Advances in Hemodiafiltration - Ed by Ayman Karkar

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Advances in Hemodiafiltration
Edited by Ayman Karkar
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Advances in Hemodiafiltration
Edited by Ayman Karkar
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Contents
Preface
Chapter 1 Advances in Hemodiafiltration - Introductory Chapter
by Ayman Karkar
Chapter 2 Principles of Haemodiafiltration: Rationale for Improved

Patients’ Survival
by Goran Imamović, Bernard Canaud, Nusret Mehmedović and Cäcilia
Scholz
Chapter 3 Fluid Convection, Generation and Reinfusion in

Haemodiafiltration
by Emily J. See, Carmel M. Hawley, John WM. Agar and David W. Johnson
Chapter 4 The Effect of Convective Dialytic Modalities on Arterial

Stiffness in End-Stage Renal Disease Patients
by Panagiotis I. Georgianos, Evangelia Dounousi, Theodoros Eleftheriadis
and Vassilios Liakopoulos
Chapter 5 Effectiveness of Ultrafiltration in Patients with Congestive

Heart Failure
by Luai Alhazmi, Abdulelah Nuqali, Ankush Moza and Mujeeb Sheikh
Chapter 6 Update on Clinical Evidence Supporting Hemodiafiltration

by Bernard Canaud, Aileen Grassmann, Laura Scatizzi and Daniele Marcelli
Chapter 7 Home Haemodialysis and Haemodiafiltration

by Sandip Mitra and Kunaal Kharbanda
Chapter 8 Quality of Life on Online Hemodiafiltration (HDF)

by Samir H. Almueilo
Chapter 9 Cost-Effectiveness of Online Hemodiafiltration

by Khalid AlSaran and Khalid Mirza
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Preface
Hemodiafiltration (HDF) is an advanced renal replacement

therapy that can reduce morbidity and mortality and improve the
quality of life of dialysis patients.
This special edition of the Advances in Hemodiafiltration book is
empowered with several well-established and experienced
authors, who have written clear and informative chapters. The
book covers basic physiologic principles of HDF and its
requirements, implementation, and achievement of best possible
clinical outcomes and includes results of published randomized
controlled clinical trials.
Advances in Hemodiafiltration can be considered as a practical
guide to daily practice and a reference for medical and nursing
staff involved in taking care of dialysis patients.
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Chapter 1
Introductory Chapter
Ayman Karkar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/64607
Conventional hemodialysis (CHD) treatment is a basic renal replacement therapy (RRT) that
has been serving and supporting the life of patients with end-stage renal disease (ESRD) for
many years. The capabilities of this modality, which is based on the physiologic principle of
diffusion, are however limited. In reality, CHD can remove excess fluids but with some difficulty
in maintaining hemodynamic stability and can only clear small-size uremic toxins of less than
500 Da such as urea and creatinine but not larger-size uremic toxins of more than 500 Da. These
include middle molecules such as β2-microglobulin and protein-bound molecules such as
indoxyl sulfate and p-cresol, where their accumulation in the blood can lead to hemodialysis-
related amyloidosis and endothelial inflammation and toxicity, respectively. This may explain,
at least in part, the high incidence of morbidity and mortality in patients treated with CHD.
Furthermore, the intradialytic complications and post-dialysis tiredness, fatigue, and exhaus‐
tion have negatively influenced the quality of life of dialysis patients.
The recent technical advances in dialysis machine specifications, production of ultrapure water
by modern water treatment system, innovation of synthetic biocompatible high-cut-off
membranes, achievement of scientific knowledge in implementing the other physiologic
principle of convection, and combining diffusion with convection have all revolutionized the
dialysis technique. For example, the modality of hemofiltration (HF), which is based on
convection, is capable of removing larger-size molecules of more than 500 Da, whereas the
modality of hemodiafiltration (HDF), which combines diffusion and convection, is capable of
removing small- and larger-size uremic toxins. In addition, both of these techniques provide
more hemodynamic stability, which is more evident with online HDF. Over many years, multiple
observational and randomized clinical trials showed plenty of clinical benefits of online HDF,
which had significant impact on morbidity and mortality rates. Since the establishment and
implementation of online HDF, a significant experience and knowledge have been gained in
ways of its application and achievement of beneficial clinical results (Figure 1).
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2 Advances in Hemodiafiltration
Figure 1. Major milestones in the development of online HDF.
The Advances in Hemodiafiltration book has been specifically designed to describe and demon‐
strate the treatment modality of HDF from its basic concepts to the most recent advances in
the techniques of its implementation. Under specific titles of specially created chapters, this
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Introductory Chapter 3
http://dx.doi.org/10.5772/64607
book covers principles of HDF, generation of ultrapure water, fluid convection and reinfusion,
factors affecting convective dose, dialysis machine-dependent technical factors, prescription
of HDF, performance and effectiveness of HDF, clinical benefits including results of major
randomized clinical trials, effects of online HDF on arterial stiffness and heart failure, quality
of life of patients on HDF, cost-effectiveness of HDF, and applicability of HDF at home.
Author details
Karkar Ayman
Address all correspondence to: aymankarkar@yahoo.com
Ministry of Health, Riyadh, Saudi Arabia

Chapter 2
Principles of Haemodiafiltration: Rationale for Improved

Patients’ Survival
Goran Imamović, Bernard Canaud,

Nusret Mehmedović and Cäcilia Scholz
http://dx.doi.org/10.5772/63067
Abstract
Haemodiafiltration (HDF) is a renal replacement modality that combines diffusion and
enhanced convection in order to remove small- and middle-molecular-weight com‐
pounds, respectively. They are removed along solvent drag effect of ultrafiltration through
increased transmembrane pressure (TMP), whereas the replacement solution is infused
intravenously at equal amount minus the desired fluid volume removal for achieving dry
weight. Limiting factors for high-volume on-line haemodiafiltration (HV oHDF) are blood
flow and viscosity (haematocrit, protocrit), filter performance and technical features of
HDF monitor. Most recent advanced technology of dynamic analysis of pressure pulses
along the blood flow pathway in the dialyser has enabled optimal ultrafiltration flow
performances. HV oHDF offers today the best compromise of cardioprotective option by
reducing cardiovascular risk factors in end-stage kidney disease patients. Recent
randomised controlled trials (RCTs), individual participant data meta-analyses and a
number of observational studies have shown the evidence of survival advantage of HDF
over conventional haemodialysis (HD). The convective volume has become the key
quantifier for HV oHDF as the measure of dialysis dose. Its cut-off values for better survival
have been recognised, but the research is still needed in the years to come to set the required
optimal volumes tailored to individual patients’ needs.
Keywords: haemodialysis, haemodiafiltration, convection, ultrafiltration, mortality
1. Introduction
The uremic syndrome is characterised by an accumulation of uremic toxins due to inadequate

kidney function. There have been more than 90 compounds considered to be uremic toxins listed
by the European Uremic Toxin Work Group. Sixty-eight have a molecular weight less than
500 Da, 10 have a molecular weight between 500 and 12,000 Da and 12 exceed 12,000 Da. Twenty-
five solutes (28%) are protein bound [1]. These figures are further increasing with the adop‐
tion of new knowledge and technology of uremic toxins detection.
The clearance of solutes during conventional haemodialysis (HD) depends on their size and
the concentration gradient across the dialysis membrane. Solutes weighing less than 500 Da
are considered low-molecular-weight solutes and they are removed by passive diffusion down
a favourable concentration gradient. Urea is considered a marker of such toxins. Its clearance,
as measured by Kt/Vurea, correlates with patient morbidity [2] showing the evidence that such
toxins contribute to the uremic syndrome.
However, despite improvements in technology and patient care, the mortality rate of patients
on maintenance dialysis remains high, at approximately 15–20% per year [3]. As specified in
the United States Renal Data System report, the expected remaining life span after the initiation
of renal replacement therapy was eight years for dialysis patients aged 40–44 and 4.5 years for
those 60–64 years of age. In general population the ranges of the expected remaining life span
at specified ages are 30–40 years and 17–22 years, respectively. The values in older dialysis
patients are only slightly better than those in patients with lung cancer [4]. Therefore, there is
an obvious need to change the practices and to attempt to approach the problem differently.
2. Historic background
In an attempt to reduce mortality, it was postulated in 1983 that a higher Kt/V than commonly
prescribed during conventional short dialysis may increase survival among patients under‐
going renal replacement therapies [5]. However, the hemodialysis (HEMO) study failed to
show a positive effect on patient survival when dialysis dose per haemodialysis session was
increased above the current K/DOQI recommendations [6]. Possible explanation for this
unfavourable outcome could be in the kinetics of urea removal which is representative of small
solutes, but not of larger sized molecules such as middle molecules, large-molecular-weight
proteins or protein-bound solutes, thereby making Kt/V misleading. Clearance of urea
accounts for only one-sixth of physiological clearance [1]. In addition, several shortcomings
are associated with short dialysis schedules that are not captured by Kt/V index such as
extracellular fluid volume control, phosphate control and adequate removal of middle and
larger uremic molecules compounds.
Beta-2 microglobulin levels are associated with the development of dialysis-related amyloi‐
dosis and possibly reduced survival [7]. It seems likely that beta-2 microglobulin is a marker
for overall middle-molecule clearance, including more toxic and as yet unidentified uremic
compounds [8–11]. Those solutes are better removed by high-flux membranes compared to
low-flux membranes due to their more porous characteristics with increased permeability.
Whether survival differs upon exposure to randomly assigned high- or low-flux membranes
was also evaluated in the HEMO study [6]. No difference was observed. The same result was
Principles of Haemodiafiltration: Rationale for Improved Patients’ Survival 7
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obtained in the Membrane Permeability Outcome study, in which patients were also randomly
assigned to high- or low-flux dialysis membranes [12].
In an attempt to improve patients’ outcomes, alternative renal replacement therapies have

been developed, since removal by diffusion becomes less efficient as the molecular weight of
a solute increases. Therefore, the need to mimic the kidney function seems to become manda‐
tory in order to enhance middle-molecule removal because the diffusion in the tubules and
loop of Henle follows filtration in glomerulus, which is the principle of convection (Figure 1).
Figure 1. Mimicking native kidney function to enhance middle-molecule removal.
Haemofiltration (HF) is the treatment modality that employs convection in order to facilitate
removal of larger molecular weight solutes while using high-flux dialysers only. In convection
the small- and large-molecular-weight solutes are removed in the ultrafiltrate by solvent drag.
Although HF is effective in the removal of the larger molecular weight solutes, it is less effective
in the removal of small molecules as it is restricted by the magnitude of the ultrafiltration
volume achievable. Haemodiafiltration (HDF) is the treatment modality that combines
diffusion and enhanced convection in order to facilitate removal of small-molecular-weight
solutes. Moreover, small-molecule removal is further increased with the use of high-volume
on-line HDF (HV oHDF) (see section “Towards more cardioprotective renal replacement
therapy”) and can be higher than haemodialysis, depending upon the volume of the
replacement solution [13].
The ratio between treatment techniques, processes and molecular weights of the solutes is
shown in Figure 2.
Figure 2. The ratio between treatment techniques, processes and molecular weights of solutes. HD, haemodialysis;
HDF, haemodiafiltration; HF, haemofiltration; KoA, mass transfer area coefficient; QB, blood flow; tHD, duration of HD
session; SC, sieving coefficient (the proportion of a substance to be removed for a particular filter).
The utilization of convective therapies has been variable. Between 1998 and 2001, about 12%
of patients were on HDF in the European countries participating in the Dialysis Outcome and
Practice Patterns Study (DOPPS) study [14].
There have not been too many studies to compare the patients’ survival between convective
modalities and high-flux HD. One of them was Italian MAMHEBI study, which was a
randomised controlled trial (RCT). Significantly higher three-year survival was noted with HF
(68% versus 52%) [15]. Dialysis Outcome and Practice Patterns Study (DOPPS) was prospective
observational study which showed better survival with HDF, but it compared high-efficiency
HDF with composite predictor of high- and low-flux haemodialysis [14]. Vilar et al. conducted
retrospective cohort study and showed better survival with on-line HDF than with high-flux
haemodialysis [16], as well as Imamović et al. in incident patients’ population [17], but the
latter three were epidemiological studies and RCT to show survival benefit of HDF over
conventional HD was still missing.
3. Technological principles of haemodiafiltration
Ultrafiltrate volume, derived from QUF times treatment time (Figure 3), is removed by the
dialysis machine through increased transmembrane pressure (TMP), whereas the replacement
solution is infused intravenously at equal volume minus the desired fluid volume removal to
preserve extracellular fluid balance and isovolemic state. The replaced solution represents
substitution volume, whereas convective volume represents the sum of substitution volume and
desired fluid volume removal during the dialysis session.
Filtration fraction (FF) (proportion of ultrafiltration volume obtained compared with total
blood volume processed during the HD session) was traditionally supposed to be 25%
(Figure 3).
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Figure 3. Filtration fraction. QB, blood flow rate; QUF, ultrafiltration flow rate.
3.1. Dilution modes
The fluid can be substituted either after the dialyser as the reference mode (post-dilution mode)
or before the dialyser (pre-dilution mode) (Figure 4), or both (mixed dilution mode).
Figure 4. Dilution modes in haemodiafiltration; HDF, haemodiafiltration.
Choice on which dilution mode to apply depends on patient haemorheology and clinical
performance (Table 1).
Post-dilution HDF Pre-dilution HDF Mixed-dilution HDF

Pros Pros Pros
High solute clearance and removal Haemodilution Avoids the drawbacks

of post- and pre-modes
Reduced consumption of substitution volume Decreased viscosity and oncotic Cons

pressure
Post-dilution HDF Pre-dilution HDF Mixed-dilution HDF

Cons Reduced fibres and membrane Requires specific
fouling hardware equipment
and software
Haemoconcentration Preserved hydraulic

and solute membrane
permeability
Increased viscosity and oncotic pressure Reduced membrane stress
Fibres and membrane fouling Cons
Reduced hydraulic and solute membrane Reduced solute clearance

permeability and removal
Increased transmembrane pressure Increased consumption of

substitution volume
Reduced sieving coefficient
Fibre clotting
Potential alarms
Increasing membrane stress
Potential albumin leakage
HDF – Haemodiafiltration
Table 1. Pros and cons of dilution modes.
4. Water for dialysis
Possible pyrogenic reactions were considerable threat to patients on HDF since the risk of
microbiological contamination with high substitution volumes was increased. Besides, costs
were greater with increased substitution volumes used as well as with storage bags for them.
Therefore, the need for the production of high purity substitution fluid at lower cost was a
challenge, not only because of threatening pyrogenic reactions and financial constraints but
also because of higher risk of accelerated atherosclerosis and malnutrition due to ongoing low-
grade inflammation [18]. Therefore, the American Association for the Advancement of Medical
Instrumentation set the microbiological standards for water for dialysis at <200 colony-forming
units (CFU) and <0.5 endotoxin units (EU)/ml. The European Pharmacopoeia was more
stringent with <100 CFU and <0.25 EU/ml. Eventually, <0.1 CFU and <0.03 EU/ml were adopted
for a solution to be considered “ultra-pure” and it is now widely used even for conventional
haemodialysis [19].
“On-line” fluid production has enabled the concept of on-line HDF (oHDF). It facilitates the
provision of an unlimited volume of sterile, non-pyrogenic substitution fluid not requiring
storage, which is an efficient approach to prevent bacterial contamination and growth at a cost
close to that of dialysate for conventional haemodialysis [20, 21]. The first step of the process
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includes the filtration of the water after it is produced using the reverse osmosis technique.
The water is then used for the production of dialysate. This step has also been adopted in
several haemodialysis machines to produce dialysate of improved purity. The second step
includes further filtration of the dialysate. Finally, a third filtration by a disposable microfilter
completes the creation of the substitution solution. The disposable microfilter is replaced at
the end of the dialysis session. The dialysate prior to the last filtration is used for the diffusive
element of HDF. The purity achieved using this approach has been repeatedly confirmed [21,
22] (Figure 5).
Figure 5. One of the examples of water treatment system in the dialysis centre in Hemodialysis Unit of Lapeyronie
Hospital in Montpellier (France) with microfilters depicted plus two microfilters within HDF machines (not depicted)
showing the water for dialysis passing through HDF machines. The amount used ends up in the sewage; RO, reverse
osmosis; HDF, haemodiafiltration.
So, an additional step to ensure full safety of dialysis and substitution fluids is to implement
two sterilising ultrafilters built in within HDF machines on the path after the dialysate was
prepared. They are disinfected regularly with the HDF machine and are replaced after a certain
time of use as defined by manufacturer.
From an economic perspective, the added cost of the ultrafilters used to prepare the substitu‐
tion solution has been nullified because of growing tendency of using ultra-pure dialysate even
in conventional haemodialysis, thereby leaving the only difference in cost in the amount of
water consumed per treatment. Above all, the remaining cost has been balanced by the
biochemical and clinical benefits of HDF [20].
5. Rational for improved patients’ survival on high-volume

haemodiafiltration
The European Dialysis Working Group (EUDIAL) performed a systematic review and meta-
analysis of randomised controlled trials on haemodiafiltration in 2014 and found the beneficial
effect of post-dilution oHDF over HD in reducing all-cause and cardiovascular mortality

(pooled RR-0.84; 95% CI, 0.73–0.96) and recommended wide acceptance of this treatment
modality [23]. EUDIAL recommends the adoption of effective convective volume as a key
quantifier for HDF. Providing time is constant and anticoagulation is adequate, limiting factors
for high-volume haemodiafiltration (i.e. the amount of substitution fluid produced) are blood
viscosity, filter performance and blood flow rate.
5.1. Limiting factors for high-volume on-line haemodiafiltration
5.1.1. Blood viscosity as a limiting factor for high-volume on-line haemodiafiltration

It is not only that FF from Figure 3 accounts for the proportion of UF volume in the blood
volume, but in reality, FF is even higher, because UF volume comes from plasma water, not
from the whole blood. Figure 6 shows the example of a patient with FF of 0.30 (UF rate 120 ml/
min and blood flow rate 400 ml/min). However, if the haematocrit of this patient is 30%, it
means that his/her plasma water flow is only 280 ml/min, which increases FF to 0.43 (Figure 6).
Figure 6. Increased filtration fraction in plasma water.
Consequently, too much convective volume increases the risk of haemoconcentration, thereby
compromising the fine balance between the two by interfering with membrane permeability
both on hydraulic and solute fluxes.
5.1.2. Filter performance as a limiting factor for high-volume on-line haemodiafiltration

The efficiency of HDF might be improved by increasing the size of the surface area of the
membranes (provided optimal blood flow was achieved), so that high efficiency might be
achieved with a surface area of 2.2 m2, as opposed to the standard surface of 1.4 m2, thereby
allowing much more substitution fluid to be replaced at a rate of 120 ml/min in post-dilution
mode, in contrast to 60 ml/min which was achieved with standard surface [24].
The size of a membrane pore dictates the sieving coefficient (SC) of a substance to be removed.
The higher the sc, the higher the UF and clearance of a particular solute. The reduction ratios
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of beta-2 microglobulin with low-flux, high-flux haemodialysis and HDF are 20, 60 and 75%
per session, respectively [25]. The EUDIAL group, nominated by the European Renal Associ‐
ation – European Dialysis and Transplant Association (ERA–EDTA), set the SC for beta-2
microglobulin at minimum of 0.6 [26] in high-flux filters (which are mandatory with HDF).
However, in order to achieve the optimal outcome for the patients, filters are nowadays
designed with even higher SC for beta-2 microglobulin of 0.8 for efficient elimination, but still
retention of albumin (Figure 7).
Figure 7. Solute membrane permeability: higher sieving coefficient for beta-2 microglobulin.
Correlation between ultrafiltered volume and beta-2 microglobulin elimination is linear, as

specified by Lornoy et al. (Figure 8) [27].
Figure 8. A linear function of ultrafiltered volume and beta-2 microglobulin elimination. HDF, haemodiafiltration
(with permission of authors).
Enhanced clearances of middle molecules such as beta-2 microglobulin [28] and phosphate
[29] and other small molecules, such as homocysteine and complement D factor [30] are the
main biochemical benefits of convective-based treatment over conventional HD.
5.1.3. Blood flow as a limiting factor for high-volume haemodiafiltration
On-line monitoring of blood parameters allows adjustment of ultrafiltration rate to identify

the patient-specific exchange rate possible at any given point in time while enabling haemo‐
dynamic stability. The substitution rate is adjusted to blood flow rate, thereby controlling
haemoconcentration, whereas blood flow rate is adjusted to dialysis flow rate to control
diffusion [31] (as for the diffusion component on-line clearance monitoring is used and the
goal is to achieve spKt/V of 1.4). Therefore, if the blood flow rate drops from 100 L to 70 L per
session, and the total UF volume remains at 25 L, the filtration fraction rises from 25% to 37%
(Figure 9), which may generate a lot of difficulty during the session, lot of alarms and lot of
critical TMP notifications, and the session may not end with a volume that was targeted.
Figure 9. The impact of blood flow on filtration fraction.

