct of 35% (± 4.2). All patients were stable and had been
more than 6 months on dialysis. Four patients were diabetic
and two had an indwelling catheter, while all other patients
had a functioning arteriovenous fistula.
Dialysis duration was 219 (± 15) minutes (min. 195-max.
240). Mean transition time from post to predilution in OL-S-
HDF from session start was 127 (± 33) minutes (min. 60 -
max. 165, and had an inversely correlated to baseline hct le-
vels (p = 0.005)
Table I shows data of all three procedures. No significant
differences were found in the real Qb reached in the three
procedures or in pre-dialysis hematocrit values. Infusion vo-
lume was significantly higher in OL-S-HDF than in OL-P-
HDF. Hemoconcentration (%HC) was more important in
OL-P-HDF than in OL-S-HDF, in which it was in turn higher
than in HD-HF.
No differences were found in Kt (ionic dialysance), Kt/V,
and urea and creatinine clearance rates between the three pro-
cedures, while the clearance rates of B2-microglobulin and
myoglobin were significantly greater for both OL-P-HDF and
OL-S-HDF as compared to HD-HF (p < 0.000). There were
no differences between both HDF procedures (table II).
A direct correlation existed between TMP and PFP during
the session in all procedures (p < 0.05), with a TMP pressure
of 145 mmHg corresponding to a PFP of 395 mmHg. Both
pressures gradually increased towards the end in OL-P-HDF
(figs. 3 and 4). Hourly PFP was found to have a positive co-
rrelation with baseline serum albumin levels (p < 0.03), Hct
values (p < 0.01), and percent hemoconcentration in the pa-
tient at end of dialysis (p < 0.01), this finding was not demos-
trated for TMP. Clearance rate of β2-microglobulin and myo-
globin had an inverse correlation with TMP and PFP (p =
0.003 and 0.01).
No clinical complications occurred in any of the sessions
studied. Only the presence of some clotted capillary at the end
of the OL-P-HDF sessions required an increase in heparin
dose in this procedure.
DISCUSSION
OL-HDF is the most complete clinical hemodialysis proce-
dure currently available.19The postdilutional modality
achieves the best performance in terms of clearance of ure-
mic toxins.14To achieve adequate results with this modality,
ultrafiltrations higher than 20 L should be achieved.9In pa-
tients with an optimal vascular access, blood flow rates hig-
her than 400 mL/min may be achieved, which would allow
for reaching that volume in about 4 hours, maintaining a
25% filtration fraction.
As shown by the study results, clearance and removal of
small molecules such as urea and creatinine are similar in
HD-HF and OL-HDF procedures. In some optimal cases with
low filtration fractions and not very high hematocrit values,
up to a 10% increase may be achieved.
J. Kanter et al. Hemodiafiltración en línea secuencial
originals
Table I. Characteristics of dialysis sessions
HD-HFOL-P-HDFOL-S-HDFp
Effective Qb (mL/min)381 ± 34 373 ± 27 370 ± 32NS
Infusion rate (mL/min)0Post 95 ± 4
Post 99 ± 11
Pre 148 ± 18
NS
Total UF vol (L/sesión) NA23.4 ± 3
14.7 ± 5 en Post
17 ± 6 en Pre
0.000
Hct (%)34.7 ± 3 35 ± 535.4 ± 4 NS
% HC 15 ± 6 38 ± 2221 ± 90.003*
Qb:actual blood flow. Post: postdilution. Pre: predilution. Total UF vol: total ultrafiltrate volumen (infusion fluid + ultrafiltrate). Hct: hematocrit. % HC: percent hemocon-
centration at end of dialysis. ([Post-dialysis Hct x 100)/Pre-dialysis Hct]-100). HD-HF: High-flux hemodialysis. OL-P-HDF: On-line post-dilutional hemodiafiltration. OL-S-HDF:
On-line sequential hemodiafiltration. NS: not significant. NA: not applicable. *Significant differences between the three procedures.
Table II. Clearance rate of small and medium-sized molecules and Kt/V during dialysis
HD-HFOL-P-HDF OL-S-HDFp
Urea 77 ± 6% 79 ± 5% 80 ± 8% NS
Creatinine68 ± 8% 72 ± 6% 71 ± 8%NS
B2-M 61 ± 7%75 ± 9% 77 ± 5%0.000*/**
Myoglobin 12 ± 15%42 ± 14%33 ± 18% 0.000*/**
Kt/V 1.6 ± 0.11.6 ± 0.21.6 ± 0.3 NS
HD-HF: high-flux hemodialysis. OL-P-HDF: on-line post-dilutional hemodiafiltration. OL-S-HDF: on-line sequential hemodiafiltration. B2-M: B2-microglobulin. Kt/V: dialysis
dose. NS: not significant.