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6. Towards more cardioprotective renal replacement therapy
In the very beginning of oHDF era, both the physician and the nurse in charge were supposed
to do manual interventions in an attempt to prescribe and to keep the desired convective
volume for each individual patient, respectively. The physician was able to do manual
calculation based on the formula that included optimal blood flow rate, desired ultrafiltration
rate to compensate for interdialytic weight gain, haematocrit, total proteins and filter per‐
formance, which was frequently producing alarms indicating threatening haemoconcentration
and possible membrane fouling due to an excessive ultrafiltration rate. Therefore, the nurse
had to carefully monitor the TMP (indicator of threatening problems) and react during the
session in three possible ways in order to prevent TMP from reaching critical level: (a) rinse
the dialyser with substitution fluid or normal saline, (b) decrease the UF rate or (c) switch to
conventional haemodialysis. The latter two interventions were reducing the anticipated
convective volume in the dialysis prescription, whereas the former intervention was only
temporarily fixing the problem.
The advanced technology of automatic adaptation by the built-in software AutoSub®,

Fresenius Medical Care or Ultracontrol®, Baxter, was later developed in order to achieve
alarm-free setting and to avoid the related problems, so that no manual calculation was needed
any more by the physician in charge, but yet not all parameters with impact on flow conditions
and blood viscosity were considered in formula. Therefore a nurse still had to do manual
interventions because warning notification used to be received by the built-in software in order
to opt for (a) ignoring the warning; (b) accepting the warning and letting the software reduce
the UF at a new recommended rate in order to be within a safe range and prevent TMP from
reaching critical level, albeit reducing the expected convective volume defined at the beginning
of the session; or (c) turning off software monitoring. Besides, the nurse can always turn off
the substitution pump and switch to HD.
Finally, with the development of the new technology for automatic ultrafiltration control in
the dialyser, alarm-free maximisation of substitution volumes has been achieved, which is
based not only on information about conditions across the membrane but also along the blood
flow pathway in the dialyser, so that calculation of substitution volume based on the param‐
eters specified above has become obsolete [32]. This was shown in a crossover study of patients
treated during 240-min sessions on the same day with three different blood flow rates (QB300,
QB350 and QB380) and switched after two consecutive weeks from conventional HDF to this
new technology. The convective volumes were 24.8 ± 3.1, 27.8 ± 3.0, 28.8 ± 2.4 and 23.9 ± 1.2,
27.2 ± 1.9, 28.5 ± 2.1, respectively (p > 0.05), to provide the evidence that the biological markers
specified above are not needed for each and every haemodialysis session in order to achieve
optimisation of the procedure [33].
This innovative technology is known as AutoSub plus mode [32] (Figure 10).
Figure 10. Switch from manual to automatic mode. TMP, transmembrane pressure.
Figure 10 shows the red line in manual mode favouring increasing convective volume and
efficacy, whereas yellow line represents safety and favours TMP limitations, which means that
TMP increases over time during the dialysis session as convective volume increases. However,
in automatic mode on the right side of Figure 10, the optimisation of substitution volume has
been achieved by setting the safety target range so that the machine itself sets the safe TMP
target range and continuously regulates the optimal UF rate at an optimal time throughout
the session in order to keep the TMP in optimal range to prevent haemoconcentration and
membrane complications specified above (Table 1). However, the nurse can still switch to
manual mode or even to conventional HD should extraordinary conditions prevent high-
volume oHDF (such as special rheologic properties of a patient's blood) [32]. Owing to
continuous analysis of haemorheological conditions throughout the dialysis session, contin‐
uous adaptation of UF flow takes place (Figure 11).
Figure 11. Continuous adaptation of ultrafiltration flow in AutoSub plus mode while keeping UF loss constant; red
line within the dialyser illustrates dynamic analysis of pressure pulses along the blood flow pathway; UF, ultrafiltrate
to be lost during the dialysis session; HDF, haemodiafiltration; FF, filtration fraction; QUF, ultrafiltrate flow; QB, blood
flow.
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For this improvement sieving coefficient for beta-2 microglobulin was further increased to 0.9
in a new series of Cordiax© dialysers (Figure 12).
Figure 12. New series of Cordiax© dialysers with sieving coefficient for beta-2 microglobulin of 0.9 achieved by wid‐
ened pore diameter which permits better molecule removal, but still retention of albumin (simplified graph based on
manufacturer’s internal data).
The result is the improved removal of middle molecules (while ensuring the retention of
albumin) due to increased filtration fraction, thereby generating increased substitution fluid
volumes, with no need to even keep the high blood flow rate, so that equally adequate dialysis
can also be delivered to patients with suboptimal blood flow rates (such as inpatients with
poor vascular access or inadequate needle size). This technology introduced the concept of
high-volume oHDF with substitution volumes >20 L as well as the related concept of cardio‐
protective haemodialysis due to its beneficial effects of cardiovascular system. It introduced
the new era of high-volume cardioprotective renal replacement therapy as the major clinical
effect of high-volume oHDF.
7. Clinical effects of high-volume oHDF
The main clinical effects of high-volume oHDF include haemodynamic stability [34, 35],
possibly improved quality of life [30], a delay in the development of dialysis-related amyloi‐
dosis [36], improvement in anaemia management [17], plasma lipid profiles [37] and inflam‐
mation [37].
Haemodynamic stability is maintained by salt loading via substitution fluid administration
[38]. A higher predialysis plasma sodium concentration in patients with higher frequency of
oHDF was reported, thus suggesting reduced sodium removal [39]. Haemodynamic stability
is maintained by decreasing core body temperature as a result of the infusion of large amounts
of fluid at a lower temperature, leading to vasoconstriction [34]. Imamović et al. demonstrated
reduction in both erythropoietin (EPO) consumption and EPO resistance index in patients on
HV oHDF compared to high-flux HD [17], which reveals the evidence of an increased
haemodynamic stability due to improved anaemia management [40].
8. The impact of substitution volume in haemodiafiltration on patients’

survival
In the era of convective treatment modalities employed in oHDF, the substitution volume
appears to be critical for patient survival in prevalent patients [14, 41–43]. The Dialysis
Outcomes and Practice Patterns Study (DOPPS) showed better survival of prevalent patients
with high-volume HDF defined as having a substitution fluid volume of >15 L compared to
low-flux HD (RR 0.65) [14]. The Turkish RCT and the CONTRAST RCT revealed survival
benefits of oHDF over conventional HD in prevalent patients with 17.4 L (RR 0.54) and 21.95 L
(RR 0.61) of substitution and convective volumes, respectively, but only in post hoc analyses
[41, 42]. The first positive RCT in favour of improved survival of oHDF over conventional HD
was the ESHOL study which showed convective volumes cut-offs of 23.1–25.4 L (RR 0.60) and
>25.4 L (RR 0.55) in the intermediate and upper tertiles, respectively, also in post hoc analysis
of prevalent patients’ data [43]. Eventually, the observational Balkan study in incident HD
patients conducted in Bosnia and Herzegovina, Serbia and Slovenia, while using European
Clinical Database (EuCliD®), [17] showed the lowest RR for mortality of 0.29 on high-volume
oHDF compared to high-flux conventional HD. The substitution volume cut-off of 20.4 L was
discriminating between low- and high-volume oHDF, which makes the convective volume at
least in the range of the one achieved in ESHOL study. Consequently, overall negative
correlation may be observed between increasing ultrafiltration volumes and mortality risks in
patients on convective-based treatments in comparison with conventional HD. Figure 13
shows descriptive hazard ratios for mortality based on literature data (not on forest-plot
analysis).
Figure 13. Negative correlation between increasing ultrafiltration volumes and decreasing relative risk of mortality in
patients on haemodiafiltration.
http://dx.doi.org/10.5772/63067
Recently, Canaud et al. aimed at determining optimal convection volume in 2293 international
incident dialysis patients treated for 4 h with oHDF in post-dilution mode. Two-year survival
rate was found to increase at about 55 L of convection volume per week and to stay increased
up to about 75 L/week [44].
9. Conclusions
HV oHDF is a renal replacement treatment modality that is becoming increasingly employed

in haemodialysis units worldwide because of a strong body of evidence of its survival benefit
over conventional haemodialysis. Optimal substitution volume has become the measure of
convective dose, reflecting mainly middle- and large-molecular-weight solutes, and it com‐
pleted former Kt/V that was mainly dedicated to small-molecular-weight solutes. Both dialysis
dose components are intent to act synergistically and provide more precise tools for assessing
dialysis adequacy. More specifically, convective dose should be tailored to individual patients’
needs depending on optimal blood flow rate, rheological blood conditions and the condition
of vascular access. Studies in this field are still needed to set the cut-offs of substitution volumes
to be adjusted based on the residual renal function. An alternative proposal for dialysis dose
is serum beta-2 microglobulin clearance or plasma level determination, but those measure‐
ments are relatively expensive and confounded by calibration differences and variations in the
generation rate. The convective volume must be set for each individual patient and should be
normalised to a body size-related factor as a surrogate for the convective dialysis dose [26],
but given that they varied a lot between the studies, research is still needed to set the required
cut-off values in the years to come [23].
Acknowledgements
The authors would like to thank Dr. Aileen Grassmann, Director Clinical and Epidemiological
Research, Fresenius Medical Care Deutschland GmbH for having the chapter critically
reviewed; Prof. Bernard Canaud and Dipl. Ing. Angelica Kneppel for providing the figures;
and Sanja Kozlik, NephroCare Manager, Bosnia and Herzegovina for covering the publication
fee.
Author details
Goran Imamović1,2*, Bernard Canaud3,4, Nusret Mehmedović5 and Cäcilia Scholz6
*Address all correspondence to: goran.imamovic@fmc-ag.com
1 Fresenius Medical Care, Deutschland GmbH, Germany

2 School of Medicine, University of Tuzla, Tuzla, Bosnia and Herzegovina
3 Centre of Excellence Medical, FMC-EMEA, Bad Homburg, Germany
4 School of Medicine, Montpellier University, Montpellier, France
5 Fresenius Medical Care, Bosnia and Herzegovina GmbH, Bosnia and Herzegovina
6 Fresenius Medical Care, Deutschland GmbH, Germany
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Chapter 3
Fluid Convection, Generation and Reinfusion in

Haemodiafiltration
Emily J. See, Carmel M. Hawley, John WM. Agar and

David W. Johnson
http://dx.doi.org/10.5772/62886
Abstract
Despite widespread use in clinical practice for over 30 years, many questions remain
unanswered regarding fluid convection and reinfusion strategies in haemodiafiltration
(HDF). Randomised controlled trials have failed to consistently demonstrate improved
survival with convective therapies, but a dose-dependent improvement in outcome has
been suggested. The ‘minimum’ and ‘ideal’ volumes of convection are undefined. Online
generation of ultrapure dialysis fluid has allowed unprecedented convection volumes;
however, delivery of fluid directly into the blood circuit requires strict monitoring. The
replacement fluid may be reinfused at multiple points in the circuit. Post-dilution HDF
is highly efficient in terms of solute clearance but is limited by haemoconcentration. Pre-
dilution HDF prolongs filter life but requires significant convection volumes to achieve
adequate solute clearance. Mid-dilution HDF utilises a specific dialyser, which is
associated with additional cost and escalating transmembrane pressure. Mixed-
dilution HDF appears to offer an attractive balance between solute clearance efficiency
and haemoconcentration, however these findings need to be confirmed in large studies.
The majority of trials comparing fluid reinfusion strategies have enrolled small numbers
of patients over brief study periods. It is unclear whether high-quality evidence examining
fluid convection and reinfusion will become available and practice may need to rely on
observational data.
Keywords: convection, online fluid generation, reinfusion, haemodiafiltration, end-

stage renal disease, outcomes, adverse effects, haemodiafiltration methods, haemo‐
dialysis solutions
1. Introduction
With its innovative integration of convective and diffusive techniques, haemodiafiltration (HDF)
enhances solute removal across a broad molecular-weight spectrum, which theoretically may
improve patient outcomes. Solute clearance by convection requires substantial volumes of
ultrafiltration, which in turn necessitates the administration of exogenous fluid replacement.
Whilst this fluid may originate from multiple sources, current practice centres around the online
generation of sterile, ultrapure dialysate which may be reinfused directly into the circulation.
This process requires strict water quality and safety monitoring but enables reinfusion of
unlimited volumes of substitution fluid, traditionally either before (pre-dilution HDF) or after
(post-dilution HDF) the dialyser. In recent years, two novel HDF techniques (mixed- and mid-
dilution HDF) have been developed which permit simultaneous pre- and post-dilution. Both
the optimal ‘dose’ of convection and the ideal site of fluid reinfusion are yet to be determined.
This chapter will discuss the evidence surrounding these topics in contemporary HDF practice.
2. Fluid convection
Convective solute transport occurs due to the sieving of solutes across an open membrane in
the context of large volumes of ultrafiltration. To achieve maximal convective flux, the volume
of ultrafiltration must be optimised. The total volume of ultrafiltration is determined by the
ultrafiltration rate and treatment time and is referred to as the convection volume. This value
is related to, but distinct from, the substitution volume, which is the quantity of replacement
fluid reinfused into the circuit. The difference between the two represents the net fluid removal
during the treatment.
Significant changes in the magnitude of the convection volume have taken place since the
inception of HDF in the 1970s. Classic HDF used an average substitution volume of 9 L per
session, which was primarily limited by cost and logistical issues associated with commercially
produced replacement fluid. This is comparable to the estimated amount of convection that
occurs during high-flux haemodialysis (HD) today. Most recently, innovations in fluid
generation have allowed online production of substitution fluid, which has facilitated
convection volumes of 25–40 L per session (and up to 60 L, depending on the mode). This
advance has revolutionised the practice of HDF and has piqued interest in the modality
worldwide. Importantly, parallel advances in fluid balancing systems have permitted the safe
and accurate regulation of ultrafiltration, even at these exceptionally high volumes.
Recently, EUDIAL has set a minimum convection volume for a treatment to be classified as
HDF. This threshold is equivalent to 20% of the total processed blood volume [1]. For example,
a 4-h treatment with a blood flow rate of 350 ml/min (~84 L/treatment) must have a minimum
convection volume of 17 L. Below this, the treatment would be classified as high-flux HD. In
general, the convection volume in the post-dilution HDF should be between 17 and 27 L per
session [2].
Fluid Convection, Generation and Reinfusion in Haemodiafiltration 27
http://dx.doi.org/10.5772/62886
Due to the obvious impact on solute clearance efficiency, the convection volume must be
standardised according to the site of fluid reinfusion. This corrected value is termed the ef‐
fective convection volume. In post-dilution HDF, the effective convection volume is the same
as the ultrafiltration volume. In mid-dilution HDF, conversion reference tables are provided
by the manufacturer. In pre- and mixed-dilution HDF, the ultrafiltration volume must be
standardised using a dilution factor (DF) [1]. This is calculated using the plasma water flow
rate (Qpw), upstream reinfusion flow rate (Qinf), blood flow rate (Qb), haematocrit (Hct) and
protocrit (Pct) according to the equation:
Q pw
DF =
Q pw + Qinf
Q pw = Qb ´ (1 – Hct ) ´ (1 - 0.016 – Pct )
N .B.(1 - 0.016 - Pct ) is approximated to 0.93.
2.1. Determinants of convection volume
The maximal achieved convection volume is dependent on several patient- and treatment-
related factors, the most important of which are treatment time and blood flow rate (Table
1). Other determinants include the transmembrane pressure gradient (TMP), specific charac‐
teristics of the dialyser (e.g. membrane surface area, UF coefficient, capillary dimensions, bi‐
ocompatibility), haematocrit and serum albumin [3, 4]. The term filtration fraction is used to
describe the ratio between the ultrafiltration rate and the blood flow rate. In post-dilution
HDF, it is limited to <0.3 to avoid complications relating to haemoconcentration, namely
membrane clotting and high TMP.
Increase convection volume High blood flow rate
Long treatment time
High filtration fraction
Large membrane surface area
Biocompatible dialyser
High UF co-efficient
Decrease convection volume Hypoalbuminaemia
Poor vascular access
High haematocrit
Small calibre membrane fibres
Table 1. Determinants of convection volume.

2.2. Effect of convection volume on patient outcome
Whilst an overall survival benefit favouring convective therapies has not been established,
several studies have supported a ‘dose–response’ relationship between convection volume
and survival (Table 2). The Dialysis Outcomes and Practice Patterns Study (DOPPS) first
suggested this effect when it showed a 35% relative risk (RR) reduction in mortality between
HDF with substitution volumes of 15–25 L and low-flux HD [5]. Since then, there have been
three large randomised controlled trials published with similar findings—the CONvective
TRAnsport STudy (CONTRAST) [6], the Turkish HDF study [4] and the Estudio de Supervi‐
vencia de Hemodiafiltración On-Line (ESHOL) study [7]. In the post hoc analyses of the
CONTRAST and the Turkish HDF study, patients with the highest convection volumes were
shown to have a survival benefit [4, 8]. In CONTRAST, this difference was seen in the tertile
of patients treated with convection volumes >21.95 L (hazard ratio (HR) 0.61) and in the Turkish
HDF study, it was seen in patients with a substitution volume >17.4 L (HR 0.54). The ESHOL
study demonstrated a similar dose–response effect in its primary analysis: patients treated
with convection volumes above 23.1 L had improved all-cause and cardiovascular mortality
(HR 0.60) with a further improvement seen at convection volumes >25.4L (HR 0.55) [7]. Further
supporting a dose-dependent effect, a pooled analysis of CONTRAST, the Turkish HDF study,
the ESHOL study and a French HDF study demonstrated a statistically significant reduction
in all-cause mortality in patients receiving the highest convection volumes (24.4–27.4 L)
compared with standard HD [8].
The effect of cumulative convection dose on survival has recently been investigated by a
retrospective observational study of incident HDF patients. They showed an association
between weekly convection volume and survival which began to be apparent at 55 L/week (30
L/week/m2) and plateaued at 70–75 L/week (40–45 L/week/m2) [9]. This is the first paper to
recognise the importance of cumulative treatment dose, taking into account session frequency,
which may be particularly relevant to mortality outcomes.
Substitution volume Convection volume RR or HR (CI)

DOPPS [5] >15 L/session >17.5 L/session 0.65
CONTRAST [6] >19.45 L/session >21.95 L/session 0.61 (0.38–0.98)
TURKISH OL-HDF [4] >17.4 L/session >19.9 L/session 0.54 (0.31–0.93)
ESHOL [7] 20.6–22.9 L/session 23.1–25.4 L/session 0.60 (0.39–0.90)

>22.9 L/session >25.4 L/session 0.55 (0.34–0.84)
Table 2. Volumes required to achieve a reduction in mortality (expressed as RR or HR with confidence interval (CI),
and assuming an average net fluid removal of 2.5 L).
2.3. Assessment of adequate solute clearance
Assessment of HDF adequacy must take into account removal of solutes across all molecular
weights. Specifically, enhanced middle- and large-molecule clearance should not occur at the
expense of inferior small-solute clearance. For practical purposes, small-solute clearance
http://dx.doi.org/10.5772/62886
should be quantified using the same approach as for HD, whether that be calculation of Kt/
Vurea or percentage reduction in urea. Of note, blood samples must be taken upstream of any
fluid reinfusion port to avoid sample dilution. This is especially relevant in the pre-dilution
and mixed-dilution HDF modes where substitution fluid is infused before the dialyser. In
terms of assessing middle-molecule clearance, convective dialysis ‘dose’ appears to be a linear
function of substitution volume so reporting of this value is routinely used [11, 12].
2.4. Consequences of high convection volume
Due to the indiscriminate nature of solute removal by large-volume ultrafiltration, inadvertent

removal of beneficial solutes is unavoidable. The most significant example of this is albumin.
The degree of albumin loss in a HDF treatment is dependent on the membrane type, ultrafil‐
tration volume and TMP. The site of fluid reinfusion is also relevant as a key determinant of
ultrafiltration volume and TMP; the use of post- and mid-dilution HDF may increase the loss
of albumin up to fivefold [12]. Albumin removal can be minimised by profiled filtration modes,
which limit initial filtration, or by regulated TMP control. Fortunately, as described in the
randomised trials and observational studies, albumin loss did not appear to affect nutritional
parameters or serum albumin concentration [4, 6, 9, 10, 13]. It should therefore not limit the
utilisation of HDF or the prescribed convection volume in current practice, but will require
ongoing evaluation in future trials given the lack of robust safety data.
2.5. Individualising convection volume
The requisite ‘dose’ of convection likely varies between individuals. This in turn has theoretical
implications for future trial design and practical implications for HDF prescription. Two
important patient characteristics that should be considered are patient size and residual renal
function [1]. Having an absolute convection volume target for all patients is not logical since
patients vary widely in size, body composition and metabolic rate. Recently, the HDF Pooling
Project Investigators looked at the effect of convection volume on mortality when stratified
convection volumes were standardised according to patient size. The survival advantage for
higher convective dose was maintained after standardising for total body water and body
surface areas, which are surrogate markers of lean body mass, but not for body weight or body
mass index [8]. Other patient factors may also be important in determining optimal convection
volume including age, ethnic background, comorbidity index, diabetic status and dialysis
vintage. The importance of these additional factors is yet to be studied.
3. Substitution fluid
The degree of ultrafiltration that occurs in HDF necessitates reinfusion of large volumes of
replacement fluid into the extracorporeal circuit. This fluid must be sterile and non-pyrogenic
with a biochemical composition similar to plasma water. The replacement fluid may be
obtained in two ways: internal substitution (e.g. internal filtration HDF, push–pull HDF,
double high-flux HDF and paired filtration dialysis) or external substitution (e.g. classic HDF
and online HDF).
3.1. Internal substitution
3.1.1. Internal filtration HDF
Internal filtration HDF uses pressure profiling to take advantage of the substantial volumes of
plasma water that can be filtered across high-flux dialysers. Difference in pressure between
the blood and dialysate compartments results in proximal ultrafiltration followed by distal
backfiltration (Figure 1). Backfiltration of dialysate is analogous to reinfusion of substitution
fluid. Sudden shifts in plasma water may lead to increased rates of haemolysis. Backfiltration
poses an additional risk of biological and endotoxin contamination; however, the use of
dialysis membranes with a high endotoxin retention capacity minimises this risk.
3.1.2. Push–pull HDF
Push–pull HDF involves rapid alternations in ultrafiltration and backfiltration across a single
high-flux dialyser using a double-pump system installed on the effluent line (Figure 1). These
alternations are controlled by fluctuations in pressure that occur due to varying the volume of
the dialysate compartment. Fluid is reinfused along the course of the dialyser, favouring the
blood outlet port where the pressure in the blood compartment is lowest. The convection
volume may be as high as 120 L throughout a standard 4 h treatment [14]. Albumin loss is
significantly lower than In post-dilution HDF due to lower TMP [15]. Intermittent backfiltra‐
Figure 1. Internal filtration HDF and push-pull HDF.

http://dx.doi.org/10.5772/62886
tion removes protein deposition on the blood side of the membrane making this technique also
suitable for extended-hour renal replacement therapy (e.g. nocturnal or continuous HDF).
3.1.3. Double high-flux HDF
Double high-flux HDF consists of two high-flux membranes connected in series and subjected
to high blood and dialysate flow rates (Figure 2). Simultaneous diffusion and convection occur
across the first membrane, whilst backfiltration of sterile dialysate occurs across the second.
Variation in pressure and flow across the two dialysers is controlled by a resistance valve.
Using this system, von Albertini was able to achieve 13 L convection per 2 h treatment and
significant clearances of both small and larger solutes [16].
3.1.4. Paired filtration dialysis
Paired filtration dialysis uses two high-flux membranes connected in series. The first is a
haemofilter with a small surface area, which performs ultrafiltration, and the second is a
haemodialyser which performs diffusion. The substitution fluid is infused between the two.
The main variation of this technique is paired filtration dialysis with endogenous reinfusion.
This is also referred to as haemodiafiltration with endogenous reinfusion (HFR): In HFR,
ultrafiltrate passes through a purifying charcoal/resin filter before being reinfused as substi‐
tution fluid (Figure 2).
Figure 2. Double high-flux HDF and paired filtration dialysis with endogenous reinfusion.
3.1.5. Classic HDF
Classic HDF consists of a single dialyser which performs haemodiafiltration. The convection
volume is replaced with packaged, commercially produced substitution fluid which is
reinfused after the dialyser (Figure 3). This practice is associated with significant expense and
obvious logistic issues [17]. These factors limit the volume of convection and therefore solute
clearance.
Figure 3. Classic HDF.
3.1.6. Online HDF
Online HDF relies on the ability of modern dialysis machines to generate unlimited quantities
of ultrapure dialysis fluid, which can be reinfused directly into the circulation. In this system,
dialysis fluid is prepared by the proportioning of ultrapure water and a concentrated electro‐
lyte solution. This fluid is then used as both dialysate and substitution fluid (Figures 6 and 7).
The integrity of the chemical composition is monitored using conductivity measurements. First
described in the 1970s, the development of online fluid generation has facilitated the evolution
of HDF from low-volume to high-volume practice [18]. It has been commercially available for
over a decade and comes at minimal additional cost compared to high flux HD. This modality
is the most widely utilised HDF technique in contemporary dialysis. It is well established in
http://dx.doi.org/10.5772/62886
Europe and Japan, and is experiencing escalating use in Australia and New Zealand (currently
representing 16% of haemodialysis modalities) [19].
3.2. Biological safety
Since significant quantities of substitution fluid are being reinfused directly into the blood
circuit, strict biological safety is essential. Many countries have specific policies outlining the
technical requirements and water monitoring processes that dialysis units must comply with
to practice HDF. Additionally, international guidelines exist which underpin the minimum
standards for microbiological and chemical quality [20]. These technical requirements include
the use of specific HDF machines and the ability to generate ultrapure water and dialysis fluid
(Table 3). Generation of ultrapure water involves a pre-treatment system (microfiltration,
softeners, activated carbon) followed by two reverse osmosis modules connected in series
(Figure 4). In some water treatment systems, the reverse osmosis modules will be followed by
a storage tank.
Regular water Ultrapure water Ultrapure dialysate