* Comparing both OL-HDF procedures to high-flux HD.
** No significant differences were seen between OL-P-HDF and OL-S-HDF.

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Anyway, these procedures are not intended to increase cle-
arance of small molecules, but that of medium and big mole-
cules, and an up to 70% increase was indeed seen in the clea-
rance rates of B2-microglobulin and myoglobin with
OL-HDF procedures. It should be emphasized that the dialy-
zer used in this study achieves in itself a significant level of
B2-microglobulin removal in hemodialysis because by retro-
filtration causes a true internal OL-HDF.
The number of patients with vascular access and high
blood flow rates are now almost a minority. With theoreti-
cal blood flow rates of approximately 300 mL/min it is
very difficult to achieve 20 L of ultrafiltration in a stan-
dard time of four hours. When an attempt is made to incre-
ase postdilutional infusion to 100 mL/min, multiple tech-
nical problems occur, including TMP elevation, partial or
total clotting of the system, and a decreased dialytic per-
formance. In our study, these problems were detected and
related better with PFP than with TMP though, as pre-
viously stated, these two pressures are significantly rela-
ted. Factors contributing to the occurrence of these pro-
blems include high hematocrit values, hyperproteinemia,
and hyperlipidemia. On the other hand, if an attempt is
made to increase pump flow, we may contribute to the oc-
currence of complications such as a marked decrease in ar-
terial line pressure or, which is the same thing, a decrease
in the real Qb/theoretical Qb ratio and recirculation of vascu-
lar access.
In our study, the factor correlating best to PFP increase was
hematocrit and progressive hemoconcentration during dialy-
sis. PFP was also related to baseline albuminemia. PFP some-
times reached levels higher than 700 mmHg. In future OL-
HDF machines it would be helpful to have a pressure gauge
to measure PFP, which is sometimes more useful than TMP.
While many of our patients have high hematocrit values and
normal albumin levels, if a 25% filtration fraction is respected
no clinical complications occur in OL-P-HDF, as shown in
our study.
In some cases where PFPand TMPare markedly increased,
a greater interference probably exists between both types of
transport, with a decrease in diffusive transport leading to a
decreased clearance of small molecules. This phenomenon
was documented in this study also for medium-sized molecu-
les such as B2-microglobulin and myoglobin, when clearance
rates were inversely related to PFP and TMP. The increase in
protein layer in the capillary membrane when a high filtration
fraction was applied would explain this phenomenon.
OL-S-HDF was shown to be better than HD-HF but similar
to OL-P-HDF for removing medium-sized molecules. The se-
quential procedure would thus be similar but not superior to
the postdilutional procedure, and would therefore not be re-
commended for stable patients and with optimal Qbs. There
are, however, patients with limited Qbs (< 300 mL/min) who
do not reach the desired 20 L in the scheduled OL-P-HDF
time. Though this study included patients with relatively limi-
ted Qbs (mean Qb of 370 mL/min and only 31% of patients
with Qb < 350 mL/min), we think that in patients with Qb <
300 mL/min, OL-S-HDF could be a therapeutic alternative to
achieve higher volumes with similar clearances.
When switching from postdilutional to predilutional infu-
sion, the UF-infusion rate was increased by 50%, but we
think that to achieve a better performance in patients with li-
mited Qbs such rate could be further increased, even doubled,
with no complications. It should be noted that the predilutio-
nal system does not involve an increased use of dialysis fluid,
though compensated systems adjusting fluid to blood flow
currently exist.
From the technical viewpoint, change in the infusion site is
simple and does not require any accessory, so that it does not
involve any additional cost. Based on the foregoing, we think
that OL-S-HDF could be a useful hemodialysis procedure in
J. Kanter et al. Hemodiafiltración en línea secuencial
originals
Figure 3. Correlation between trans-
membrane pressure (TMP) and pre-
filter pressure (PFP) in the on-line
postdilutional hemodiafiltration (OL-
P-HDF) procedure. Values are given
in mmHg.
300.00
250.00
200.00
150.00
100.00
50.00
0.00
TMP mmHg
100.00 200.00300.00 400.00500.00600.00 700.00
PFP mmHg
R Sq Linear = 0.145
Correlation between TMP and PFP in OL-P-HDF