Microbial contamination <100 CFU/ml <0.1 CFU/ml <0.1 CFU/ml
Bacterial endotoxins <0.25 IU/ml <0.03 IU/ml <0.03 IU/ml
Table 3. Water purity definitions.
Figure 4. Conversion of tap water to ultrapure water.
Ultrapure water is converted to ultrapure dialysis fluid by combination with an electrolyte

concentrate. The fluid then undergoes cold sterilisation, a process involving a series of filters
with bacterial and endotoxin retentive properties at intermediate points in the circuit. An
inbuilt infusion pump diverts a proportion of ultrapure dialysate through another safety filter
prior to being directly infused into the patient’s bloodstream as replacement fluid (Figure 5).
Figure 5. Conversion of ultrapure water to ultrapure dialysate.
Beyond the actual production of ultrapure dialysate, frequent disinfection of the water
treatment system and dialysis machine, Thermochemical destruction of the biofilm, regular
change of filters and maintenance of a permanent circulation of water are essential. Microbio‐
logical and endotoxin monitoring must also be carried out.
Several clinical studies have confirmed the safety of online HDF provided that appropriate CE
marked and certified HDF machines are used and the best clinical practices are applied [21].
The three largest RCTs comparing HDF to HD did not demonstrate any higher incidence of
infectious complications using online fluid generation [4, 8, 9].
4. Site of fluid reinfusion
Online HDF modalities are classified according to the location at which the replacement fluid
is administered in the extracorporeal circuit. The replacement fluid has traditionally been
http://dx.doi.org/10.5772/62886
reinfused either before (pre-dilution) or after (post-dilution) the dialyser. Simultaneous pre-
and post-dilution HDF techniques (mixed- and mid-dilution) have gained popularity in recent
years. Each has relative advantages and disadvantages (Table 4). Other novel hybrid modal‐
ities have been proposed including ‘pre-dilution on demand’ and ‘backflush on demand’.
Post-dilution Pre-dilution Mixed-dilution Mid-dilution

Small-solute clearance +++ + +++ ++
Medium solute clearance ++ + +++ +++
Protein-bound solute clearance ++ + +++ ++
Albumin loss ++ + + +++
Filter clotting ++ + + +++
High TMP ++ + + +++
Table 4. Relative advantages and disadvantages of fluid reinfusion site.
4.1. Post-dilution HDF
Post-dilution HDF is regarded as the most efficient form of HDF in terms of solute clearance
and is the most common format used in contemporary clinical practice. By reinfusing fluid
after the dialyser, a continuous concentration gradient is maintained along the entire course
of the dialyser (Figure 6). This approach has been shown to be superior to both high-flux HD
and pre-dilution HDF in terms of small-solute and middle-molecule clearance [11, 22].
The efficiency of solute clearance in this system occurs at the expense of escalating haemo‐
concentration, which increases the risk of filter clotting, membrane pore occlusion and a
subsequent increase in TMP. In extreme cases, red cell damage and protein denaturation may
occur. There is also an increased risk of albumin loss as a result of the high TMP. The potential
for haemoconcentration means that the filtration fraction must be limited which in turn
necessitates a high blood flow rate to achieve adequate convection (typically >350 ml/min).
Therefore, in patients with poor vascular access, inadequate blood flow may compromise the
ability to achieve satisfactory clearances. Similarly, the risk of filter clotting means that patients
with high haematocrit, cryoglobulinemia or gammopathy should be preferentially managed
with pre-dilution or mixed-dilution HDF.
4.2. Pre-dilution HDF
In pre-dilution HDF, the substitution fluid is reinfused before the entry of blood into the
dialyser (Figure 6). This avoids complications relating to haemoconcentration which extends
filter life and lowers TMP. Because of the lower risk of clotting, heparin dose can be minimised
and heparin-free dialysis for high-risk patients is possible [23]. In Japan, where this technique
is used most widely, improvements in shear stress, blood pressure and haematological
parameters (especially neutrophil and lymphocyte function) have also been reported [24, 25].
This same group have described improvements in dialysis-related symptom burden including
itch, restless legs syndrome and insomnia compared to the post-dilution HDF.
Pre-dilution HDF has obvious deleterious effects on the efficiency of solute clearance. The
reduced efficiency of this system means that ultrafiltration rates must be at least twofold higher
than those in post-dilution HDF to achieve equivalent solute clearance. In fact, ultrafiltration
rates of up to 100% of the blood flow rate are often used.
Figure 6. Post-dilution HDF and pre-dilution HDF.
4.3. Mixed-dilution HDF
In mixed-dilution HDF, fluid is simultaneously reinfused both before and after the dialyser in
a ratio that is automatically regulated by the TMP and ultrafiltration feedback (Figure 7). An
internal feedback mechanism maintains the TMP between 250 and 300 mmHg and ensures a
maximum filtration fraction after considering the blood and dialysate flow, internal pressure
and hydraulic permeability of the dialyser. Convection volume tends to be 30–40 L/session.
TMP is calculated according to the pressure measured at four points in the system: blood entry
http://dx.doi.org/10.5772/62886
into the dialyser entry (Pblood in), blood exit from the dialyser (Pblood out), dialysate entry into the
dialyser (Pdialysate in) and dialysate exit into the dialyser (Pdialysate out).
Figure 7. Representation of the mixed-dilution and mid-dilution HDF.
TMP = 0.5 ´ [( Pblood in + Pblood out ) - ( Pdialysate in + Pdialysate out )]
If the TMP rises beyond its maximum tolerated value, a fraction of infused dialysate is diverted
from post- to pre-dilution, which decreases haemoconcentration and lowers the risk of
membrane pore occlusion. Similarly, if the TMP falls below the target range, fluid is redirected
towards the post-dilution mode to increase system efficiency.
Mixed dilution HDF has been shown to be non-inferior to post-dilution HDF in terms of small
and protein-bound solute clearance and superior to post-dilution and pre-dilution HDF in
terms of β2−microglobulin clearance (β2−M) [26–29]. Whilst these were relatively small rando‐
mised trials which require larger studies to confirm their findings, mixed-dilution HDF
appears to offer an attractive balance between efficiency of solute removal and minimisation
of haemoconcentration-related complications. Specifically, it may be suitable for patients in
whom target convection volumes are not achieved by post-dilution HDF because of high
haematocrit, high plasma protein, or inadequate vascular access and blood flow rate.
4.4. Mid-dilution HDF

Mid-dilution HDF similarly combines pre- and post-dilution fluid reinfusion into a hybrid
system (Figure 7). It does so by utilising a specialised haemodiafilter, the Nephros OLpur
MD 190. This filter is constructed in such a way that blood enters through the central core
fibres of the dialyser and returns in the opposite direction peripherally. This model effec‐
tively comprises two dialysers in series. Substitution fluid is incorporated at the midpoint of
the system, which creates an initial post-dilution stage followed by a pre-dilution stage. This
enables a high-concentration gradient and encourages movement of small solutes in the first
stage and maximal ultrafiltration of plasma water and convective removal of larger mole‐
cules in the second stage. Reinfusion rates up to 10–12 L/h are possible.
Unfortunately, due to the nature of the specialised dialyser, mid-dilution HDF is associated
with higher costs. There is also a higher degree of albumin loss, which is not insignificant.
Concerns exist regarding generation of a high TMP, which could compromise membrane
permeability. A TMP of up to 1000 mmHg has been reported as necessary to achieve the
required minimum ultrafiltration of 6 L/h [30]. This high TMP is especially problematic in the
first section of the dialyser where the post-dilution phase takes place and is thought to be the
result of partial fibre clotting and increased resistance to blood flow due to the reduced
capillary diameter in this segment [31]. Given the pro-coagulant effect of rapid convection,
adequate anticoagulation is necessary to ensure device patency. Reversal of the configuration
of the blood tubing (i.e. connecting the arterial line to the venous port of the dialyser and vice
versa) has been successfully trialled in mid-dilution HDF without significant effect on plasma
clearances if adequate infusion rates are maintained [32, 33]. Consideration should also be
given to the use of larger-surface filters (e.g. Nephros OLpur MD 220) [34].
When compared to post-dilution HDF, mid-dilution HDF is associated with inferior small
solute but superior middle-molecule clearance (β2M, myoglobin, prolactin, RTP) and similar
clearance of protein-bound solutes [35–37]. With increasing molecular weight, differences in
treatment efficiency between mid- and post-dilution HDF rise [36]. Phosphate clearance is
similar between the two groups. Whilst few studies have compared mid- and mixed-dilution
HDF, one small prospective randomised trial found greater small-solute and middle-molecule
clearance with mixed-dilution HDF though differences in dialyser membranes may have
confounded their outcomes [30]. Another small prospective crossover study compared ‘simple
mid-dilution’ (using two dialysers in series, rather than the Nephros OLpur MD 190) and
mixed-dilution HDF. They similarly found that mixed-dilution HDF provided significantly
greater clearances of urea, creatinine and β2M compared To ‘simple mid-dilution’ HDF with
equivalent phosphate clearances [38]. These outcomes require examination in larger trials.
4.5. Novel systems

Two novel systems, ‘pre-dilution on demand’ and ‘backflush on demand’, have recently been
proposed as potential alternatives to the standard online HDF modalities [39]. These sys‐
http://dx.doi.org/10.5772/62886
tems utilise inbuilt automated software to balance ultrafiltration against haemoconcentra‐

tion. In pre-dilution on-demand mode, escalating TMP is managed by temporarily pausing
ultrafiltration and diverting a proportion of filtered dialysate into the dialyser in pre-dilu‐
tion mode as a bolus. This produces sudden haemodilution. In backflush on demand, rising
TMP results in an automatic cessation of filtration and an infusion of ultrapure dialysate in‐
to the dialyser. This creates positive pressure in the dialysate compartment, which back‐
flushes the membrane pores and reduces haemoconcentration. These modes are currently
experimental but offer a novel and intuitive solution to some of the inherent technical barri‐
ers of the existing HDF modes. Of note, these machines and dialysers would carry addition‐
al expense, which would need to be considered.
5. Summary
Many questions remain unanswered in the field of fluid convection, generation and reinfu‐
sion in haemodiafiltration. Although convection volume appears to have a dose-dependent
relationship with survival, randomised trials have failed to consistently demonstrate im‐
proved mortality in their primary analyses. Furthermore, the critical ‘dose’ required to im‐
prove patient outcomes is yet to be determined and may need to be individualised
according to patient factors, including patient size and residual renal function. Online gener‐
ation of ultrapure dialysate has revolutionised the practice of HDF by allowing large con‐
vection volumes, although this approach requires strict monitoring in terms of quality and
safety. The preferred site of fluid reinfusion is not known and warrants careful considera‐
tion of the opposing factors of solute clearance efficiency and the consequences of haemo‐
concentration. Hybrid modalities appear to present a promising balance between the two.
Given the lack of robust clinical trials confirming the benefits of HDF, the increasing uptake
of HDF worldwide has largely been driven by industry. Lack of a harm signal, cost neutral‐
ity and optimism that patient benefits will arise from large convective volumes have facili‐
tated acceptance amongst the Nephrology community. It is unclear whether high-quality
data from randomised trials will be available to guide convection and reinfusion strategies
and it is likely that practice will need to rely on the results of observational studies.
Author details
Emily J. See1, Carmel M. Hawley1, John WM. Agar2 and David W. Johnson1*
*Address all correspondence to: david.johnson2@health.qld.gov.au
1 University of Queensland at Princess Alexandra Hospital, Brisbane, Australia
2 University Hospital Geelong, Geelong, Australia

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Chapter 4
The Effect of Convective Dialytic Modalities on Arterial

Stiffness in End-Stage Renal Disease Patients
Panagiotis I. Georgianos, Evangelia Dounousi,

Theodoros Eleftheriadis and Vassilios Liakopoulos
http://dx.doi.org/10.5772/63369
Abstract
Among end-stage renal disease (ESRD) patients receiving hemodialysis, increased

arterial stiffness is an independent cardiovascular risk predictor. Over the past few
years, arterial stiffness attenuation has been increasingly recognized as a novel
therapeutic target toward cardiovascular risk reduction in the dialysis population.
Structural alterations related to the long-term arteriosclerotic process are difficult to
modify; with the exception of blood pressure (BP)-lowering, there are no other
therapeutic interventions with well-documented benefits in delaying the progression
of arteriosclerosis among dialysis patients. Enhanced clearance of middle-to-high
molecular weight solutes by combining convective and diffusive transport through
hemodiafiltration and the associated benefits on microvascular endothelial function
have generated the hypothesis that convective dialytic modalities may be advanta‐
geous in improving large-artery stiffness. This notion is supported by some clinical
studies showing that switching ESRD patients from low-flux hemodialysis to high-
efficiency on-line hemodiafiltration was associated with significant reduction in arterial
stiffness. These beneficial effects, however, were not confirmed in a recent subanaly‐
sis of the CONvective TRAnsport STudy (CONTRAST) trial. In this chapter, we
summarize the currently available evidence on the effect of hemodiafiltration versus
hemodialysis on arterial stiffness, discussing also the potential clinical implications of
this effect.
Keywords: arterial stiffness, hemodiafiltration, hemodialysis, pulse wave velocity,

vascular calcification
1. Introduction
Patients with end-stage-renal-disease (ESRD) receiving maintenance hemodialysis have one

of the highest rates of cardiovascular morbidity and mortality [1, 2]. Although classical
atheromatosis of middle-sized arteries is an important contributor to this elevated cardio‐
vascular risk, atherosclerotic cardiovascular events (i.e., myocardial infarction and stroke)
can only partially explain the huge burden of cardiovascular mortality in ESRD. Among
these patients, serious arrhythmias and sudden cardiac deaths related to the high preva‐
lence of left ventricular (LV) hypertrophy and disturbances in electrolyte balance repre‐
sent another major cause of cardiovascular death [3]. This phenomenon is explained by the
fact that the spectrum of arterial remodeling in ESRD is much broader, including also long-
term structural alterations in the visco-elastic properties of the biomaterial constituting the
wall of the aorta and large conduit arteries [4, 5]. The so-called “arteriosclerotic process” is
accompanied by substantial hemodynamic alterations and is considered one of the most
important pathogenic mechanisms of isolated systolic hypertension, LV hypertrophy, and
subendocardial hypoperfusion [4, 5]. It is therefore unsurprising that among ESRD pa‐
tients, increased arterial stiffness is a strong and powerful predictor of cardiovascular
morbidity and mortality [6, 7].
Given the strong prognostic association of arterial stiffness with cardiovascular outcomes,
regression of the arteriosclerotic process is increasingly recognized as a novel therapeutic
target toward cardiovascular risk reduction in dialysis patients. However, whether arterial
stiffness in this particular population is modifiable and if so, which therapeutic interven‐
tions are effective in delaying the progression of arteriosclerosis are aspects that remain
unclear [5, 8]. Observational evidence and a few randomized studies suggested that blood
pressure (BP)-lowering and use of agents blocking the renin-angiotensin-aldosterone-
system (RAAS) may be of some benefit [5, 8, 9]. The modality of renal replacement therapy is
suggested to be another factor possibly determining the progression of arteriosclerosis in
dialysis patients. In this regard, higher clearance of middle-to-large molecular weight solutes
by combining diffusive and convective transport and the associated improvement in phos‐
phate control, endothelial dysfunction, and circulating inflammatory biomarkers [10–14] is
proposed to be translated into a beneficial impact of hemodiafiltration on large-artery
structure and function in dialysis patients.
The aim of this chapter was to review the currently available evidence on the effect of hemo‐
diafiltration versus hemodialysis on the long-term progression of the arteriosclerotic process
and discuss the potential implications that this effect may have in the choice of the most
appropriate dialytic modality for ESRD patients.
2. Arterial stiffness in dialysis patients
Acceleration of the arteriosclerotic process is the typical feature of arterial remodeling in

ESRD. Aortic and carotid-artery stiffness is significantly higher in ESRD patients than in
The Effect of Convective Dialytic Modalities on Arterial Stiffness in End-Stage Renal Disease Patients 47
http://dx.doi.org/10.5772/63369
age-, sex-, and BP-matched controls with normal renal function [15]. Among dialysis pa‐
tients, arteriosclerotic process is a pathophysiological continuum of structural alterations
that begin from the early stages of renal impairment, with several studies showing a step‐
wise increase in arterial stiffness with advancing stage of chronic kidney disease (CKD)
[16, 17]. Structural alterations related to arterial stiffening in ESRD include fibro-elastic
intimal thickening, calcification of elastic lamellae, increased extracellular matrix deposi‐
tion, elastynolysis and inflammation, increased collagen, and decreased elastic fiber con‐
tent [4, 18, 19]. The mechanistic background of these arterial wall alterations is complex
and not yet fully elucidated. Apart from the contribution of accumulated traditional cardi‐
ovascular risk factors, it is suggested that specific mechanistic pathways related to the
ESRD status and renal replacement therapy may play a particular role in the progression
of arteriosclerosis in this population. Some of the most important ESRD-specific mecha‐
nisms involved in the pathogenesis of arteriosclerosis include impaired mineral metabo‐
lism and elevated calcium-phosphate product, vascular calcification, excessive activation
of the RAAS, endothelial dysfunction, inflammation, oxidative stress, and chronic volume
overload [4, 18, 19]. Compared with traditional cardiovascular risk factors, these ESRD-
specific pathways were shown to be stronger determinants of the progression of arterio‐
sclerosis over time [20].
The main physiological role of the aorta and large conduit arteries is (i) to dampen the
high-pressure oscillations generated from the intermittent LV ejection and (ii) to transform
the cyclic blood flow in the aorta into a continuous capillary flow pattern required for
perfusion of organs and tissues [4, 19, 21]. During systole, the stroke volume ejected by
the left ventricle interacts with the elastic properties of the aorta to generate a pulse wave
(incident or forward-traveling) that is propagated at a pulse wave velocity (PWV) that
progressively increases across the arterial tree. Structure of the arterial system is normally
characterized by progressive increase in arterial wall stiffness from the ascending aorta to
the peripheral muscular-type arteries (so-called stiffness gradient) [4, 19, 21]. Impendence
mismatches at the transition between these segments generate pulse wave reflections.
These reflected waves travel from the periphery back to the ascending aorta (backward-
traveling reflected wave), opposing pulsatile energy transmission downstream to microcir‐
culation. In young subjects with elastic central arteries, this process is coupled with
slower pulse wave propagation and the overlap of the incident and reflected waves in the
ascending aorta occurs in late systole or early diastole. This phenomenon results in rise of
diastolic aortic pressure, favoring coronary perfusion during diastole. Arteriosclerotic
process, however, affects preferentially the wall of the aorta and large central arteries, re‐
versing the normal stiffness gradient between central and peripheral arterial segments
[22]. In conditions of accelerated arterial stiffness, such as ESRD, there is premature arriv‐
al of reflected waves back to the ascending aorta, during systole rather than diastole [4,
19, 21]. This results in augmentation of central aortic systolic pressure, thereby increasing
cardiac after load and promoting adverse myocardial remodeling toward fibrosis and hy‐
pertrophy. In addition, greater pulsatile energy transmission from macro- to microcircula‐
tion promotes microvascular damage in peripheral organs and tissues (Figure 1) [4, 19,
21].
Figure 1. Pathophysiological role of increased arterial stiffness in ESRD.
The close pathophysiological association of arterial stiffness with promotion of end-organ

damage is in line with a strong epidemiological association of increased arterial stiffness with
worse cardiovascular outcomes. Among dialysis patients, prospective observational studies
have for long-connected higher aortic PWV with increased risk of all-cause and cardiovascular
mortality independently from other cardiovascular risk factors [7]. In the first study conducted
in the late 1990s in a cohort of 241 hemodialysis patients prospectively followed for a mean
period of 6 years, Blacher et al. [6] showed that the fully adjusted odds ratio (OR) for aortic
PWV > 12.0 versus PWV < 9.4 m/s was 5.4 [95% confidence intervals (CIs): 2.4–11.9] for all-
cause mortality and 5.9 (95% CI: 2.3–15.5) for cardiovascular mortality [6]. The strong prog‐
nostic association between aortic PWV and cardiovascular outcomes was confirmed in several
subsequent cohorts of hemodialysis patients [15, 23]. Similarly to patients receiving hemo‐
dialysis, more recent observational studies have demonstrated the strong and independent
prognostic significance of arterial stiffness in the whole spectrum of CKD, showing that aortic
PWV is an independent predictor of mortality in patients receiving peritoneal dialysis [24] in
renal transplant recipients [25] and in patients with CKD not yet on dialysis [26]. Most
importantly, regression of arterial stiffness in response to BP-lowering was shown to be
associated with improvement in survival [9], providing evidence that arterial stiffness is not
simply a risk predictor, but a true cardiovascular risk factor in the dialysis population.
3. Studies comparing the effect of hemodiafiltration versus hemodialysis

on arterial stiffness
Uremic toxin accumulation, particularly retention of protein-bound solutes and middle-

weight molecules as a result of their inadequate clearance through conservative dialytic
http://dx.doi.org/10.5772/63369
modalities, is proposed to play a prominent role in promoting vascular atherosclerosis and

pathogenesis of cardiovascular disease among dialysis patients. In support of this notion,
background and clinical studies have shown that accumulation of p-cresol and indoxyl sulfate,
two protein-bound uremic toxins, acts as a triggering factor for the expression of pro-inflam‐
matory cytokines and adhesion molecules, induces shedding of endothelial microparticles,
and disrupts the nitric oxide signaling pathway [27–29]. Importantly, in recent prospective
observational studies, high concentrations of both p-cresol and indoxyl sulfate in hemodialysis
patients have been associated with increased risk of cardiovascular morbidity and mortality
independently from other traditional cardiovascular risk factors [30–32].
Hemodiafiltration is a dialytic modality that uses a combination of convective transport and

diffusion to enhance the removal of middle-to-high molecular weight solutes in comparison
with standard hemodialysis [33, 34]. In some clinical studies, enhanced middle-molecule
clearance achieved through convective dialytic modalities was shown to be associated with
improvement in phosphate control, better preservation of intradialytic hemodynamic stability,
as well as, with a number of beneficial actions on vasculature, such as reduction in circulating
markers of vascular inflammation and oxidative stress and improvement in flow-mediated
endothelium-dependent vasodilatation [11–14, 35]. These beneficial effects of hemodiafiltra‐
tion on the vasculature have generated the hypothesis that switching ESRD patients from
conventional hemodialysis to high-efficiency hemodiafiltration may be a therapeutic
maneuver with potential advantages in causing regression of arterial stiffness. This hypothesis
was tested in a number of clinical studies summarized in Table 1 and discussed in detail below.
Author Year n Patient Design Intervention Follow-up Change in arterial Overall

characteristics (months) stiffness over time effect
Beerenhout 2005 40 ESRD patients RCT Pre-dilution on- 12 Aortic PWV increased Neutral
et al. [35] treated with line HDF versus similarly over time in
thrice-weekly low-flux HD both dialytic
low-flux HD modalities (HDF: 12 ±
5 versus 13 ± 5 m/s;
HD: 12 ± 3 versus 13 ±
5 m/s)
Bellien et al. 2014 42 ESRD patients RCT Post-dilution on- 4 Carotid artery Better
[37] treated with line HDF versus distensibility was
thrice-weekly high-flux HD increased in the on-line
high-flux HD HDF group, but not in
the HD group
(between group
difference: −6.7 kPa−1 ×
10−3, 95% CI: −9.9 to
−3.5 kPa−1 × 10−3, P =
0.048)
Author Year n Patient Design Intervention Follow-up Change in arterial Overall

characteristics (months) stiffness over time effect
Mostovaya 2014 189 ESRD patients RCT Post-dilution on- 36 Aortic PWV remained Neutral
et al. [39] participating in line HDF versus unchanged over time
the CONTRAST low-flux HD with both dialytic
trial modalities (annual rate
of PWV change: HDF
group: −0.01, 95% CI:
−0.41 to 0.40 m/s/year;
HD group: −0.04, 95%
CI: −0.31 to 0.23 m/s/
year; p value HDF
versus HD: 0.89)
Charitaki et 2014 289 ESRD patients Observational 69 patients on 6 Aortic PWV increased Better
al. [38] on maintenance low-flux HD over time in the low-
HD versus 78 flux HD group (9.5 ±
patients switched 1.9 versus 10.2 ± 2.2
from low-flux m/s, p < 0.01) as well as
HD to HDF in the HD to HDF
versus 142 group (9.4 ± 1.9 versus
patients on HDF 10.1 ± 2.2 m/s, p < 0.01),
but remained constant
in the HDF group (9.9
± 2.1 versus 10.1 ± 2.2
m/s)
Georgianos 2014 48 ESRD patients Observational HDF versus low- Single Aortic PWV remained Neutral
et al. [36] on maintenance flux HD dialysis unchanged from pre-
HD session to postdialysis either
with HDF or with low-
flux HD (HDF: 9.3 ± 0.5
versus 9.4 ± 0.5 m/s, p
= 0.686 low-flux HD:
9.1 ± 0.4 versus 8.9 ±
0.4 m/s, p = 0.396)
HD, hemodialysis; RCT, randomized controlled trial.
Table 1. Prospective studies comparing the effect of hemodiafiltration versus standard hemodialysis on arterial
stiffness.
3.1. Acute effects of hemodiafiltration on arterial stiffness
In a nested case-control design, Georgianos et al. [36] compared the acute changes in aortic
PWV from pre- to postdialysis in 24 ESRD patients receiving hemodiafiltration and in 24 age-
http://dx.doi.org/10.5772/63369
and sex-matched controls receiving low-flux hemodialysis. Aortic PWV was not significantly
changed from pre- to postdialysis during both the first and second weekly dialysis sessions.
These modest acute changes in aortic PWV from pre- to postdialysis were no different between
the hemodiafiltration and low-flux hemodialysis groups in both dialysis sessions studied [36].
With regards to wave reflections, augmentation index and related parameters were signifi‐
cantly reduced from pre-to postdialysis in both dialysis sessions and patient groups. Similarly
to aortic PWV, intradialytic reduction in wave reflection indices was no different between
patients treated with hemodiafiltration and standard low-flux hemodialysis [36]. These
findings suggest an acute intradialytic improvement in wave reflections from the periphery
but not in aortic stiffness, an effect that was independent of the mode of dialysis. However,
these comparable acute alterations in large-artery cushioning function do not necessarily
prespecify the pattern of long-term progression of the arterial stiffness in patients treated with
different dialytic modalities.
3.2. Long-term effects of hemodiafiltration on arterial stiffness
Studies evaluating the long-term effects of hemodiafiltration relative to hemodialysis on

arterial structure and function provided contradictory results. Beerenhout et al. [35] random‐
ized 40 ESRD patients treated with conventional low-flux hemodialysis to switch to high-
efficiency pre-dilution on-line hemodiafiltration or to continue on the same dialytic modality.
After 12 months of follow-up, aortic PWV increased similarly in both low-flux hemodialysis
(12 ± 3 versus 13 ± 5 m/s) and on-line hemodiafiltration groups (12 ± 3 versus 13 ± 5 m/s).
Notably, change in 48-h ambulatory systolic and diastolic BP and in LV mass index over time
were also no difference between the two dialytic modalities [35]. Furthermore, on-line
hemodiafiltration was not superior to low-flux hemodialysis in inhibiting the formation of
advanced glycation end-products and reducing the circulating levels of asymmetric dimethy‐
larginine (ADMA) and markers of oxidative stress or total anti-oxidant capacity. In a subse‐
quent study, 42 ESRD patients were randomly assigned to switch from high-flux conventional
hemodialysis to high-efficiency post-dilution on-line hemodiafiltration or to remain on high-
flux hemodialysis for a mean follow-up period of 4 months [37]. Arterial stiffness assessed
with the use of the distensibility co-efficient of the common carotid artery was improved in
the on-line hemodiafiltration group, but not in the high-flux conventional hemodialysis group
(between-group difference: −6.7 kPa−1 × 10−3, 95% CI: −9.9 to −3.5 kPa−1 × 10−3, p = 0.048) [37].
Improvement in carotid artery distensibility was accompanied by a significant improvement
in Kt/V urea, predialysis levels of β2-microglobulin, circulating levels of ADMA and tumor
necrosis factor (TNF)-a, and brachial artery flow-mediated endothelium-dependent vasodila‐
tation. In a multiple regression analysis model, hemodiafiltration-induced improvement in
conduit artery endothelial dysfunction and stiffness was associated with the changes in Kt/V
urea and predialysis levels of β2-microglobulin, suggesting that enhanced clearance of middle-
to-high molecular weight solutes is one factor potentially contributing to the beneficial effect
of hemodiafiltration on large-artery stiffness.
A beneficial effect of hemodiafiltration on arterial stiffness is supported by another observa‐

tional study, in which aortic PWV measurements were performed 6 months apart in three
different groups of ESRD patients [38]. The first group consisted of 69 ESRD patients receiving
conventional low-flux hemodialysis, the second group consisted of 78 ESRD patients who were
switched from low-flux hemodialysis to on-line hemodiafiltration, and the third group
included 142 ESRD patients receiving long-term renal replacement therapy with on-line
hemodiafiltration. Over the 6-month observational period, a significant increase in aortic PWV
was noted in those patients treated with hemodialysis (9.5 ± 1.9 versus 10.2 ± 2.2 m/s, p < 0.01)
as well as in those switched from hemodialysis to hemodiafiltration (9.4 ± 1.9 versus 10.1 ± 2.2
m/s, p < 0.01); in contrast, aortic PWV remained unchanged in the group of hemodiafiltration
(9.9 ± 2.1 versus 10.1 ± 2.2 m/s) [38]. The most important finding of this study was that aortic
PWV remained constant during follow-up only in those patients receiving long-term treatment
with hemodiafiltration, whereas aortic PWV increased in patients who were switched from
hemodialysis to hemodiafiltration. This observation could be interpreted in two different
ways: either the 6-month-long therapy with hemodiafiltration might be inadequate in order
to modify the arterial wall structure and stiffness, or aortic PWV increased in those patients
switched to hemodiafiltration due to a carry-on effect of previous long-term therapy with
conventional hemodialysis.
The above beneficial impact of hemodiafiltration in causing regression of arterial stiffness was
not confirmed in a recent subanalysis of 189 prevalent dialysis patients participating in the
CONvective TRAnsport STudy (CONTRAST) trial [39]. In this study, ESRD patients receiving
conventional low-flux hemodialysis were randomly assigned in a 1:1 ratio for treatment with
on-line hemodiafiltration or continuation of low-flux hemodialysis for a mean follow-up
period of 36 months. Median aortic PWV at baseline was 9.8 m/s (interquartile range: 7.5–12.0
m/s). Aortic PWV was not significantly changed over time, and the annual rate of PWV change
had no difference between the on-line hemodiafiltration and hemodialysis groups (hemodia‐
filtration group: −0.01 m/s/year, 95% CIs: −0.41 to 0.40 m/s/year; hemodialysis group: −0.04 m/
s/year, 95% CI: −0.31 to 0.23 m/s/year; p value for the between-group comparison: 0.89) [39].
The absence of difference between the two dialytic modalities in the rate of PWV change was
consistent across subgroups of age, sex, residual renal function, dialysis vintage, diabetes, and
history of pre-existing cardiovascular disease. Of note, the annual rate of PWV change had
once again no difference between the two dialytic modalities regardless of the convection
volume used for on-line hemodiafiltration (convection volume <18.9 L/session: 0.37 m/s/year;
95% CIs: −0.25 to 0.98 m/s/year, p = 0.23; convection volume >18.9 L/session: −0.01 m/s/year;
95% CIs: −0.59 to 0.57, p = 0.99) [39].
4. Studies comparing the effect of hemodiafiltration versus hemodialysis

on mortality
The above contradictory results of clinical studies that evaluated the comparative effectiveness
of hemodialfiltration versus standard hemodialysis in causing regression of arterial stiffness
http://dx.doi.org/10.5772/63369
are in line with the uncertain superiority of hemodiafiltration on mortality across large-scaled
randomized controlled trials that included “hard” cardiovascular outcomes as primary
endpoints. For example, in the primary analysis of the aforementioned CONTRAST study [40],
714 ESRD patients were randomly assigned to switch from low-flux hemodialysis to on-line
hemodiafiltration or continue renal replacement therapy with low-flux hemodialysis. After a
mean follow-up period of 3 years, incidence of all-cause mortality [Hazard Ratio (HR): 0.95;
95% CIs: 0.75–1.20] and occurrence of fatal and non-fatal cardiovascular events (HR: 1.07; 95%
CIs: 0.83–1.39) were not different between the two dialytic modalities [40]. The subsequent
Turkish on-line hemodiafiltration (OL-HDF) study enrolled 782 ESRD patients receiving
standard thrice-weekly hemodialysis who were randomly assigned in a 1:1 ratio to post-
dilution on-line hemodiafiltration or high-flux conventional hemodialysis [41]. Over a mean
follow-up period of 22.7 ± 10.9 months, the occurrence of the composite primary outcome of
all-cause mortality and non-fatal cardiovascular event was identical in both study arms (event-
free survival of 77.6% in hemodiafiltration versus 74.8% in the high-flux group, P = 0.28) [41].
Contrary to the above results, the Estudio de Supervivencia de Hemodiafiltración On-Line
(ESHOL) study supports the notion that on-line hemodiafiltration is superior over hemodial‐
ysis in reducing all-cause and cardiovascular mortality [42]. In this open-label, randomized
controlled trial, 906 prevalent hemodialysis patients were randomly assigned either to switch
to high-efficiency post-dilution on-line hemodiafiltration or to remain on standard low-flux
hemodialysis. Switching from low-flux hemodialysis to on-line hemodiafiltration was
associated with a 30% risk reduction for all-cause mortality (HR: 0.70; 95% CI: 0.53–0.92), 33%
risk reduction for cardiovascular mortality (HR: 0.67; 95% CIs: 0.44–1.02) and 55% risk
reduction for infection-related mortality (HR: 0.45; 95% CIs: 0.21–0.96) [42].
5. Conclusion
In summary, the currently available evidence from observational and randomized clinical
studies does not conclusively support a clear superiority of hemodiafiltration versus standard
hemodialysis in improving arterial compliance. The contradictory results of clinical studies
with respect to PWV, a surrogate cardiovascular risk factor, are in line with the uncertain
survival benefit of convective dialytic modalities in large-scaled clinical trials evaluating
“hard” cardiovascular outcomes. Additional research efforts are urgently warranted to fully
elucidate the comparative effectiveness of hemodiafiltration versus conventional hemodialysis
on arterial stiffness attenuation. In the meantime, we believe that dialysis treatment optimi‐
zation is undoubtedly one useful tool toward cardiovascular risk reduction for patients
receiving maintenance hemodialysis.
Author details
Panagiotis I. Georgianos1, Evangelia Dounousi2, Theodoros Eleftheriadis1 and

Vassilios Liakopoulos1*
*Address all correspondence to: liakopul@otenet.gr
1 Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA

Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
2 Department of Nephrology, Medical School, University of Ioannina, Ioannina, Greece
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Chapter 5
Effectiveness of Ultrafiltration in Patients with

Congestive Heart Failure
Luai Alhazmi, Abdulelah Nuqali, Ankush Moza and

Mujeeb Sheikh
http://dx.doi.org/10.5772/63393
Abstract
Among all cardiac diseases, congestive heart failure (CHF) is the leading cause of patient
rehospitalization. Fluid overload and lung congestion are the major reasons for these
recurrent admissions. This disease can be associated with worsening renal function, a
phenomenon called cardiorenal syndrome (CRS), which is challenging to manage.
Conventional diuretic therapy of both CRS and diuretic resistance has offered limited
efficacy. Compared with conventional therapy, hemodiafiltration (HDF) has shown
promising results for fluid removal in some clinical trials, with inconclusive effects on
all-cause mortality and rehospitalizations. Nonetheless, the results are inconsistent
because of the high heterogeneity among these studies. In this chapter, we shed light
on the role of different methods of ultrafiltration, including peritoneal ultrafiltration,
sustained slow efficiency dialysis, and HDF, in the management of CHF, and review
the current literature.
Keywords: congestive heart failure, cardiorenal syndrome, peritoneal ultrafiltration,

sustained low efficiency dialysis, hemodiafiltration
1. Introduction
Congestive heart failure (CHF), sometimes called chronic heart failure or simply heart failure,
is a disease that affects a patient’s everyday life and can have deleterious effects on both physical
and mental well-being [1–3]. Patients with CHF have a worse health-related quality of life than
those with many other chronic diseases, such as chronic obstructive pulmonary disease,
hypertension, diabetes mellitus, and myocardial infarction [3, 4]. Moreover, rehospitaliza‐
tions are a major concern among these patients, their families, and their health service provid‐
ers. CHF causes the highest rehospitalization rate among all chronic diseases, reaching up to
27% [5]. Patients with CHF have a poor prognosis, with a 1-year survival rate that is compara‐
ble or worse than that for common neoplasms such as prostatic or breast malignancies. Stewart
et al. showed that the median survival time for patients with CHF was 16 months with 25% 5-
year survival rate [6, 7]. Despite all advances in the management of CHF, it is still the leading
cause of mortality among cardiac diseases [8, 9]. Fluid overload and lung congestion are the
most recurrent cause of admissions in these patients [10]. Almost 50% of them are discharged
with residual congestion, and most rehospitalizations occur in patients who are diuretic resistant
[11]. Diuretic resistance, in which patients with CHF have reduced diuresis and natriuresis in
response to diuretics, causes higher mortality and rehospitalizations [10, 12, 13]. CHF is also
associated with cardiorenal syndrome (CRS), a condition in which renal function worsens and
is challenging to manage [14]. Conventional diuretic therapy of both CRS and diuretic resist‐
ance has shown limited efficacy with no robust data on efficacy in terms of well-designed
randomized clinical controlled trials [15, 16]. However, hemodiafiltration (HDF), isotonic fluid
replacement through positive hydrostatic pressure, has recently emerged as an alternative or
last resort for these complex patients. The aim of this physiological approach is to decrease
neurohumoral activation, which in turn curbs the vicious cycle leading to cardiac and renal
insult [17, 18]. Some promising results have been reported in initial studies, but the data conflict
and are inconclusive. As a result, no clinical guidelines to date have adopted HDF as an alternative
to diuretic therapy [10, 19–22].
2. Diuretic resistance and CRS syndrome
No specified definition is available for diuretic resistance, as it is the outcome of treatment and
not a pathological condition in itself. The efficacy of loop diuretics can be evaluated as a
measure of urine output, change in weight, and balance in net fluid [23]. Patients unable to
meet their needs for decongestion despite high doses of loop diuretics are generally labeled as
diuretic resistant. Some current studies have reported the efficacy of diuretics in terms of
clinical outcomes in patients with CHF [24–31]. Although these studies used different methods
and metrics, the outcomes were similar in all: patients with diuretic resistance showed poor
outcomes compared with those without diuretic resistance. Even after correcting for glomer‐
ular filtration rate (GFR), a strong correlation between worse clinical results and diuretic
resistance was observed, showing that the efficacy of diuretics and the GFR each have a
different impact on clinical outcomes. GFR is a good indicator of the kidney’s clearance ability.
When this rate is normal, the renal tubules are able to maintain homeostasis of electrolytes and
euvolemia. Even if the GFR is reduced to up to 20 mL/min, usually 28.8 L of fluid is filtered,
and sodium excretion is about 4000 mEq. The metrics used in current studies for diuretic
efficacy are indirectly related to the effectiveness of loop diuretics for sodium excretion.
Consequently, these metrics indicate a better prognosis than does the GFR in terms of the
kidneys achieving euvolemia.
Effectiveness of Ultrafiltration in Patients with Congestive Heart Failure 61
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Several studies that used different metrics tried to establish a correlation between efficacy of
diuretics and heart failure-related clinical outcomes. In the case of patients having reduced
diuretic efficacy, Testani et al. [24] found high mortality rates even after correcting for diuretic
dose and fluid output. Valente et al. [25] and Voors et al. [31] observed increased death and
rehospitalization rates associated with diuretic resistance in heart failure at 60 days, whereas
Ter Maaten et al. [28] reported similar outcomes at 30-day follow-up. After correcting for the
GFR, Verbrugge et al. [29] and Singh et al. [26] reported higher death and rehospitalization
rates related to diuretic resistance.
On the contrary, CRS is a condition that becomes apparent from a decrease in the GFR and
acts as a barrier to the treatment of CHF by limiting the renal function [32]. At first, a decrease
in blood flow in the kidney was considered to cause a low GFR, but recently a number of
studies have shown that cardiorenal interactions have several complex mechanisms, some of
which may be reversible. In a commonly used classification given by Ronco and colleagues
[33], CRS is grouped into four types: type 1 is characterized by acute heart failure, leading to
acute kidney injury; type 2 involves chronic cardiac impairment such as CHF, resulting in
chronic kidney disease; type 3 is a result of primary kidney function impairments, resulting
in acute cardiac impairment that may become evident as heart failure; and type 4 involves
chronic cardiac impairments influenced primarily by primary chronic kidney disease such as
uremic cardiomyopathy. A further type 5 CRS involves systemic disorders of the chronic or
acute type such as sepsis; diabetes causes both cardiac and renal dysfunction.
Acute CRS is a reflection of worsening renal function in patients with CHF [34]. CRS is found
in 25–33% of all patients with acute decompensated heart failure (ADHF) [35, 36]. Extrarenal
hemodynamic changes, cellular dysregulation, neurohormonal activation, and intrarenal
microvascular and oxidative stress underlie acute CRS [34, 37]. In a few cases, intravenous
diuretic-mediated renal injury is responsible for worsening renal function [16, 38, 37]. Other
proposed mechanisms of CRS pathophysiology include neurohumoral adaptations, reduced
renal perfusions, elevated venous pressure, and dysfunction of the right ventricle [39, 40].
3. Peritoneal ultrafiltration (pUF)
In advanced stages of CHF, a decline in renal function can often be seen, consistent with type
2 CRS (CRS-2). Several therapies have been evaluated for this group of patients; however, the
optimal therapy for “chronic” CRS remains elusive. It is believed that peritoneal ultrafiltration
(pUF) may lead to improvement in the clinical function of these patients, with a reduction in
the number of hospitalizations.
A study performed on patients without end-stage renal disease evaluated the efficacy of pUF
in the treatment of chronic refractory heart failure (HF) [41]. For this evaluation, 39 consecutive
patients with end-stage CHF and stable CRS-2 were given ambulatory pUF and prospectively
followed for 1 year. The primary end point was all-cause hospitalization. Mortality, treatment
changes, and weight changes with New York Heart Association (NYHA) functional class and
quality of life were considered as the secondary end points. Compared with the control group,
who received standard treatment, in the pUF group, there was a reduction in the number of
1-year hospitalization days (p = 0.07). However, the 1-year mortality was found to be 33% in
the pUF group and 23% in the control cohort, although this result was not statistically
significant. In comparison to standard medical treatment, pUF was found to significantly
improve volume overload (p < 0.05), the NYHA functional class (p < 0.001), and mental health
(p < 0.05) of the patients. Furthermore, in the pUF group, the hospitalization days for all causes,
including cardiovascular incidents, were significantly reduced during the interim periods (p
< 0.05 and p < 0.001, respectively).
Another study evaluated pUF in patients with severe HF that was refractory to aggressive
drug therapy [42]. Treatment with pUF was considered in these patients, as they had been
hospitalized at least three times in the preceding year for ADHF that had required extracor‐
poreal UF. This study comprised 48 patients; of those, 30 received one nocturnal icodextrin
exchange, 5 received two daily exchanges, and the remaining 13 received two to four sessions
per week of automated peritoneal dialysis (PD). In the first year of therapy, renal function
remained stable with a decline in pulmonary artery systolic pressure to 40 ± 6.09 mmHg from
45.5 ± 9.18 mmHg (p = 0.03). At the same time, significant improvement was noted in the NYHA
functional status. Furthermore, patient hospitalizations decreased to 11 ± 17 days/patient-year
from 43 ± 33 days/patient-year seen in the preceding year, which was before the onset of PUF
treatment (p < 0.001). Thus, this study confirms the efficacy of PUF treatment in elderly patients
with chronic HF.
Recently, a systematic review conducted to evaluate the efficacy of PD in patients with

refractory CHF identified 21 studies from 13 countries [43]. This review comprised 673 patients
and suggested that in patients with refractory CHF, PD can be an effective and safe treatment
option, leading to improved heart function and weight control. It also reported that PD can
reduce patient hospitalization days without any progressive worsening of renal function. The
rates of PD complications such as peritonitis were also found to be acceptable.
4. Sustained low-efficiency dialysis (SLED) in patients with CHF
Sustained low-efficiency dialysis (SLED), or sustained low-efficiency daily dialysis (SLEDD),

is a conventional hemodialysis that is performed over a longer period (6–12 h) of time using
lower rates of blood flow (50–200 mL/min) and dialysate flow (200–400 mL/min). It is an
alternative treatment in critically ill patients with affected kidney function [44–46], where fluid
is removed slowly over longer time ensuring better hemodynamic stability [47]. This is in
particular the case when the cost of HF/HDF is considered expensive. It combines the logistic
advantages, the cost-effectiveness and the scheduling flexibility of the intermittent dialysis,
and the hemodynamic stability of continuous renal replacement therapy with fewer side effects
during the fluid removal [48]. There is still a limited clinical data in the literature on the
effectiveness of SLED in patients with CHF. However, Iorio et al.’s experience suggested that
SLED is an alternative treatment for acute dialysis in patients with diuretic resistant systolic
CHF [49]. Violi et al. mentioned that the SLED as an alternative treatment is the most indicated
in NYHA class IV CHF [50].
http://dx.doi.org/10.5772/63393
5. Hemodiafiltration in a nutshell
Dialysis refers to diffusive clearance. During dialysis, low-molecular weight solutes such as
sodium and potassium move down their concentration gradient. The solute must be of
appropriate size to pass through a semi-permeable membrane. By passing fluid across the
membrane countercurrent to blood flow, equilibration of plasma and dialysate solute concen‐
trations occur. This process may remove or add solute to the plasma water space depending
upon the relative concentrations in dialysate and plasma. At the same time, water will also
move along a gradient, in this case the osmolar or osmotic gradient, in effect “following” the
solute. Diffusive clearance is more effective at removal of small solute, such as serum ions and
urea, than for larger solutes.
Hemofiltration (HF) or ultrafiltration (UF) refers to convective clearance. The difference from
dialysis is that pressure gradient rather than concentration gradient has its main effect on water
movement. Solute movement is secondary and in conjunction with water. The transmembrane
pressure difference can be adjusted as needed to remove water from the body down a pressure
gradient. The flow of plasma water “drags” solute with it in the formation of ultrafiltrate. UF
or HF is far superior for fluid clearance than diffusive clearance, and small solute clearance is
almost identical. Slow continuous ultrafiltration (SCUF) is a term used for removing isotonic
plasma water, which is indicated in patients with fluid overload such as those with CHF.
Figure 1. Principle of hemodiafiltration.

Hemodiaflitraion refers to a combination of convective and diffusive therapies. An example

is the use of continuous venovenous hemodiafiltration (CVVHDF) in critically ill patients. It
constitutes lower blood flow rate and slower fluid removal which may cause less hemody‐
namic instability in a hypotensive critically ill patient [51].
The setup for HDF requires a double-lumen central venous catheter, a peristaltic pump, and
a filter inserted into a venovenous extracorporeal circuit [52] (Figure 1). Negative pressure
generated by the pump allows blood circulation in the circuit, starting from the central vein
and returning to the patient through the filter. Pore fibers of the filter keep water and small
particles separated from blood through convective transport. Plasma water flow makes the
blood concentration transient, eventually causing intravascular refilling while transferring
liquids from the outer to the inner vascular space, thus safeguarding the circulating volume.
After the dispatched intravascular fluid is replaced by extravascular fluid refilling, hypovo‐
lemia can be prevented, thus preventing hemodynamic worsening. According to previous
reported studies, fluid removal through HDF has affirmative hemodynamic effects. A study
was done on 24 patients with resistant CHF undergoing UF; blood gas analysis (in both
systemic and pulmonary arteries), plasma volume changes, and plasma refilling rate were
measured after every liter of plasma water removed; UF was performed safely without side
effects or hemodynamic instability; and mean right atrial, pulmonary artery and wedge
pressures progressively reduced during the procedure [18]. Heart rate and systemic vascular
resistance did not increase, and other peripheral biochemical parameters did not worsen
during UF. Cardiac output increased at the end of the procedure and, to a greater extent, 24 h
later, in relation to the increase of stroke volume. Intravascular volume remained stable
throughout the entire duration of the procedure, indicating that a proportional volume of fluid
was refilled from the congested parenchyma. Thus, UF is associated with hemodynamic
improvement. Fluid refilling from the over-hydrated interstitium is the major compensatory
mechanism for intravascular fluid removal, and hypotension does not occur when plasma
refilling rate is adequate to prevent hypovolemia.
When a patient in decompensated heart failure is treated with HDF, it is important to ensure
that the amount of removed intravascular water is below the amount of the capillary refilling
rate; otherwise, neurohumoral activation can lead the patient to hypotension and abnormal
renal function [18]. Thus, the distinctive feature of HDF is its effectiveness in removing
extravascular fluids without increasing or decreasing the circulating volume and in turn
avoiding neurohormonal activation and its consequences [52]. Respiratory symptoms such as
dyspnea and orthopnea can be improved not only by total fluid removal but also by improve‐
ment in lung mechanics, pulmonary gas exchange, interstitial edema, vascular congestion, etc.
[53, 54]. The two strategies (mechanical and pharmacological) of fluid withdrawal can have
different effects on intravascular volume, hemodynamics, neurohumoral activity, and other
regulatory mechanisms, leading to differing clinical outcomes. The tonicity of the fluid
removed by the two strategies is different (isotonic with ultrafiltration [UF] and hypotonic
with loop diuretics) [52, 55, 56]. With HDF, intravascular volume can be preserved, whereas
it can be reduced with loop diuretics. After HDF, a better water-salt balance can be achieved
and maintained in the body, whereas rapid worsening of this balance to the baseline abnormal
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state can occur with loop diuretics. A number of pathophysiology-oriented studies have
documented these concepts [18, 53, 57]. Still, some ambiguity remains regarding the exact
mechanisms of HDF in treating CRS and diuretic resistance.
6. Overview of clinical trials on HDF
An Israeli study aimed to determine the appropriateness and safety of UF therapy in patients
with CHF who were admitted to outpatient clinics between April and September 2013 [58].
HDF was used to treat several patients with chronic CHF with NYHA III-IV and diuretic
resistance. A total of 38 courses of treatment were administered. The results showed that about
1982 mL of fluid was removed per course, and patients reported having a subjective feeling of
improvement in symptoms. Another Singaporean retrospective study was conducted among
44 patients who were admitted to the hospital from October 2011 to July 2013 [59] for decom‐
pensated heart failure and diuretic resistance. The study authors concluded that HDF is an
effective and safe treatment strategy that can ameliorate the health of diuretic-resistant Asian
patients with decompensated CHF.
Therefore, HDF has proven to be an effective method for fluid removal. It is adjustable in terms
of both fluid volumes and rates with no changes in the levels of serum electrolytes. However,
despite the effectiveness of HDF in fluid removal, clinical studies have not discovered any
clinical benefit of this method over diuretic therapy. Furthermore, compared with diuresis,
HDF does not preserve renal function.
In February 2016, a published study compared the effectiveness of HDF and loop diuresis in
patients with heart failure (HF) [60]. This study comprised 105 patients with HF who were
receiving UF and 108 patients with HF who were receiving adjustable loop diuretics. The aim
of the study was to compare the recurrence of HF in the two groups at 90-day follow-up.
However, the small sample size provided inconclusive data, which could not be used to
identify a significant difference between the two patient groups. The authors of this study
reported that the first HF event within 90 days of hospital discharge was seen in 25% of patients
who received adjustable UF and in 35% of patients who received adjustable loop diuretics.
Furthermore, there were approximately 62 days leading to the first HF event in the 25% patient
group and 34 days leading to this even in the 35% patient group. Despite the trend toward
better results with HDF, this difference did not reach statistical significance (log rank p 1∕4
0.106). The hazard ratio, which was found to be 0.663 (95% confidence interval [CI] 0.402 to
1.092), suggested a 37% lower risk of an HF event with adjustable UF compared with adjustable
loop diuretic therapy, but this result was statistically insignificant. The results should be
interpreted with caution, as the study was unilateral and was prematurely terminated by the
sponsor.
Another study that included 188 patients investigated UF in CRS [37]. Half of the patients were
given stepped pharmacological therapy, and the other half were treated with UF. The bivariate
change of the serum creatinine level and body weight from baseline, calculated after 96 h, was
the primary end point of the study. The patients were then followed for 60 days. After 96 h,
patients undergoing stepped pharmacological therapy had superior renal function compared
with that in patients receiving UF. A similar amount of weight loss was noted in both groups
of patients. In addition, UF was found to be associated with a higher rate of adverse events.
For patients with CHF, UF is usually reserved for cases of renal failure or unresponsiveness
to pharmacological therapy. To study the safety and effectiveness of UF in patients
hospitalized with decompensated CHF, investigators conducted the relief for acutely fluid-
overloaded patients with decompensated congestive heart failure (RAPID-CHF) trial. This
study, the first randomized controlled trial to compare UF with medical therapy, comprised
40 subjects [61]. A single 8-h course of UF with peripherally inserted catheters, along with
supportive care and treatment, was compared with supportive care only. Patients who
received UF had a greater volume of fluid removal (median 4650 vs. 2838 mL, p = 0.001) and
improved signs and symptoms of congestion. Treatment with UF was well tolerated by the
patients and did not result in any major adverse effects such as hemodynamic and renal
complications. Thus, as can be deduced from the study, early treatment with UF for patients
with CHF is a feasible treatment option that is well tolerated and can result in significant weight
loss and fluid removal.
Another study supporting the findings of the RAPID-CHF trial was the ultrafiltration versus
intravenous diuretics for patients hospitalized for acute decompensated heart failure (UN‐
LOAD) trial [62]. The purpose of this randomized controlled trial was to study the safety and
effectiveness of early treatment with primary UF in patients with ADHF. The study comprised
200 subjects with two or more signs of hypervolemia. At 48 h after the onset of treatment,
weight reduction (5.0 ± 3.1 vs. 3.1 ± 3.5 kg, p = 0.001) and net fluid loss (4.6 vs. 3.3 L. p = 0.001)
were higher in patients who were receiving UF. Furthermore, compared with the patients who
were receiving diuretic therapy, the UF group showed lower rates of rehospitalization (0.22 ±
0.54 vs. 0.46 ± 0.76) with fewer days of in-hospital stay (1.4 ± 4.2 days vs. 3.8 ± 8.5 days) and
fewer unscheduled medical visits (21% vs. 44%) within 90 days of hospital discharge. Through‐
out the study, changes in serum creatinine levels were similar in both groups. Episodes of
hypotension during the first 48 h after hospitalization were similar (4% vs. 3%) in both groups.
Thus, the UNLOAD trial demonstrated that, in patients with ADHF, UF is a safe treatment
choice that produces higher weight and fluid loss compared with treatment with intravenous
diuretics. In addition, UF also reduces a 90-day resource utilization in patients with ADHF.
UF may thus prove to be an effective alternative to high doses of diuretic therapy in patients
with ADHF, particularly in the presence of renal insufficiency.
Another small study designed for patients with ADHF investigated the effects of UF and
standard intravenous diuretic (furosemide) therapy on the GFR and renal plasma flow [63].
The study comprised 19 patients who were randomized to receive UF (n = 9) or intravenous
diuretics (n = 10). After treatment, no significant difference was seen in the GFR, renal plasma
flow, and filtration fraction in the two groups. The difference in the net 48-h fluid removal
between the two groups was also found to be insignificant. However, urine output during the
first 48 h was significantly higher in the furosemide group than in the UF group.
The results of these randomized trials demonstrate that UF is associated with no major safety
concerns, and compared with diuretics, it improves total fluid volume removal with decreased
http://dx.doi.org/10.5772/63393
hospitalizations for CHF at 90 days in selected patients. However, the clinical trials have not
evaluated theoretical concerns such as predisposition to infections and bleeding complications,
which can be caused by the systemic heparinization and large-bore intravenous access needed
during the UF procedure.
7. Systematic reviews and meta-analyses on HDF
Recently, several meta-analyses have been performed to compare UF with diuretics for treating
volume overload in patients with ADHF. The first meta-analysis comprised nine studies
involving 613 patients [22]. The mean weight loss in patients receiving UF therapy was 1.78
kg (95% CI −2.65 to −0.91 kg, p < 0.001). This loss was more than for those treated with standard
diuretic therapy. However, between the two groups, there was little difference in post-
intervention creatinine levels (mean change = −0.25 mg/dL, 95% CI −0.56 to 0.06 mg/dL, p =
0.112). In addition, the results showed that, compared with patients treated with standard
diuretics, in those treated with UF, the risk of all-cause mortality persisted (pooled risk ratio
= 1.00, 95% CI 0.64–1.56, p = 0.993).
Figure 2. Forest plot of: a) Changes in weight loss at 48 h post therapy, b) all-cause mortality, c) all-cause rehospitaliza‐
tion. Reprinted from Cheng et al. [21], copyright with permission from International Heart Journal.
The second meta-analysis comprised seven RCTs with a total of 569 participants who met the
eligibility criteria [21]. This analysis demonstrated that after 48 h of treatment, significantly
higher amounts of weight loss and fluid removal were observed in the UF group compared
with the diuretic group. Serum creatinine levels and changes in creatinine were found to be
similar. There was no difference in all-cause mortality and all-cause rehospitalizations. In
addition to these results, the authors noted that there were only minor differences between the
UF and control groups in the incidence of adverse events, such as infections, anemia, hemor‐
rhage, progressive HF, and other cardiac disorders (Figure 2).
8. Recommendations for the use of HDF in clinical practice
UF recommendations for HF from the 2013 guideline by the American College of Cardiology
Foundation/American Heart Association Task Force [64] are shown in Table 1, along with
recommendations from the Canadian Cardiovascular Society [65] and the European Society
of Cardiology [66].
Reference Guidelines
American College of Cardiology/ “Ultrafiltration may be considered for patients with obvious volume overload to
American Heart Association (2013) alleviate congestive symptoms and fluid weight.
[64]
Ultrafiltration may be considered for patients with refractory congestion not
responding to medical therapy.”
Canadian Cardiovascular Society “Venovenous ultrafiltration may be of benefit in relieving congestion particularly
(2012)[65] in diuretic-resistant patients”
European Society of Cardiology “Venovenous isolated ultrafiltration is sometimes used to remove fluid in patients
(2012)[66] with heart failure, although it is usually reserved for those unresponsive or
resistant to diuretics.”
Table 1. Recommendations and guidelines for the use of hemodiafiltration in patients with congestive heart failure.
9. HDF challenges and cost-effectiveness
Controversy still exists regarding the efficacy of HDF reported in clinical trial results to restore
diuretic responsiveness in patients with CHF. The studies evaluating HDF showed consider‐
able heterogeneity in terms of (1) study population, (2) causes of acute decompensation, (3)
indications and protocols used for the prescription of HDF, (4) the “standard management”
used in the control arm, and (5) end points. Marenzi et al. recommended using HDF as a
complementary intervention along with diuretics rather than solely as an alternative inter‐
vention in patients with ADHF [52]. Moreover, HDF should probably be prescribed on an
individual basis in diuretic-resistant patients to achieve safe decongestion. From a financial
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standpoint, expenditures associated with HDF usage are still a major concern. Although
initially these expenditures were considered non-prohibitive, a decision-model analysis has
since found HDF to be expensive from a societal and hospital perspective. Nonetheless, for a
Medicare payer, HDF can be cost-effective if existing nephrology resources such as dialysis
machines, disposable supplies, and nursing staff are used as alternatives [67].
10. Conclusion
In patients with ADHF, decongestion is a major treatment goal. HDF techniques seem to be
an effective tool for removal of fluid, but more robust studies are required to clarify the benefits
of HDF and to characterize the group of patients who would benefit most from using it over
standard diuretic therapy. Despite recent studies, crucial clinical questions are left unan‐
swered. It is nonetheless apparent that HDF is an effective treatment strategy that should be
used only for a selected group of suitable patients and performed by skilled professionals. The
next research step for UF should not involve evaluating its effectiveness over that of diuretics;
rather, it is more important to identify the patients who best respond to this technique to help
restore their diuretic responsiveness.
Author details
Luai Alhazmi1, Abdulelah Nuqali2, Ankush Moza2 and Mujeeb Sheikh2*
*Address all correspondence to: Mujeeb.sheikh@utoledo.edu
1 Department of Internal Medicine, University of Toledo Medical Center, Toledo, Ohio, USA
2 Division of Cardiovascular Medicine, Department of Internal Medicine, University of Tol‐

edo Medical Center, Toledo, Ohio, USA
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Chapter 6
Update on Clinical Evidence Supporting

Hemodiafiltration
Bernard Canaud, Aileen Grassmann,

Laura Scatizzi and Daniele Marcelli
http://dx.doi.org/10.5772/63027
Abstract
The aim of this chapter is to define hemodiafiltration target efficiency, to clarify the
concept of “optimal convective dose,” and to facilitate hemodiafiltration (HDF)
implementation in clinical practice by addressing the need for the establishment of best
clinical practices for HDF. The approach taken was to conduct a comprehensive
summary of clinical evidence supporting HDF. Convective dose is the total ultrafil‐
tered volume and is complementary to diffusive dose (urea Kt/V) as a dose‐depend‐
ent parameter. It can be quantified and adjusted to patient characteristics. Factors
affecting convective dose are discussed: patient characteristics, prescription‐depend‐
ent factors, and technical and machine‐dependent factors. The key issue of HDF
prescription and implementation of best practices is addressed as are intermediary and
endpoint clinical outcomes. The main messages are as follows: (1) HDF is safe and
effective provided that best clinical practices are followed and the right convective dose
is delivered; (2) HDF is easy to perform with new technology; and (3) depending on the
convection volume, HDF reduces all‐cause and cardiovascular mortality. Open
challenges remain, namely, the implementation of best practices to (a) achieve optimal
convection volume, (b) define patient subsets that would benefit more from HDF, and
(c) evaluate new tools that fine‐tune HDF prescription according to individual patient
needs.
Keywords: convective dose, substitution modality, treatment outcome, convection

volume, clinical evidence
1. Introduction
Conventional diffusion‐based dialysis modalities, namely, low‐flux and even high‐flux

hemodialysis (HD), are limited in their capacity to effectively remove large uremic toxins and
to improve outcomes for chronic kidney disease (CKD) patients [1]. By increasing convective
solute transport, hemodiafiltration (HDF) enhances solute removal capacity over a broad range
of middle‐ and large‐size uremic toxins implicated in the pathophysiology of CKD [2, 3]. In
addition, convective‐based modalities have been shown to improve hemodynamic stability [4,
5] and to reduce patients’ inflammation profile—both factors implicated in CKD morbidity and
mortality [6–8]. Growing clinical evidence indicates that HDF‐based modalities provide CKD
patients with a number of clinical and biological benefits, including improved outcomes.
Interestingly, it has recently emerged that the clinical benefits associated with HDF are positively
associated with the total volume of fluid removed by ultrafiltration per session or per week [9–
12]. This finding adds a new component to the conventional dialysis adequacy concept, namely,
convective dose.
In this chapter, we elucidate the concept of convective dose and discuss the threshold above
which an improvement in CKD patient outcome can be expected. In addition, factors impli‐
cated in the achievement of an optimal convective dose in the sense of best clinical practice are
reviewed and clinical evidence supporting the use of HDF today is summarized.
1.1. Why is hemodiafiltration needed?
From a nephrologist's perspective, it is disappointing to observe that outcomes of end‐stage

kidney disease (ESKD) patients remain poor despite significant progress in hemodialyzer
performances, HD machines and monitoring devices, better understanding of uremic toxicity,
and improved patient management. Even without an in‐depth analysis of root causes and
reasons for renal replacement therapy (RRT) limitations, several factors are easily recognizable
as contributing to this outcome. It is usually convenient to group these into two categories:
“nonmodifiable factors,” such as age, gender, ethnicity, comorbidity profile, and kidney
disease history, and “modifiable factors,” such as RRT modality and treatment adequacy.
Changing the renal replacement treatment paradigm and improving practice patterns to
ensure customized and better care are the only ways to improve the outcomes of ESKD
patients.
In this context, two main options are available. First, HDF is today's most innovative, prom‐
ising, and advanced alternative to high‐flux HD. By combining diffusive and enhanced
convective solute mass transfer, HDF offers the most efficient RRT today over a wide spectrum
of uremic toxins including middle‐ and large‐sized solutes. Using ultrapure dialysis fluids
(water and dialysis fluid), HDF constitutes a highly biocompatible system and suppresses the
occurrence of microinflammation processes [13–15]. By reducing the incidence of hypotensive
episodes as well as dialysis intolerance symptoms [16–18], HDF may reduce or prevent
repetitive cardiovascular insults and their deleterious long‐term consequences. By giving
access to an unlimited amount of substitution fluid at the cost of ultrapure dialysis fluid, online
HDF provides a cost‐effective approach for optimizing and customizing HDF treatment
Update on Clinical Evidence Supporting Hemodiafiltration 79
http://dx.doi.org/10.5772/63027
prescription to the patient's metabolic needs. Provided that best clinical practices and hygienic
rules are applied, HDF offers a reliable, efficient, and cost‐effective RRT tool.
Second, the extension of treatment time is the more physiologic approach to improving patient
outcome, even if not the most popular one. Increasing treatment time and/or frequency is the
best way to facilitate sodium mass removal and thereby restore extracellular fluid volume, to
ensure removal of uremic compounds with low intracorporeal mass transfer coefficients or
tightly bound to albumin, and to minimize “nonphysiological” changes due to the aggressive
nature of intermittent treatment schedules. These two approaches, HDF and extended
treatment time, should not be considered competitive but rather complementary. Only a few
studies have combined the solute mass transfer capacity of HDF with increased treatment time
[19–21] and all clinical trials have confirmed the tremendous benefits of such combination on
intermediary and long‐term outcomes.
1.2. What is the clinical evidence for hemodiafiltration?
Although many studies associate HDF with significant improvements in ESKD patient
outcomes, still some conflicting data or cost concerns have hampered general clinical and
widespread acceptance of this method. Here, we attempt to reconcile facts and concerns
regarding HDF. To begin, it should be stressed that a differentiated understanding of HDF
should be adopted as opposed to considering HDF to be a generic term that covers all
convection‐based renal replacement modalities. The differentiation necessary lies in the
magnitude of the convection dose that must be delivered to improve outcomes of ESKD
patients. Based on published literature and our own experience, we revisit the current
definition of convective dose and its threshold value for improved patient outcome, we review
the factors affecting convective dose delivery, we summarize the best clinical practices in HDF
prescription, and we summarize the main studies addressing clinical outcomes.
2. Convective dose concept—from minimal to optimal dosage
According to the EUDIAL group recommendations, convective dose is the total volume of
ultrafiltration achieved per HDF session (L/session) and summed to week (L/week), standar‐
dized to postdilution convection volume for the various other dilution modalities (i.e., pre‐,
mixed, or mid‐HDF), taking differences in the fluid volumes into consideration [22]. This is an
easy and clinically relevant surrogate indicator of the convective component. Knowing that
only hemodialyzers containing membranes that are highly permeable to both water (Kuf>50)
and solutes (sieving coefficient β2‐microglobulin [β2M] >0.6) are used for HDF, it is possible
to calculate the convective component of solute clearance. An alternative proposal was to focus
more on the biological effect of middle‐molecule removal using biomarkers that reflect the
convective action of the HDF. Among uremic toxins, β2M, a 12‐kDa peptide, seems to be the
most clinically relevant representative of the middle‐molecule uremic toxins and strongly
implicated in both morbidity and mortality of CKD patients.
Following international guidelines, urea Kt/V has been established as the principle dialysis
dose quantifier and is regularly used as a quality‐control tool for treatment delivery. To be
valid, this approach requires certified methodology (appropriate urea sampling method and
time, suitable formula) and appropriate timing of measurements (minimum of once monthly)
to capture early deviation in dialysis efficacy. The ionic dialysance (iK) measurement embed‐
ded in some HD monitors is an option. This offers an interesting and cost‐effective alternative
that may be performed routinely at each session providing a true continuous quality‐control
tool. Using then the simplified concept of iKt, where iK stands for the average ionic dialysance
measured by HD monitor and t stands for the duration of the dialysis session, one can estimate
the total diffusive dose delivered per session (L/session).
The effective total dialysis dose (i.e., diffusive and convective) delivered to the ESKD patient
can be easily assessed. Convective dose as estimated by total ultrafiltered volume per session
(L/session) could be considered as a complementary component of the diffusive dose delivered
and estimated by iKt (L/session).
A systematic review of studies [retrospective cohorts, prospective randomized controlled trial

(RCT)] exploring the relationship of convective dose and patient outcome has shown that
survival benefit is observed only when a minimum threshold ultrafiltration volume has been
delivered [23]. The critical ultrafiltration volume per session (or per week) required for better
patient outcome is between 20 and 22 L/session for a typical European ESKD patient. More
recently, it has been shown that total ultrafiltered volume per session (or per week) acted as a
continuous variable mimicking a sigmoidal dose‐response curve [24].
The normalization of the convective dose to the patient's anthropometric characteristics has
been proposed to match with patient metabolic needs and also to facilitate the generalization
of this relationship with different patient profiles (e.g., Asian and American). In fact, such
normalization attempts using different scalings (i.e., body weight, height, body surface area,
and total body water) have been adopted in different studies, including the Estudio de
Supervivencia de Hemodiafiltración On‐Line (ESHOL) [25] and the individual personal data
meta‐analysis that was part of the European pooled project [26]. Interestingly, none of these
scaling factors have enhanced sensitivity in predicting the relative risk (RR) of mortality. Crude
convection volume per session (or per week) or convection volume scaled to body surface area
or total body water tend to perform best in predicting survival benefits or mortality risks where
HDF is concerned.
3. Factors affecting convective dose
Best clinical practices are essential in daily practice to achieve optimal ultrafiltration flow and
the total ultrafiltered volume targeted. Schematically, three basic components need to be
considered: patient‐dependent factors, prescription‐dependent factors, and technical or
machine‐dependent factors.
http://dx.doi.org/10.5772/63027
3.1. Patient‐dependent factors
3.1.1. Vascular access
The achievement of “high” blood flows (>350 mL/min) depends on the type of vascular access
(i.e., central venous catheter, arteriovenous fistula, or graft) and on the provision and mainte‐
nance of vascular access patency. Vascular access is defined as inadequate when an extracor‐
poreal blood flow of at least 300 mL/min cannot be reached. Basically, patients treated with
online HDF require a vascular access capable of delivering a consistent extracorporeal blood
flow between 350 and 400 mL/min or higher. Such extracorporeal blood flows could be reached
with large bore tunneled central venous catheters and with arteriovenous fistulas or grafts
delivering access flows of ≥500 mL/min. High blood flow is essential to ensure that a sufficient
amount of blood is processed during the treatment session. Vascular access flow performances
and needle sizes assume a fundamental role in preserving the advantages of applying a high
convection volume.
3.1.2. Individual patient criteria
Hematocrit and protocrit (the volume fraction of plasma proteins that may be calculated as
the product of 0.000718 and the total protein concentration of plasma proteins in g/mL [22])
affect negatively the plasma water volume and plasma water flow. High hematocrit (e.g.,
resulting from anemia management and hemoglobin targets) and high total protein concen‐
tration (e.g., due to the particular nutritional and inflammatory status of the patient) enhance
viscosity tremendously, reduce ultrafiltration capacity (filtration fraction), and provide
unfavorable conditions for ultrafiltration flow. The additional ultrafiltration applied to achieve
a given weight loss is an additive factor that may affect total ultrafiltration. Finally, a dynamic
interaction between blood flow (shear rate and shear stress), blood components (hematocrit
and protocrit), filtration fraction (ultrafiltration flow to blood flow ratio), and membrane
surface (protein layer formation) is crucial to facilitate ultrafiltration flow. Many of these factors
are taken into consideration in modern dialysis machine technology.
3.2. Prescription‐dependent factors
3.2.1. Blood flow
The effective extracorporeal blood flow delivered is a fundamental determinant of all extrac‐
orporeal cleansing therapies. Among factors that determine the efficiency with which uremic
solutes are removed during dialysis, extracorporeal blood flow, whether instantaneous (flow
rate) or cumulative (total blood volume processed over the session), is the most critical.
Treatment efficiency assessed either in terms of solute clearance or solute mass removal is then
dependent on the total blood “processed” within a dialysis session.
High blood flows are critical in HDF, as they have a dual action, one being to maximize the
amount of solute removed and the other being to preserve membrane permeability by
retarding the formation of a protein layer on the membrane (secondary layer formation). The
choice of needle size matters in HDF. Following Poiseuille's law, needle size is a barrier to high
blood flow: 15‐gauge needles (optimally 14‐gauge needles) are required to sustain blood flow
of ≥350 mL/min at an acceptable pressure regimen.
3.2.2. Choice of hemodiafilter
The choice of a specifically designed hemodiafilter is important to optimize ultrafiltration flow

and prevent dysfunction or alarms occurring on the HDF monitor due to hemorheological
changes in the dialyzer. Preferred hemodiafilter features, apart from being equipped with
highly permeable membranes, should favor the following to reduce internal convective
processes: low blood flow resistance (large lumen diameter of fibers (e.g., 200 μm), short length
of dialyzer housing, and increased number of fibers per sectional surface area.
3.2.3. Anticoagulation
Methods of anticoagulation will not addressed here in detail. However, anticoagulation is

required to prevent thrombosis of extracorporeal blood circuit and to ensure a safe and efficient
HDF session. Different kinds of antithrombotic agents can be used systematically by intrave‐
nous (IV) injection.
Unfractionated heparin (UH) is administered as an IV bolus dose (30–50 IU/kg) at the start of
the HDF session followed by continuous IV infusion (500–700 IU/h). The heparin dosing
regimen for HDF does not differ from that in regular HD.
The use of low molecular weight heparin (LMWH) is nowadays favored by many centers
because of its ease of use and its better risk profile. In this case, LMWH should be preferably
administered IV into the venous line and not into the arterial line to prevent significant loss
during the first hemodialyzer passage.
3.2.4. Treatment time prescription
The prescription of HDF treatment time duration and frequency is usually based on the
patient's metabolic needs, extracellular fluid management, and cardiovascular and session
tolerance. Increasing both the duration and frequency will facilitate the delivery of a high
volume of ultrafiltration. A pragmatic approach is to establish a suitable convective dose for
a given patient and to increase the treatment time according to the limitation of effective blood
flow delivery.
3.3. Technical or machine‐dependent factors
3.3.1. Transmembrane pressure management
Achieving high ultrafiltration rates and targeted ultrafiltration volumes can be challenging
and requires the careful management of the transmembrane pressure (TMP) according to the
treatment modality selected. In attempting to achieve high ultrafiltration volumes, hemocon‐
centration within the filter commonly results in high TMP, triggering pressure alarms and
http://dx.doi.org/10.5772/63027
potentially causing cell damage. Basically, the augmented protein layer formation occurring
naturally at the blood‐membrane surface during the course of the HDF session fouls the
membrane pores and reduces the membrane's hydraulic permeability. In combination with
the increased oncotic pressure (total protein increase) along the fibers, this tends to reduce the
ultrafiltration flow. Faced with situations of high TMP increase and/or pressure alarms,
nursing staff manually reduce the substitution flow and thus reduce the chances of achieving
the targeted ultrafiltration volume.
3.3.2. Machine options
New features to optimize HDF performances and achieve optimal convective doses are
currently available. The adjustment of the substitution mode was the most obvious and
primary focus of investigation. When postdilution is problematic, switching to pre‐, mixed, or
mid‐dilution mode may be a viable alternative. In all these cases, the targeted convection
volume needs to be adjusted for the dilution factor corresponding to the HDF modality chosen
(e.g., x2 for predilution HDF or x1.5 for mid‐dilution HDF in manual prescription) to match
efficacy with the postdilution mode.
New technical features involving specific software algorithms are currently being implement‐
ed and tested in new online HDF machines. Basically, the idea is to provide an automatic
ultrafiltration control system to reduce membrane fouling and ensure maximal ultrafiltration
flow considering basic operational conditions of blood flow, hemorheological conditions, and
prescription setting. Schematically, the system avoids excessive hemoconcentration by the
continuous adaptation of the substitution flow according to changes in blood viscosity within
the dialyzer as identified by signal analyses of the pressure pulses transmitted from the
peristaltic blood pump. Signal analysis is conducted several times per minute, and the
substitution rate is automatically adapted based on pressure pulse attenuation and cross‐
membrane pressure assessment. Using such automatic control systems, it is possible to
increase the ultrafiltered volume per session by 10 to 20% without harming the patient, filter,
or cells.
3.3.3. Other machine‐related variables
As mentioned previously, treatment time is one of the factors limiting the increase of “dialysis
dose”. In the current models of delivering dialysis in dialysis units, based on shifts assigned
to nurses with a ratio of one nurse to three to five patients, any further increase of treatment
time has an associated cost. Out of the 5.5 to 6 h of the shift length for each single nurse, it is
possible to deliver a median of 4 h of treatment to three to five patients. There are two ways
to achieve a cost‐neutral increase in treatment time. The first is to reduce the time needed to
prepare the dialysis equipment before initiating treatment. Faster disinfection of the dialysis
machine is achievable with more simple hydraulic components and/or more effective disin‐
fection processes. Also, the disinfection of the machine surface can be simpler, safer, and faster;
this is achievable with especially designed equipment surfaces having as few discontinuities
as possible. The second way is to reduce the number and complexity of nurse interventions.
This approach may allow nurses to treat more patients, thus decreasing the cost of treatment
for each patient per hour. Consequently, it could be possible to increase the time of the shift
and the treatment time in a cost‐neutral manner. Is this possible? According to Tsobanelis et
al. [27], new dialysis equipment under testing in HDF mode for fistula patients had a 24%
reduction in the number of major handling steps compared to the previous dialysis machine
from the same company.
Other aspects to be considered when targeting an increase of patient to nurse ratio are those
related to safety. The risk of harm has to be reduced as much as possible, and one option is to
reduce this risk by the improved design of the equipment. As an example, we can again
mention the recent experience of Tsobanelis et al. [28], who reported that the tested new
equipment had 27% fewer major process steps and touch points critical to hygiene compared
to the current machine version. The authors found it particularly noteworthy that it was
possible to avoid disconnection of the arterial line from the arterial needle with the redesigned
process of blood reinfusion at the end of the session.
Finally, in the time of green economy, the authors also highlighted that the switch from
an infusion line to an integrated infusion port reduced the volume of contaminated waste.
The major source of waste relates to the disposables (bloodlines and dialyzers), so that
newly designed, integrated disposables can facilitate a reduction of disposable waste, for
example, of approximately 0.2 kg/session as reported by Schleser et al. [29], which, given
an average of 10,000 treatments yearly delivered by a dialysis unit, translates into 2000 kg
less waste. In terms of carbon footprint, one should also consider the consumption of water
and energy and how this can be limited, for example, by having a more efficient water
treatment system.
4. HDF prescription and implementation of best practices
4.1. Current status
Online HDF can no longer be considered an experimental treatment but has now developed
into a mature and accepted RRT. In fact, this dialysis modality is employed for sustaining the
lives of more than 160,000 ESKD patients worldwide, including 80,000 in Europe, Middle East,
and Africa. Europe played a leading role in developing this therapy, where the prevalence of
HDF is close to 18% (varying across countries from 0 to 100%). The annual growth rate is
approximately 6% [30]. In 2013, Japan treated 31,273 patients with HDF (23,445 thereof on
online HDF), representing 10% of its total dialysis population (294,605 patients; Kawanishi,
personal data). The number increased by 4% between 2013 and 2014 as positively influenced
by the implementation of a specific reimbursement fee in 2012. Interestingly, in Japan, the
predominant HDF mode is predilution HDF (90.8% of HDF treatments).
4.2. Treatment schedule prescription
The prescription of the HDF treatment schedule is based on the usual target of providing
optimal RRT to the ESKD patient. It is a composite and trade‐off between patient‐specific issues
http://dx.doi.org/10.5772/63027
(e.g., metabolic needs, treatment tolerance and acceptance, and patient‐treatment interaction),
local logistical and practical issues (e.g., facility and/or modality availability), and health
regulation and reimbursement policies.
The duration and frequency of sessions are based on two main components: (1) patient's
metabolic needs and dialysis adequacy targets and (2) extracellular fluid management and
cardiovascular tolerance depending on ultrafiltration rate. Increasing session length and
frequency will facilitate the achievement of a high ultrafiltration volume. A pragmatic
approach is to estimate a suitable convective dose for a given patient and to increase the
treatment time according to the limitations present regarding effective blood flow or other
hemorheological factors.
In clinical practice, prescription comprises the setting of the substitution rate (substitution
volume per session extended to weekly volume) and adding the required weight loss to
achieve the dry weight for that patient. Based on the results of recent studies, a minimal
substitution volume of 60 L/week (or 40 L/m2 body surface area) is required in individual
ESKD patients to improve patient outcome. The additional ultrafiltration volume required
for the correction of extracellular fluid volume excess has to be added to the substitution
volume.
The hemodialyzer used for HDF must contain membranes that are highly permeable for both
water (Kuf>50 mL/h/mmHg) and solutes (sieving coefficient for β2M≥0.6) with adequate
dialyzer surface area. Filter design should favor a low internal blood flow resistance, thereby
reducing membrane fouling and minimizing backfiltration as much as possible. A simple rule
of thumb commonly applied in clinical practice is to consider 1 m2/each 200 mL/min effective
extracorporeal blood flow, meaning that a 2.0 m2 hemodialyzer is appropriate for a blood flow
of 400 mL/min [31].
In the past, the composition of the dialysis fluid differed from that of the substitution fluid.
This is not the case in online HDF. Given the current definition of convective treatment
adequacy, based on 23 L/session of convective dose in postdilution HDF, this equality of fluid
compositions, and also the HDF mode, may affect the mass balance of electrolytes during the
treatment session. Several studies dealing with the dialysate/substitution fluid prescription
and focusing on sodium, calcium, and bicarbonate have been published.
Sodium: The importance of the correct sodium balancing during dialysis, preventing sodium
overload with resultant thirst and water overload, has long been recognized. This risk of
sodium loading also has to be considered in high efficiency treatments coupling diffusion and
high volume convection. In a 1991 evaluation of HDF sessions with convective doses ranging
between 9.1 and 16.7 L/week, Pedrini et al. [32] found that sodium balance was mainly affected
by the sodium concentration gradient between initial plasma water and dialysate, the sodium
level in the substitution fluid, and the imposed ultrafiltration rate. In the same patients treated
with similar operating conditions, significantly lower net sodium removal was observed when
on predilution compared to postdilution HDF [33]. Despite the complexity of managing the
multifactorial equations describing the relationship between affecting variables and sodium
balance (e.g., the laboratory method for the determination of sodium and the negative charge
of plasma proteins) [33], ideal modern equipment should be able to automatically address
sodium balance.
Calcium: The target in the case of calcium is to maintain a neutral calcium balance, as an
excessive calcium load has been associated with vascular calcification, whereas calcium
depletion has been linked to worsening secondary hyperparathyroidism and decreased bone
mass [34]. Here also, the modality of HDF affects the balance. Although calcium balance during
postdilution online HDF does not differ from standard HD, it is usually recommended to
increase the dialysate/substitution fluid calcium concentration by 0.25 mmol/L in predilution
HDF mode in order [34]. In addition, discrepancies between expected and observed concen‐
trations in the dialysate/substitution fluid play an important role in the case of online HDF. In
a volumetric system based on conductivity, the sodium for the bicarbonate dialysate/substi‐
tution fluid comes in part from a basic component and in part from an acidic component. In
cases of a decrease in dialysate sodium with concomitant increase of bicarbonate, a lower
proportion of the acid component will produce a lower than expected calcium level in the
dialysate/substitution fluid [35].
Bicarbonate: a positive bicarbonate balance is targeted during the treatment session to

neutralize the interdialytic accumulation of strong acid anions and to avoid starting the next
session with metabolic acidosis. However, there is also a risk of postdialysis alkalosis. In a
recent publication by Havlin et al. [36] analyzing 68 patients on postdilution HDF treated for
4 to 5 h with 80 to 90 mL/min of substitution fluid (19–27 L/session) with a dialysate bicarbonate
concentration of 32 mmol/L, 34% of patients were acidotic at dialysis initiation, but 80% had
metabolic alkalosis after dialysis. They speculated that this was due to an excessive elimination
of retained and endogenous anions. According to the authors, this observation requires further
investigation. In any case, several factors affect the mass balance. A significantly lower
bicarbonate gain was observed in predilution HDF versus postdilution HDF [37]. As is true
for all electrolytes, the difference in concentration between bicarbonate levels in the dialysate/
substitution fluid and in the blood at the initiation of the session is positively correlated to the
mass transfer. Therefore, to maintain the same bicarbonate balance when moving from
postdilution HDF to predilution HDF, dialysate bicarbonate concentration should be increased
by 2 mmol/L. In fact, in predilution HDF, bicarbonate levels of the blood entering in the
dialyzer increase, enhancing the loss across the membrane and reducing the normal gain by
diffusion from dialysis fluid to blood [33].
5. Clinical outcomes
5.1. Intermediary treatment outcomes (short‐term studies)
In this section, intermediary treatment outcomes stand for surrogates of primary outcomes in
assessing HDF safety, efficacy, and tolerance. For this purpose, we focus on cardiovascular
stability and treatment tolerance, solute removal (phosphate, β2M), and inflammation,
oxidative stress, and anemia.
http://dx.doi.org/10.5772/63027
5.1.1. Cardiovascular stability and treatment tolerance

In the short term, a significant reduction in the episodes of intradialytic hypotension was
observed in HDF compared to conventional HD [16]. This has been ascribed to negative
thermal balance (due to the infusion of relatively cool replacement fluid), a high sodium
concentration of the substitution fluid, and/or removal of vasodilating mediators [4].
5.1.2. Solute removal: phosphate, β2‐microglobulin

Several controlled studies have confirmed enhanced clearance and mass removal of β2M with
HDF (30–40% higher than high‐flux HD) accompanied by a 10 to 20% decline in circulating
blood β2M concentrations [38, 39]. It must be reminded that reduction of circulating predialysis
β2M takes time, as plasma levels reflect the equilibrium between production and elimination
rates. Thus, 3 to 4 weeks are required to achieve a new steady‐state and a serum concentration
change [40]. Recently, it has been calculated in a large cohort of incident ESKD patients that
each additional 10 L convection volume was associated with a 0.8 mg/L reduction of β2M [24].
Phosphate mass removal and serum phosphate is a major concern in ESKD patients. RRT
accounts for 60 to 70% of the total amount of phosphate removed to restore weekly phosphate
mass balance. The other 30 to 40% needs to be eliminated by feces through the combined action
of diet and phosphate binders. Although still a matter of controversy, high efficiency HDF has
been shown to enhance the phosphate mass removed by 15 to 20% [41] with a subsequent
predialysis serum phosphate level reduction of 6%. The percentage of patients reaching target
pretreatment serum phosphorus levels with HDF was reported to increase from 64 to 74% in
the Convective Transport Study (CONTRAST) [42].
Higher clearances of a number of other uremic compounds have also been documented with
HDF: complement factor D (a proinflammatory mediator), leptin (16 kDa; involved in loss of
appetite), FGF23 (30 kDa, implicated in metabolic bone disorders and vascular calcification),
various cytokines, circulating advanced glycosylation end products (AGEs), and AGE
precursors [43, 44].
5.1.3. Inflammation, oxidative stress, and anemia

Inflammation and oxidative stress profiles tend to be improved in patients treated by HDF.
Several prospective studies have shown that levels of C‐reactive protein (CRP) and other
sensitive biomarkers of inflammation (e.g., interleukin‐6) and/or proinflammatory cells are
reduced. In this field, the Rischio cardiovascolare nei pazienti afferenti all'area vasta in dialisi
(RISCAVID) study is certainly one of the more convincing studies, being conducted in a large
cohort of dialysis patients [7, 45]. A meta‐analysis has recently reemphasized that the regular
use of ultrapure dialysis fluid was the main driving force for such benefits [14].
The erythropoiesis‐stimulating agent (ESA) dose could be reduced in HDF, as reported in
several clinical studies and summarized in a systematic review [46]. The benefit was attributed
to the combined effects of the higher removal of middle‐sized toxins (erythropoietic inhibitor
substances) and reduced inflammation due to the use of higher‐quality water and dialysis fluid
[47, 48]. However, this effect was not confirmed in a recent meta‐analysis [49].
5.1.4. Clinical benefits
Several large cohort studies have indicated that the extended use of high‐flux membranes and
convective therapies has a beneficial impact on the development of β2M amyloidosis in the
long term, reducing the incidence of carpal tunnel syndrome and other related manifestations
[50, 51]. This beneficial effect probably results from the regular use of ultrapure water and
biocompatible materials, reducing inflammation, combined with convective modalities that
enhance β2M removal [52].
5.2. Endpoint outcomes (morbidity and mortality)
In this section, endpoint outcomes are hard primary outcomes in assessing HDF long‐term
efficacy. Consequently, the focus here is on mortality (all‐cause and cardiovascular) and
morbidity (hospitalization, dialysis‐related pathology).
5.2.1. Observational (cohort) studies on hemodiafiltration and clinical endpoints
Locatelli et al. [50] conducted a retrospective observational study (Lombardy registry) of 6444
patients with ESKD who started RRT on HD, HDF, or hemofiltration (HF) between 1983 and
1995. A total of 1082 patients were treated with HDF or HF (first choice in the case of 188); the
median follow‐up time was 29.7 months. Interestingly, after adjustment for age, gender, and
comorbidities (including diabetes), the RR for carpal tunnel surgery and mortality was 42%
(statistically significant) and 10% lower (not statistically significant) in patients treated with
HDF or HF.
In 2006, Canaud et al. [53] reported results of a prospective, nonrandomized observational

study from the Dialysis Outcomes and Practice Patterns Study (DOPPS) of 2165 patients
followed between 1998 and 2001 in five European countries. Patients were stratified into four
groups: low‐flux HD (n=1366), high‐flux HD (n=546), low‐efficiency HDF (n=156; substitution
volume 5–14.9 L/treatment), and high‐efficiency HDF (n=97; substitution volumes 15–24.9 L/
treatment). Patient characteristics (including age and sex), 14 comorbidities, and time on
dialysis were similar in each group. High‐efficiency HDF patients had lower crude mortality
rates than low‐flux HD patients. After Cox regression analysis with adjustment, high‐efficiency
HDF patients had a 35% significantly lower mortality risk than those receiving low‐flux HD.
Also in 2006, Jirka et al. published the results of an observational study of 2564 ESKD patients
(394 on HDF) treated in Fresenius Medical Care clinics and followed for 12 months. Data were
collected in the European Clinical Database (EuCliD) [54]. In this patient cohort, all‐cause
mortality was reduced by 43% and unadjusted mortality was reduced by 35% in patients
treated with HDF compared to HD. Convection volume was not reported.
In 2008, Panichi et al. [7] reported the results of a prospective observational study performed
in the northwestern part of Tuscany that included 757 ESKD patients (RISCAVID study) who
were followed for 30 months. Treatment with low‐ or high‐flux HD (n=424) was compared to
treatment with HDF using substitution fluid delivered in bags (130 patients on low‐volume
HDF with acetate‐free biofiltration (AFB) and 74 patients on HDF with convection volumes of
http://dx.doi.org/10.5772/63027
10–15 L/treatment) and treatment with online HDF (129 patients on HDF with convection
volumes of 22–25 L/session). Cox proportional hazards regression analysis showed that online
HDF and bag HDF patients had a significantly better survival than HD patients, having a 22%
reduced risk of all‐cause mortality after adjustment.
One year later, Vilar et al. [55] reported the results of an observational study of 858 incident
ESKD patients in the United Kingdom followed over 18 years. Patients treated with online
HDF (n=232) received 79% of treatments with this modality and a mean filtration volume of
14.9 L/session. The control group was treated exclusively with high‐flux HD (n=626) and pure
dialysis fluid. The mortality risk was significantly reduced in patients receiving predominantly
HDF [hazard ratio (HR) 0.45; p<0.001] after adjustment for age, gender, body mass index, and
comorbidities.
Imamovic et al. reported the Balkan experience in 2014. In this cohort study of 442 incident
patients, the risk of death for HDF‐treated patients relative to high‐flux HD patients was 0.87
(nonsignificant) for low‐volume HDF and 0.29 (highly significant) for high‐volume HDF. After
adjustment for covariates, the HR for patients on low‐volume HDF remained statistically not
significant compared to high‐flux HD (HR 0.84; nonsignificant), whereas patients on high‐
volume HDF had a significantly lower HR (0.29; nonsignificant) than high‐flux HD. In the
time‐dependent analysis, the mortality risk was not lower in high‐volume HDF compared to
high‐flux HD (HR 0.48; nonsignificant), but this may be because 44% of the patients changed
treatment modality during follow‐up [56].
In 2015, Siriopol et al. published a report on the Romanian experience with HDF. In this study,
the group of 221 prevalent patients treated with online HDF (mean convection volume was
22.2 L) was propensity score matched to a group of 431 patients treated with HD [57]. Online
HDF was associated with a reduced mortality risk (HR 0.62; statistically significant). A second
cohort consisting of 265 incident patients on HDF were matched with 530 patients treated with
HD. The mortality risk was significantly lower in patients treated with HDF (HR 0.22; highly
statistically significant).
In another study, Canaud et al. reported results based on the EuCliD database involving 1590
incident patients in 12 European countries. The patient groups receiving high volume HDF
(≥21 L/session) were propensity score matched to the group receiving HD. Patients were
followed for 2 years (HD group) or 1.6 years (high‐volume HDF group) [58]. In this study, a
nonsignificant survival advantage of HDF was found (HR 0.88; nonsignificant). Using inverse
probability of censoring weighting (IPCW) to take bias due to the large amount of modality
crossover during the follow‐up time into consideration (7% HDF patients switched to HD; 55%
HD patients switched to high‐volume HDF), a statistically significant survival advantage of
high‐volume HDF was found (odds ratio 0.501; highly significant).
Canaud et al. [24] recently published the results of a dose‐finding study exploring the optimal
convection volume required to observe an increase in patient survival. This was a retrospective
analysis involving 2293 incident HDF patients whose treatments were documented in the
EuCliD database. Advanced statistical tools, including cubic spline analyses, were applied for
the determination of the range of convection volume over which a survival benefit was
observed. The relative survival rate of online HDF patients, adjusted for age, gender, comor‐
bidities, vascular access, albumin, CRP, and dialysis dose, was found to increase at approxi‐
mately 55L/week and to stay increased up to approximately 75L/week. Similar analysis of
predialysis β2M concentrations found a nearly linear decrease in marker concentration, as
convection volume increased from 40 to 75L/week. The analysis of log CRP levels showed a
decrease over the same convection volume range.
Mercadal et al. reported a study using data from the French national Renal Epidemiology and
Information Network (REIN) registry to assess the effects of HDF on mortality in the total
population of incident dialysis patients (treatments were performed between 01/01/2008 and
31/12/2011 and patients were followed up to the end of 2012) [59]. Analyses were performed
at both patient and facility levels. Here, 5526 out of 28,407 ESKD patients used HDF for a
median of 1.2 years and 2254 of them used HDF exclusively. All‐cause and cardiovascular
mortality associated with HDF use were significantly reduced (HR 0.84 and 0.73, respectively).
In patients treated exclusively with HDF, the beneficial effects on all‐cause and cardiovascular
mortality were more pronounced (HR 0.77 and 0.66, respectively). At the facility level,
increasing the percentage of patients using HDF from 0 to 100% reduced the HR for all‐cause
and cardiovascular mortality (HR 0.87 and 0.72, respectively). The authors concluded that,
irrespective of whether analyzed at patient or facility level, HDF treatment was associated with
better survival.
5.2.2. Prospective RCTs
Four prospective controlled or randomized studies comparing HDF and standard HD have
been reported in the past which were not designed (short term <12 months) or sufficiently
powered (<100 patients) to assess mortality differences between modalities [25, 38, 60, 61].
These will not be discussed in this chapter.
The Dutch CONTRAST was performed in 29 centers in The Netherlands (n=26), Canada (n=2),
and Norway (n=1) [62]. Here, 714 patients were randomized between treatment with low‐flux
HD and online postdilution HDF between 2004 and 2009, both with ultrapure dialysate. The
primary endpoint was all‐cause mortality, and the main secondary endpoint was a composite
of fatal and nonfatal cardiovascular events. Of 358 HDF patients, 121 discontinued treatment
during the study due to transplantation, switch to another center or therapy, or other reasons.
Of 356 HD patients, 118 patients discontinued the allocated treatment. The mean follow‐up
was 36 months (range 5–79 months); during this period, 269 deaths occurred in 2170 person‐
years. All‐cause mortality (HR 0.95; nonsignificant) as well as cardiovascular events (fatal and
nonfatal; HR 1.07; nonsignificant) were not affected by treatment modality. Although the target
convection volume was set at 24 L/treatment, the mean volume achieved was 20.7 L/session
and only one third of centers achieved at least 24 L/session. Post hoc analyses based on
convection volume delivered (tertiles) showed a significantly lower mortality in patients
receiving the highest convection volume (>21.95 L/session). In this subgroup, mortality risk
was reduced by 39% compared to HD (HR 0.61; significant), which remained after extensive
adjustments.
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The Turkish Hemodiafiltration Study with 782 patients was conducted between 2007 and 2010
in 10 centers; patients were randomized to treatment with online postdilution HDF or high‐
flux HD [63]. Patients with central venous catheters, poor blood flow, and significant residual
urine output were excluded. The primary endpoint was a composite of all‐cause mortality and
first nonfatal cardiovascular event. Of 391 patients treated with HDF, 110 discontinued the
study (28%), including 40 (10%) who terminated early due to vascular access problems. Of 391
patients randomized to HD, 90 patients (23%) dropped out. The mean follow‐up time was 23
months (range 1–38 months). The mean substitution volume was 17.2 L/session and the mean
intradialytic weight gain was 2.4 L/treatment, corresponding to a mean total convection
volume of 19.6 L/treatment. The RR of death and first cardiovascular event was 0.82 (non‐
significant), and the RR for all‐cause and cardiovascular mortality was 0.79 (nonsignificant)
and 0.72 (nonsignificant), respectively. In a post hoc analysis, patients who achieved a
convection volume above the median of 17.4 L/session had a significant lower risk of all‐cause
and cardiovascular mortality (RR 0.54 and 0.29, respectively; both highly significant). This
association remained after extensive adjustments for age, gender, comorbidity, and practice
patterns.
The Catalonian Hemodiafiltration Study (ESHOL) included 906 Spanish dialysis patients in
27 units who were randomized to online postdilution HDF (n=456) and HD (n=450) [64]. In
the HD group, 8% of the patients were treated with low‐flux membranes and 92% were treated
with high‐flux membranes. The mean follow‐up time was 23 months. Here, 355 patients
dropped out of the study for various reasons and were censored at the time of loss (36% in the
HD group and 42% in the HDF group). Centers involved in the study received a short training
course on how to achieve the targeted convection volume. The median convection volume in
HDF treated patients was 22.9 to 23.9 L/treatment. Here, 207 events were observed in 1730
patient‐years. A significant 30% decrease in all‐cause mortality and 33% decrease in cardio‐
vascular mortality were observed in the HDF group. Interestingly, a post hoc analysis based
on convection volume showed that the highest convection volume tertile (>25.4 L/treatment)
was associated with a lower mortality risk (HR 0.55; highly significant) compared to HD
patients.
5.2.3. Meta‐analyses
Several meta‐analyses comparing conventional HD and convective‐based therapies have been
published over the last decade.
Rabindranath et al. from the Cochrane group performed two analyses in 2005 and 2006. The
latter included 20 trials (657 patients). Mortality results were available only in 4 trials (336
patients) and different therapies were mixed (AFB, HF, and HDF). The authors found no
difference in mortality risk for patients treated with convective‐based therapies [26, 65]. This
systematic review was severely criticized due to its poor methodology [66, 67].
Susantitaphong et al. [49] compared convective‐based therapies to standard low‐flux HD. HF,
HDF, AFB, and high‐flux HD were all included in the convective therapy group. This meta‐
analysis aggregated data of 12,182 patients. Convective therapies resulted in a nonsignificant
decrease in all‐cause mortality (RR 0.88) and all‐cause hospitalization (RR 0.91); a significant
decrease in therapy‐related hypotension (RR 0.55) and cardiovascular mortality (RR 0.84) was
reported. The authors concluded that convective therapies were associated with improved
clearance of uremic solutes, but the potential long‐term benefits of specific convective modal‐
ities could not be confirmed.
Wang et al. [68] conducted a systematic review and meta‐analysis that included 16 trials and
3220 patients treated with convective‐based therapies (HDF and HF) and with standard HD
(low- and high-flux). Convection volume was not considered as a confounder in this analysis.
On the one hand, the authors concluded that convective modalities did not significantly reduce
the risk of cardiovascular events (RR 0.85) or all‐cause mortality (RR 0.83). On the other hand,
they noted that convective modalities reduced intradialytic symptomatic hypotension (RR
0.49) and reduced serum β2M levels (‐5.95 mg/L).
Mostovaya et al. [69] compared exclusively HDF to HD (low- and high-flux) including 2402
patients. The meta‐analysis identified six RCTs. The convective arm consisted exclusively of
HDF patients treated with different HDF modes (a mixture of postdilution, mid‐dilution, and
predilution HDF, and of online HDF and HDF with bags) and achieving a specified minimum
convection volume. All‐cause and cardiovascular mortality were reduced with HDF compared
to HD (RR 0.8 and 0.73, respectively).
Nistor et al. [70, 71] from the Cochrane group updated the previous systematic review of 2005
and compared HD (low- and high-flux) to convective‐based modalities (HF, AFB, bag HDF,
and online HDF) without considering convection volume. Thirty‐five trials (4039 patients)
were included in this meta‐analysis and the effects on mortality were estimated. The convective
group consisted of 1648 patients, but 227 of them were treated with low convection volumes.
Within the limitations of the review (e.g., studies reviewed were partially old and referred to
a diverse mixture of HDF modalities), the authors concluded that convective therapies had no
significant effect on reducing all‐cause mortality (RR 0.87), cardiovascular mortality (RR 0.75),
and intradialytic hypotension (RR 0.72) but had uncertain effects on nonfatal cardiovascular
events (RR 1.14) and hospitalization (RR 1.21).
5.2.4. Individual participant data meta‐analysis
An alternative to the aggregated data meta‐analysis approach is to perform meta‐analysis of

individual participant data in which the raw “individual level data” for each study are
obtained and analyzed. The term “individual participant data” relates to the data recorded for
each participant in a study. Individual participant data sets of four randomized trials were
pooled and used to compare online HDF to HD. The four studies aggregated 2793 patients and
were designed to examine the effects of HDF on mortality endpoints. Bias by informative
censoring of patients was resolved. HRs comparing the effect of online HDF versus HD on all‐
cause and cause‐specific mortality were calculated using Cox proportional hazard regression
models.
In the first part of this individual participant data meta‐analysis, Davenport et al. [72] analyzed
the relationship between convection volume and patient outcomes. After a median follow‐up
time of 2.5 years, 769 of the 2793 participants had died (292 cardiovascular deaths). Convection
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volumes were either not standardized or standardized to weight, body mass index, body
surface area, and total body water. Data were analyzed by multivariable Cox proportional
hazards modeling from 2793 patients. All‐cause mortality was reduced when the convective
dose was unstandardized or standardized to body surface area or total body water; corre‐
sponding HRs were 0.65 (0.51–0.82), 0.74 (0.58–0.93), and 0.71 (0.56–0.93). Standardization by
body weight or body mass index was not associated with significant survival advantages.
Higher convection volumes were generally associated with greater survival benefit with online
HDF, but results varied across the different ways of standardization for body size. Further
studies should take body size into account when evaluating the impact of convection volume
on mortality endpoints.
In the second part of this analysis, Peters et al. [73] also investigated the effects of convection
volume on patient outcomes. HRs comparing the effect of online HDF versus HD on all‐cause
and cause‐specific mortality were calculated using Cox proportional hazards regression
models. The relationship between convection volume and the study outcomes was examined
by delivered convection volume standardized to body surface area. Online HDF reduced the
risk of all‐cause mortality by 14% and cardiovascular mortality by 23%. There was no evidence
for a differential effect in predefined convection volume subgroups. The largest survival
benefit was for patients receiving the highest delivered convection volume (>23 L/1.73 m2 body
surface area per session), with a multivariable‐adjusted HR of 0.78 (95% confidence interval
0.62–0.98) for all‐cause mortality and 0.69 for cardiovascular disease mortality. This pooled
individual participant analysis indicates that online HDF reduces the risk of mortality in ESKD
patients. This effect holds across a variety of important convection volume subgroups of
patients and is most pronounced for those receiving a higher convection volume normalized
to body surface area.
6. Conclusions
Online HDF can no longer be considered an experimental treatment; it is a mature RRT that
is applied daily to sustain the lives of more than 160,000 ESKD patients worldwide, including
80,000 in Europe, Middle East, and Africa. Europe has played a leading role in developing this
therapy, where the prevalence of HDF is close to 18% with variations across countries from 0
to 100%.
Interestingly, it has recently been also shown that clinical benefits associated with HDF were
directly correlated with the total ultrafiltered volume delivered, either per session or per week.
This finding adds a new component, namely convective dose, that needs to be integrated into
our conventional dialysis adequacy concept. In addition, accumulating evidence from both
retrospective and prospective RCT studies confirm the clinical safety and sustainability of HDF
therapy and support its superiority over conventional HD in terms of morbidity and mortality.
In line with these facts, the remaining and crucial challenges today are to implement best
clinical practices to achieve the optimal convective dose required, to define which subset of
ESKD patients should benefit most, and to evaluate new tools facilitating and fine‐tuning HDF
prescription according to ESKD patient needs (e.g., electrolyte balancing and quantification
and homeostasis).
7. Compliance with ethical standards
Conflict of interest: Bernard Canaud, Aileen Grassmann, Laura Scatizzi, and Daniele Marcelli
are employees of Fresenius Medical Care.
Author details
Bernard Canaud1*, Aileen Grassmann2, Laura Scatizzi2 and Daniele Marcelli2
*Address all correspondence to: bernard.canaud@fmc‐ag.com
1 Center of Excellence Medical, Fresenius Medical Care, Bad Homburg, Germany
2 Clinical and Epidemiological Research, Fresenius Medical Care, Bad Homburg, Germany
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Chapter 7
Home Haemodialysis and Haemodiafiltration
Sandip Mitra and Kunaal Kharbanda
http://dx.doi.org/10.5772/64095
Abstract
There has been a resurgence in home haemodialysis over the last decade and interest
in online haemodiafiltration in gaining momentum with advances in technology and
the results of recent clinical trials. Both increasing haemodialysis frequency and
treatment time have a number of potential benefits in improving dialysis efficiency and
are ideally placed in the home setting. This chapter describes the rationale behind
dialysis treatments, which go beyond conventional haemodialysis (CHD) and future
avenues for home dialysis, which may involve combining convective therapy with more
frequent treatment.
Keywords: haemodialysis, haemodiafiltration, extended haemodialysis, home haemo‐

dialysis
1. Introduction
Haemodialysis treatment has changed the lives of millions of patients around the world who
have advanced kidney disease. The treatment has advanced considerably since the first
treatment on a human, lasting just 15 minutes and performed by George Haas in Giessen,
Germany, in October 1924 [1]. It was not until the 1960s when maintenance haemodialysis
really started and at present, over 90 years since Haas, there are over 400,000 prevalent users
in the USA alone [2]. Dialysis provides a bridge to transplantation for some, and for others, it
allows survival when residual kidney function is no longer sufficient to sustain life. While the
survival of patients has improved since the early days of its inception, the survival of
haemodialysis patients remains unacceptably poor. In the United Kingdom, 18% of those aged
65–74 starting haemodialysis will not survive 1 year [3]. Five‐year survival data has often been
compared to those of patients with cancer to make the figures more tangible. With recent
figures showing 50% survival at 5.8 years in the 55–64 years group [4], it is not hard to see why
this comparison is made. Clearly, one of the key challenges for the nephrology community is
to change this unacceptably high mortality rate. In addition to this, there are many other factors
that make a large difference to the patient in front of us, and arguably, these are as impor‐
tant to address and considerably improve.
2. Background
The aim of haemodialysis is to replicate normal physiology as much as possible. Although this
may sound straightforward initially, there are a vast array of factors to consider. The ideal
treatment should give good survival rates, prevent cardiovascular events and hospitalizations,
effectively manage fluid and salt balance and address the anaemia and mineral‐bone disorder
associated with chronic kidney disease (CKD). Patient well‐being, cognition, sleep, the ability
to work and nutritional status are also hugely important factors which need addressing and
the list could continue. For a treatment, which for the majority of patients is performed for 12
hours of the week (just 7% of the week in terms of time), this is an incredibly tall order and it
is not entirely surprising that outcomes remain poor.
Conventional haemodialysis (CHD) is the most common treatment schedule and lasts for 3–4
hours thrice weekly. This treatment mainly takes place in a hospital or in a dedicated dialysis
unit. Other treatment regimes include short daily haemodialysis (SDHD), which is performed
for 1.5–3 hours 5–7 times per week, long nocturnal daily haemodialysis (LNDHD) which is
performed for 6–8 hours 5–7 times per week and long conventional haemodialysis (LHD),
which is typically 8 hours 3 times per week.
Although CHD is the most common treatment regime now, LHD was the most common
treatment initially in the 1960s [5]. This treatment came about purely by convention. Home
haemodialysis in the United Kingdom was started in London in 1964 by Shaldon and his team
[6] and expanded following this. Home haemodialysis was necessary as hospital facilities were
sparse, treatment times were lengthy and home dialysis offered both financial and logistical
benefit. Prevalence in the United Kingdom peaked in 1982 when 62% of HD patients were at
home [3]. As dialysis treatment time shortened and patient numbers increased, haemodialysis
practice changed from a predominantly home‐based therapy to a predominantly hospital‐
based therapy.
The National Cooperative Dialysis Study (NCDS) (n = 151) [7] was published in 1981. It showed
no difference between the shorter and longer duration dialysis groups (2.5–3.5 hours three
times per week vs. 4.5–5 hours three times per week). This further paved the way to the
adoption of CHD. Data from this study were later used to develop a method for calculating
haemodialysis adequacy [8] Kt/Vurea (Kt/V) which is now used worldwide. Kt/V exclusively looks
at small molecule clearance as a marker of dialysis adequacy. There is an association between
dialysis dose and mortality [9]; however, the benefit (from the NCDS data) was seen up until
a Kt/V of 1.2 with no survival advantage with doses above this. This was later echoed in the
much larger HEMO study (involving 1846 patients) and again showed no advantage in
Home Haemodialysis and Haemodiafiltration 103
http://dx.doi.org/10.5772/64095
increasing the dialysis dose above a Kt/V of 1.3. Dialysis treatment time was not investigated
in this study.
It would seem therefore that with Kt/V we have reached a ceiling where improvements can no
longer be made within the restrictions of a thrice weekly schedule, and we must start looking
at other ways to improve outcomes in haemodialysis. The most significant causes of death in
haemodialysis patients are cardiovascular in nature and this has been well known for some
time. UK registry data show that almost a third of deaths in dialysis patients are cardiovascular
in nature [4]. It is also clear that the two‐day gap in CHD is harmful with all‐cause and
cardiovascular mortality being higher on the day after the long interval [10]. Further data show
the highest rate of cardiovascular events in the first month after starting haemodialysis and a
high‐risk period extending to 4 months [11].
Based on all of this, a strong argument can be made to further explore more frequent and
extended haemodialysis treatments.
3. Extracorporeal dialysis therapy
The basic principle behind dialysis is the removal of solutes across a semipermeable mem‐
brane. Haemodialysis relies on the process of diffusion where solutes move from an area of
high concentration to an area of low concentration. Solutes pass from the patients’ blood to
the dialysis fluid across the dialysis membrane in this manner. The concentration gradient is
maintained by the countercurrent flow of dialysate and blood and the maintenance of adequate
blood and dialysate flow.
Haemofiltration allows the clearance of larger molecules through the process of convection. A
hydrostatic pressure gradient is used to pass the patient's blood across a membrane with a
large pore size. Solutes follow water through a process called “solvent drag” [12]. Large
volumes of fluid are typically filtered and a replacement fluid is required, which enters the
dialysis circuit and is mixed with the patient's blood before it is returned.
Haemodiafiltration (HDF) combines the techniques of both haemodialysis and haemofiltra‐
tion. Solutes are cleared by both diffusion and convection, thus allowing more efficient
clearance of both small and middle molecules. The replacement fluid can either be obtained
from pre‐prepared bags or prepared “online” by the machine (OL‐HDF), which is able to
produce ultrapure fluid. This dialysis therapy has a number of potential advantages, which
are discussed in more detail later in this chapter.
3.1. Clearance in extracorporeal dialysis
Kt/V is widely used to give us information on dialysis adequacy; however, it is solely dependent
on the clearance of urea. Urea has the advantage of being easy to measure; however, it may
not be directly toxic and many of the identified uraemic toxins are larger in size and are not
cleared efficiently by conventional haemodialysis [13]. In general, molecules are classified as
small molecular weight (MW) molecules (<500 Da), middle MW molecules (>500 Da) and
protein‐bound molecules. β2‐microglobulin (B2M), which is commonly used as a marker of

middle molecules, has a molecular weight of around 11,800 Da. It has been demonstrated that
outcomes are improved when middle molecular clearance (1000–50,000 Da in the study) are
enhanced [14]. There has been much interest in increasing middle MW molecule clearance,
and it is clear that accumulation of middle MW molecules can be harmful such as in the case
of B2M which can lead to dialysis‐related amyloidosis [15].
β‐Trace protein, cystatin‐C and B2M are all middle MW molecules that are freely filtered,
resorbed and catabolized in the tubular cells. A study by Lindström et al. [16] has shown clear
differences in the clearance of these molecules by different dialysis modalities—CHD did not
change the concentrations of any of these proteins while in HDF both cystatin C and B2M were
reduced and β‐trace protein was only reduced in HDF. This demonstrates a clear difference
between dialysis modalities in terms of clearance and a clear biomarker that could be meas‐
ured. Moreover, β‐trace protein had been found to be an independent predictor of both death
and cardiovascular mortality in haemodialysis patients [17]. The use of such molecules could
be part of the way that we assess haemodialysis adequacy in the future and tailor treatment
to the patient.
3.2. Biocompatibilty in dialysis
The specifications of dialysis membranes have improved considerably. The use of cellulose‐
based membranes were common initially; however, they were associated with complement
and leucocyte activation [18] resulting in dialyser reactions. The majority of dialysis mem‐
branes in use now are synthetic and are more biocompatible—reactions can still occur however
and anaphylactoid reactions have been reported, particularly in patients on ACE inhibitors
[19]. More recently, dialysis membranes have been manufactured with larger pore sizes to
allow a higher ultrafiltration rate and allow clearance of larger molecules. Membranes can be
classified as high flux or low flux and for the purposes of the HEMO study [20] were defined
as B2M clearances of <10 ml/min for low flux and >20 ml/min for high flux. High‐flux mem‐
branes have been found to lower pre‐dialysis B2M concentrations [21] and may prevent
dialysis‐related amyloidosis [22]. Several observational studies have identified a survival
benefit with high‐flux dialysers [23, 24]. Although the HEMO study showed no benefit from
high‐flux membranes, the study may not have been sufficiently powered to detect a significant
benefit [25]. The subsequent European study, the MPO Study [26], showed survival benefit to
those patients with a serum albumin of <40 g/l. Several guidelines now recommend high‐flux
dialysers including the European Renal Association [27] and practice has also changed
considerably.
The production of a high‐quality infusion fluid is of paramount importance in HDF. More than
20 litres of infusion fluid can be administered to the patient during a typical HDF session and
thus ultrapure water and dialysis fluid are required. Ultrapure water is defined by the standard
for replacement fluid requiring <0.1 colony‐forming units (CFU)/ml and an endotoxin
concentration <0.03 endotoxin unit (EU)/ml [28]. The use of ultrapure dialysis fluid is associ‐
ated with a reduction in inflammatory markers and an improvement in serum albumin,
haemoglobin and ferritin [29].
http://dx.doi.org/10.5772/64095
4. Increasing haemodialysis frequency and length with home

haemodialysis
The seminal paper in 1992 by Bernard Charra and his group in Tassin, France, showed hugely
impressive survival rates of their haemodialysis patients of 87% at 5 years and 43% at 20 years,
which far surpassed matched patients on both European and US registries. All patients
received 8 hours of haemodialysis three times per week (LHD). It is likely that the survival
association is related to achieving good blood pressure control (antihypertensives were seldom
required in the group) through optimized ultrafiltration and the enhanced clearance of
uraemic toxins provided by the longer treatment. Their publication sparked interest once again
in extended haemodialysis. With the continued increasing demand for renal replacement
therapy and limited resources in hospitals, novel ways of providing haemodialysis were
required. Home haemodialysis seemed an attractive option and could also accommodate more
frequent and extended schedules. The first daily nocturnal haemodialysis programme was set
up in Toronto in 1994 [30].
The prescription of home haemodialysis in the United Kingdom remains very variable;
however, the most common prescription in 2009 was still 4 hours thrice weekly (51.9% of home
HD patients), followed by alternate day dialysis (20.5%), short daily (17.4%) and nocturnal
(2.9%) [31]. This is a surprising finding given the benefits of more frequent and extended
haemodialysis (which we will now expand on). This does however reflect patient choice and
the comfort of both patients and clinicians with a CHD schedule.
4.1. The benefits of extended and more frequent haemodialysis
Several benefits have come to light from more frequent and extended haemodialysis and these
will be outlined in this section.
4.1.1. Survival, cardiovascular outcomes and hospitalizations
Observational studies show a significant mortality benefit associated with home haemodial‐
ysis, even when adjustments are made for age and comorbidity [32]. These findings are also
apparent in studies in Australia and New Zealand [33], which have a higher uptake of home
haemodialysis. Figures of 90% survival at 5 years and 45% at 20 years have been quoted [34].
Figure 1 shows a clear survival advantage to home haemodialysis over both peritoneal dialysis
and facility‐based HD. These data have to be interpreted with care given the high number of
confounders. Patients selected for home haemodialysis are generally younger with a low
comorbidity burden. They are usually highly motivated and take an interest in their healthcare.
The frequent haemodialysis network (FHN) trials were setup to give a more definitive answer
to the benefits of more frequent and extended haemodialysis [35, 36]. The SDHD arm of the
trial randomized 245 patients to either frequent (6 times per week) or conventional haemo‐
dialysis and the nocturnal arm randomized 87 patients to either CHD or LDNHD. Two
coprimary composite endpoints were used—death or change in LV mass or death or change
in physical‐health composite score. There was a favourable outcome with regard to both
coprimary endpoints for the SDHD trial but not with the LNDHD trial. Looking purely at
survival, there was no significant benefit from either trial. With a 12‐month follow‐up period
and the numbers involved with the trials, they were not powered to detect an effect on
mortality. The question therefore still remains unanswered as to whether more frequent and
extended haemodialysis does have a favourable effect on survival.
Figure 1. The survival of home HD patients in New Zealand compared with facility HD and peritoneal dialysis (PD).
Image adapted from Marshall et al. [35].
There is an associated reduction in cardiovascular‐related admissions in converting patients

from CHD to LDNHD [37]. There are also fewer cardiovascular‐associated hospital admissions
associated with SDHD compared with matched CHD; however, all‐cause hospitalizations
remain unchanged [38]. The FHN studies once again showed no change in the rate of hospi‐
talizations.
4.1.2. Ultrafiltration and blood pressure control
There is a strong association between a high ultrafiltration rate (>10 ml/kg/hour) and mortality
[39, 40]. Chronic fluid overload contributes to an increased LV mass and congestive cardiac
failure [41] and this is likely to be highly significant in terms of cardiovascular morbidity and
mortality. Increasing haemodialysis treatment time improves the tolerance of ultrafiltration
[42, 43]. There are also many reports of improved blood pressure control both in LNHD and
in SDH [44–46] and a regression of left ventricular hypertrophy [47]. It has also been shown
that ejection fraction, in those with heart failure, can be improved through more frequent
haemodialysis and ultrafiltration [48]. With CHD, it often the case that dry weight is not
achieved. Patients that experience hypotension during haemodialysis often have their
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ultrafiltration stopped, receive saline infusions and thus never achieve their dry weight and
in fact can exacerbate the situation further. Extended dialysis allows much lower ultrafiltration
rates and thus less haemodynamic disturbance. It is likely the effect that extended dialysis has
on blood pressure goes beyond the optimization of volume status. When compared to patients
on CHD, some patients with a high extracellular volume (measured by bioimpedance) but on
extended haemodialysis achieve normotension [49]. A theory put forward for this phenom‐
enon is that extended haemodialysis may lead to efficient removal of vasoactive factors that
contribute to hypertension.
4.1.3. Small molecule clearance
Increasing haemodialysis frequency provides more efficient clearance of small MW molecules.

It provides a lower peak urea, lower mean urea and less fluctuation [50]. This provides a lower
time‐averaged concentration (TAC). Looking purely at Kt/V would, however, be misleading
as this would remain the same despite the enhanced clearance.
4.1.4. Phosphate balance
There is a clear association between raised serum phosphate and adverse cardiovascular
outcomes in patients with CKD [51, 52]. Conventional haemodialysis does provide sufficient
phosphate removal for western diets, and as a result, there is a net phosphate gain [53]. As a
result of this, multiple phosphate binder tablets are often required to reduce the absorption of
phosphate from the gut. On average, haemodialysis patients have an average pill burden of
19 pills per day and many of these are phosphate binders [54]. A higher pill burden in this
setting is associated with lower quality of life scores [54].
Phosphate removal on haemodialysis has been found to be time dependent [55] and thus is
significantly enhanced in NHD. Phosphate removal is also increased by SDHD but not to the
same extent as NHD [56]. In LNDHD, many patients will discontinue their phosphate binders
[57] and some require supplementation that can be added to the dialysate [58].
4.1.5. Anaemia
Reports are mixed when it comes to more frequent haemodialysis and anaemia management.
Reduced erythropoietin doses have been reported when patients switch to SDHD from CHD
[59] and in NHD [60]. One of the theories put forward for this change is the control of inflam‐
mation and reduction in IL‐6 levels which improve erythropoietin responsiveness [61]. The
exact effect that more frequent or extended dialysis has on anaemia, however, is still unclear.
Again both FHN studies showed no effect on erythropoietin dose.
4.1.6. Quality‐of‐life measures and carer burden
Home haemodialysis allows patients the independence to fit their dialysis treatment around
their lifestyles. One may expect this to bring significantly improvements to quality of life;
however, this may be offset by the burden of having to perform the treatment so frequently,
which can lead to burnout or the increased burden on carers. While there are many reports of
improvements in quality‐of‐life measures from switching to NHD [62] or SDHD [63], some
show only small improvements in kidney‐specific measure of quality of life [64], while others
show no difference. Larger studies have shown a reduction in depressive symptoms related
to increased dialysis frequency [65].
Data from the recent FHN daily trial showed a significant increase in quality‐of‐life score in
the SDHD group [35] with no specific benefit from NHD over CHD at home. In the FHN NHD
arm, however, both groups had an increase in their quality‐of‐life score showing the positive
effect that the setting of the haemodialysis treatment has on this outcome [36] regardless of
prescription. Perceived burden on unpaid carers is high among HD patients [66]; however, the
FHN trials did not show a higher perceived burden with either SDHD or LDNHD [67].
The patient‐reported experience on both LDNHD and SDHD has been positive in terms of
physical, psychological and lifestyle aspects [68]. There is also an associated faster recovery
time with home haemodialysis [69]. Once again, it is fair to say once again that the jury is still
with regard to whether these treatments truly impact on quality of life. In general, the effect
seems to be positive with a paucity of data suggesting a negative impact.
4.1.7. Pregnancy
Intensive dialysis has been used very successfully in pregnancy. A case series from Canada
[70] shows a markedly improved live birth rate and duration of pregnancy with a dose
response between dialysis and pregnancy outcomes. Women who had >36 hours of dialysis
per week had significantly improved live birth rates (85 vs. 45% in those who had <20 hours
of dialysis per week), which again demonstrates and gives strength to high‐dose dialysis.
4.2. Disadvantages of more frequent and home haemodialysis
While there are many advantages of home haemodialysis, the treatment is not suitable for all
patients and it is not a treatment without disadvantages. Although exceedingly rare, there is
always the possibility that human error can occur resulting in significant blood loss through
a variety of mechanisms. There are reports of patient deaths from exsanguination while on
home haemodialysis [71]. The sophistication of safety mechanisms is continually improving
to make this event less likely with blood leak detectors, pressure monitoring and line discon‐
nect detectors featuring on newer machines.
A clear finding from the FHN trial was an increase in interventions needed for vascular access
with 47% of the frequent dialysis group requiring intervention compared with 29% in the CHD
group. Interventions to fistulas were required much more often than in catheters. This was not
an entirely surprising finding given the considerably increased use of vascular access form
more frequent haemodialysis. A solution to this could be the use of a buttonhole technique for
fistula cannulation or using single‐needle haemodialysis to reduce the number of needling
events. The evidence, however, is not there to support this practice and a systematic review of
buttonhole cannulation in home haemodialysis patients found an increase in infectious events,
an increase in staff support required and no reduction in surgical interventions compared with
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the “rope ladder” technique [72]. The FHN nocturnal trial used single‐needle haemodialysis,
and despite this, there was still a trend towards increased vascular interventions in this group.
Finally, globally, the uptake of extended higher frequency haemodialysis remains low, despite
a range of benefits and favourable health economics. There can be major patient and clinical
factors driving modality uptake. A key determinant, however, is patient motivation and
choice. Extended time or frequency on home HD may add to patient and carer burden and is
therefore often perceived as a barrier limiting its uptake.
5. Haemodiafiltration
Haemofiltration allows clearance of solutes of up to 20 kDa through the process of convection

as previously described. Large volumes of replacement fluid are required for the treatment,
and this can be administered either before the filter (pre‐dilution) or after the filter (post‐
dilution). Newer technology also allows a mix of pre‐ and post‐dilution or mid‐dilution in an
attempt to gain the advantages of both pre‐ and post‐dilution (largely the anticoagulant
requirement) [73].
Conventional HDF provides enhanced B2M clearance compared with HD [74]. It is associated
with a reduction in pro‐inflammatory cytokines such as IL‐6 and TNF‐α [75] and reduced
episodes of hypotension during treatment [76]. There does not appear to be a benefit in terms
of left ventricular mass, pulse wave velocity or ejection fraction [77]. This could be due to
achieving low substitution volumes or large interdialytic fluid shifts induced by conventional
thrice‐weekly schedule.
There have been three recent large prospective clinical trials, which have compared HDF with
high‐flux HD with contrasting results. The ESHOL study [78], a Spanish study, showed
promising results with a 30% lower all‐cause mortality, a 33% lower cardiovascular mortality
and 55% lower infection‐related mortality compared with haemodialysis. A Dutch study [79]
showed no difference in outcome between HDF and HD and a Turkish [80] study drew the
same conclusion. Looking back at these studies, the ESHOL study achieved the highest
convective volumes (22.9–23.9 l per session) and post hoc analyses of the Turkish and Dutch
study also show an association between high convection volume and a survival benefit.
In order to provide HDF with high convection volumes, large volumes of sterile replacement
fluid are required (>15 l), which would not be practical with pre‐packaged solutions. Instead
of online preparation of fluid, which is the most practical solution, HDF uses an additional 50–
80 l of water per session [81] (with a typical haemodialysis session using around 500 l of mains
water to generate dialysate [82]). Ultrapure dialysate must be generated by the machine to the
standards previously described.
5.1. Adding HDF in the home setting
There appears to be a benefit from high convective volume haemodiafiltration. The biggest
determinants to achieving a high convective volume are treatment time and blood flow [83].
A blood flow between 360 and 500 ml/min is required to achieve the necessary transmembrane
pressure [84]. A well‐functioning vascular access would therefore also be required. Although
there are reports of achieving a convective volume of >20 l with a haemodialysis catheter, a
well‐functioning AV fistula would allow higher blood flows [84].
Given that treatment time is clearly an important factor in achieving the dose of HDF associated
with improved outcomes, the home setting is an ideal place to deliver the treatment. Vascular
access would not be a barrier and combining frequent haemodialysis with a convective
treatment should maximize middle molecule clearance. Switching patients from a conven‐
tional HDF schedule to a short daily schedule has been reported to result in a higher removal
of middle and large molecules, a reduction in phosphate binders, the disappearance of post‐
dialysis fatigue, an improvement in nutritional status as well as a 30% reduction in left
ventricular mass [85]. The improvements in switching to more frequent OL‐HDF are outlined
in Table 1.
Baseline Month 3 Month 6

spKt/V 2.30 ± 0.20 1.13 ± 0.15 b
1.11 ± 0.11b
eKt/V 1.96 ± 0.17 0.90 ± 0.12b 0.88 ± 0.08b
URR % 84.3 ± 2.5 64.2 ± 5.3b 63.3 ± 4.2b
Weekly spKt/V 6.90 ± 0.59 6.78 ± 0.91 6.67 ± 0.64
Weekly eKt/V 5.88 ± 0.52 5.39 ± 0.75 a

5.30 ± 0.50a
EKR mL/min 19.2 ± 0.5 24.2 ± 2.6b 23.8 ± 1.9b
stdKt/V 2.62 ± 0.1 3.87 ± 0.3b 3.86 ± 0.2b
Weekly URR % 253 ± 7.5 385 ± 32b

380 ± 25b
a: P<0.05;
b: P<0.01 with respect to baseline value.
Adapted from Maduell et al. [85].
Abbreviations: URR, urea reduction ratio; spKt/V, single‐pool Kt/V; eKt/V, equilibrated Kt/V; stdKt/V, standard Kt/V; TAC,
time average concentration; TAD, time average deviation; ERK, equivalent renal urea clearance.
Table 1. Change from three times a week on‐line haemodiafiltration (OL‐HDF) to short daily on‐line
haemodiafiltration (D‐OL‐HDF): comparison of urea kinetics during the two study periods.
While the technology to provide HDF in the home setting exists, it is not widely used at present
and there is very little published literature about HDF as a home therapy. Until recently, there
have not been haemodialysis machines specifically manufactured for the home market. As a
result, patients have been trained on the machines used in the main dialysis unit. Using the
same technology both in the home and in the main dialysis unit makes the logistics of
maintenance much easier. The health care team, including the technicians, are often more
comfortable and experienced using and providing support for a single machine. As technology
has developed and haemodialysis machines have become more advanced, it is important that
http://dx.doi.org/10.5772/64095
more user‐friendly technology, specifically for the home market, is developed. This will allow
further uptake and expansion of home dialysis programmes.
The ideal home HD machine has been described [86] as one which is fast and easy to setup,
allows a range of prescriptions (such as short daily and nocturnal), teaches and interacts with
the patient and allows the patient to deliver intravenous fluid at the push of a button. The
description suggests the ability of the machine to re‐use blood sets and dialysers, prepare all
fluids to a standard beyond ultrapure and have the ability to provide HDF. There are many
machines in development and it is likely that this “ideal machine” will be in existence in the
near future. There is the potential for HDF machines to be complex given the choice in pre‐
dilution, post‐dilution and mixed dilution and the blood and dialysate flow. Technology
should strike a balance, remaining simple for safe use with minimal margin for error and fast
training times but also allow some flexibility to tailor treatment.
As previously described, providing a high water quality is of great importance given the high
volume that is infused into the patient. The body of evidence to support the use of ultrapure
water really lies in convective treatments, and thus, an essential requirement for any home
HDF programme will be the production of ultrapure dialysate. Water may contain both
chemical and microbiological contaminants, and in the home setting, this is likely to vary
considerably depending on the local feed water. A variety of contaminants can have clinical
consequences, such as chloramines, leading to haemolytic anaemia [87], calcium and magne‐
sium contributing to a “hard water syndrome” [88] and nitrates [89], zinc [90] and fluorides
[91] have all been documented to have potential clinical effects. After initial assessment of the
feed water and the subsequent installation of the filters and water softeners, a surveillance
programme for chemical contaminants, endotoxins and bacteria is important. This logistics of
such a programme needs to be considered as the sampling protocol, laboratory protocols and
the transport and storage of samples must all be carefully planned.
Microbiological contamination can still theoretically occur. Reverse osmosis units filter out
substances with a molecular weight > 200 kDa and thus bacterial fragments and small
endotoxins can still pass through [92]. Vigilance must be employed for unexplained febrile
episodes or signs of chronic inflammation. This would apply to both home haemodialysis and
haemodiafiltration.
Portability is an important factor for dialysis patients. Peritoneal dialysis has provided a
treatment that can be carried out virtually anywhere making the treatment appealing for
patients who work or need to travel. To date, the quantity of water and the size of the water
treatment devices has limited the portability of haemodialysis. Increasingly, there are haemo‐
dialysis machines that allow portability by utilizing sorbent technology to purify water and
thus reduce water requirements [93]. With the high convective volumes required for adequate
HDF, water requirements remain high and thus limit portability. Developments in this area
are needed allow to make HDF a more appealing home treatment for patients. Water use must
be minimized and where possible, water should be recycled. Water rejected from reverse
osmosis units can be recycled and used elsewhere in the home or dialysis unit and this is being
increasingly utilized [82].
Anticoagulation must be a major consideration for any extracorporeal dialysis therapy. Many
patients on home haemodialysis manage well with the administration anticoagulation, and
unfractionated heparin and low molecular weight heparin are in common use. These strategies
can also be used in HDF and should not pose a barrier to home HDF use. HDF may allow
dialysis without anticoagulation through the use of pre‐dilution HDF. This may be particularly
helpful in patients with prolonged bleeding or intolerances to anticoagulation.
Today's dialysis technology enables HDF to be delivered in the home setting safely with the
production of ultra‐pure dialysate and detection of venous dislodgement. There is a growing
experience of centres using this technology [94] with a positive experience. Further details
on optimal heparinization regimes, water quality variability and its surveillance in home
HDF are necessary to define best clinical practice. It is likely that new technology coupled
with increasing HDF uptake in dialysis centres will lead on to increasing use of HDF at
home.
5.2. Economic impact of HD and HDF
Haemodialysis treatment in general is very costly, and in the United Kingdom, 1–2% of the
National Health Service budget is spent on renal care with only 0.05% with ESRF [95]. After
consumables, a large proportion of the cost is made up of direct nursing care and transportation
[96] (both of which are considerably less in home haemodialysis). Home haemodialysis has
been estimated to cost over a third less than hospital‐based haemodialysis in the United
Kingdom [96] and frequent home haemodialysis has been shown to offer a cost saving in both
Canada and Australia too [97].
In addition to the reduced transport and nursing costs, savings are also offered from a
reduction in hospital admissions [37] and a reduction in medication costs (particularly
phosphate binders) [98].
The initial setup costs of home haemodialysis are high due to the cost of training, the equipment
and installation. These initial costs are usually paid back by 14 months after which savings
occur [99], making home haemodialysis an attractive option not only from the clinical benefits
but also from the cost‐saving aspect.
Costs of high‐flux dialysers have also reduced considerably over time and high‐flux haemo‐
dialysis is now the common standard care. A UK Study looked at the costs of 34 patients
switching to OL‐HDF and 44 who remained on high‐flux HD. The cost of the treatment was
either more expensive or cheaper depending on the choice of blood lines. There was a cost
saving in the OL‐HDF group in terms of phosphate binders. Lebourg et al. [81] looked at
>28,000 dialysis treatments in a single centre and once again HDF was found to be either
cheaper or more costly (-€1.29 to +€4.58 per session) depending on treatment variables
selected. It is clear that from a cost perspective, there is little difference between HDF and
high‐flux HD.
http://dx.doi.org/10.5772/64095
6. Conclusion
Home haemodialysis provides a convenient and clinically effective way of providing both
frequent and extended haemodialysis treatment. Although the hard outcome data for survival
from prospective randomized trials are lacking, it is unlikely that a larger, adequately powered
trial with sufficient follow‐up time will be feasible and the answer may need to come from
registry data. It is also time to look beyond urea clearance and towards markers, such as
convective volume and β‐trace protein, as this may pave the way to further improve haemo‐
dialysis care in the future.
However, it is clear that there are a number of clinical benefits from more frequent and
extended haemodialysis and aside from this, home haemodialysis is a treatment preferred by
many patients if choices are given [100] and a treatment that is associated with an increased
satisfaction [101].
HDF is also a feasible treatment in the home setting and is already in use. There is growing
evidence from randomized trials that dialysis patient outcomes may be improved by high‐
frequency HD and by using HDF with high convective volumes. Combining increased fre‐
quency HD with convective treatment would give patients the benefits of both small and
middle MW clearance without additional patient burden or cost implications. This may
pave the way to further improved patient outcomes; however, further randomized clinical
studies will be needed for a more definitive answer.
Author details
Sandip Mitra and Kunaal Kharbanda*
*Address all correspondence to: k.kharbanda@nhs.net
Department of Nephrology, Central Manchester Foundation Trust, Manchester Academy of

Health Sciences Centre (MAHSC), Manchester, United Kingdom
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Chapter 8
Quality of Life on Online Hemodiafiltration (HDF)
Samir H. Almueilo
http://dx.doi.org/10.5772/64591
Abstract
Online hemodiafiltration (OL-HDF) as a renal replacement therapy is gaining
momentum due to the perceived added benefit from enhanced clearance of potential‐
ly harmful middle molecules. Favorable effect of OL-HDF on all-cause mortality and
cardiovascular mortality and morbidity has been suggested by some clinical trials.
Health-related quality of life (HRQOL) is an important component of hemodialysis
patients’ care. HRQOL is of interest to both health care providers and patients.
Improved quality of life in hemodialysis patients has been associated with improved
outcome in terms of reduced rate of hospitalization and mortality. Data on HRQOL in
end-stage renal disease (ESRD) patients under OL-HDF is scarce and of marginal
quality. In this review, we will try to summarize the available evidence on this subject.
Keywords: Quality of life, Health-related quality of life, Online hemodiafiltration, He‐

modiafiltration, End-stage renal disease
1. Introduction
End-stage renal disease (ESRD) is characterized by significantly increase rate of mortality and
morbidity. Survival of patients with end-stage renal disease is substantially decreased com‐
pared to counterparts without renal failure. It is estimated that 10–20 % of dialysis patients die
annually [1]. Historically, in patients with ESRD, survival has been commonly utilized as a
measure of outcome, as both health care providers and patients are most interested in prolong‐
ing life.
Quality of life (QOL) is curtailed in these patients not only due to the physical burden of the
disease but also due to its effect on psychological, social interaction, rehabilitation, and
employment component of patient life. Renal replacement therapy decreases morbidity related
to uremia and improves many of the uremic symptoms such as anorexia, fatigue, and pruritus
that have a negative impact on the quality of daily life.
Conventional hemodialysis (HD) is reasonably effective in removing small solutes by way of

diffusion across membranes. However, middle molecules which are implicated in adverse
outcome are poorly removed by such mechanism. Secondary analysis of the HD trial had
suggested that survival may depend on clearance of such middle molecules [2]. Convective
therapy is more effective in removing larger toxic middle molecules such as β2-microglobulin.
High-volume online hemodiafiltration (OL-HDF) effectively achieves significant clearance of
middle molecules. Such treatment has been shown to be beneficial in terms of lower risk of
all-cause and cardiovascular mortality when compared to standard hemodialysis. Secondary
analysis of initially negative clinical trials also demonstrated decreased mortality in recipients
of high-volume OL-HDF [3–7].
Hemodiafiltration (HDF) combines diffusive and convective clearance of uremic solutes. It

involves convection of large volume of fluid and infusing in the patient a replacement fluid
that is ultrapure, sterile, and free of pyrogens. Utilization of online HDF where replacement
fluid is prepared by further purifying dialysate fluid instead of manufacturer-provided
solutions made it more practical and cost effective. It is believed that high-volume HDF by
increasing clearance of middle molecules could potentially improve symptomatology, reduces
morbidity, and may even improve survival [8]. These in turn could result in improved quality
of life. Improved quality of life in hemodialysis patients has been associated with improved
outcome. Analysis of data using the Kidney Disease Quality of Life Short Form (KDQOL-
SFTM) obtained from 10,030 randomly selected hemodialysis patients from the USA, five
European countries and Japan in the Dialysis Outcomes and Practice Patterns Study (DOPPS)
demonstrated associations between HRQOL and the risk of death and hospitalization. Scores
were determined for three components of HRQOL: (1) physical component summary (PCS),
(2) mental component summary (MCS), and (3) kidney disease component summary (KDCS).
Lower scores for the three major components of HRQOL were strongly associated with higher
risk of death and hospitalization in hemodialysis patients, independent of a number of
demographic and comorbid factors [9].
Information on quality of life in patients receiving renal replacement therapy in the form of
OL-HDF is scarce and inconclusive. The studies often involve small sample size and uses
different methods of quantifying HRQOL. In this report, we will attempt to address HRQOL
in patients under OL-HDF treatment by way of defining HRQOL, describing the most common
instruments used to evaluate HRQOL and presenting brief summaries of clinical studies that
investigated HRQOL in individuals receiving convective therapy.
2. What is health-related quality of life (HRQOL)
The concept of HRQOL has been around for many decades. In its constitution, the World
Health Organization has defined health as “a state of complete physical, mental and social
Quality of Life on Online Hemodiafiltration (HDF) 125
http://dx.doi.org/10.5772/64591
well-being and not merely the absence of disease or infirmity” [10]. Quality of life (QOL) is a
broad multidimensional concept that usually includes subjective evaluations of both positive
and negative aspects of life [11]. It is often defined differently by variable groups and profes‐
sional societies. This adds to the difficulty of measuring QOL. Health constitutes an important
component of QOL assessment. However, other parameters such as employment, education,
housing, and family life are important contributors to the overall QOL. Cultural and religious
beliefs and values also add to the complexity of assessing quality of life.
The World Health Organization defines QOL as “an individual’s perception of their position
in life in the context of the culture and value system where they live, and in relation to their
goals, expectations, standards, and concerns” [12]. Assessment of quality of life should
encompass not only the physical condition but also factors that have an impact on the
individual’s well-being such as social, economic, emotional, and psychological factors. Quality
of life and health are closely related. Each can have a positive or a negative impact on the other
depending on condition. Such a relationship is demonstrated by the notion that greater
survival is associated with a higher-measured QOL [13, 14].
Assessments of HRQOL have evolved over the years to include aspects of overall quality of
life that can be obviously shown to affect physical as well as mental health (MH) [15–17].
On the individual level, this includes physical and mental health perceptions and their
correlates including health risks and conditions, functional status, social support, and socioe‐
conomic status. On the community level, HRQOL includes resources, conditions, policies, and
practices that influence a population’s health perceptions and functional status. The construct
of HRQOL enables health agencies to legitimately address broader areas of public health policy
in collaboration with a wider circle of health partners, including social service agencies and
community planners.
HRQOL questions about perceived physical and mental health and function have become an
important component of health surveillance and are generally considered valid indicators of
service needs and intervention outcomes. Self-assessed health status also proved to be a more
powerful predictor of mortality and morbidity than many objective measures of health [9].
The measurement of QOL should encompass many factors that affect a subject’s well-being.
It should include not just the physical aspect but also the social, emotional, intellectual, and
cultural components that comprise daily life. According to this foundation, we can define an
aspect of QOL as being health related. This health-related quality of life (HRQOL) represents
the “physical, psychological, and social domains of health that are influenced by a person’s
experience, beliefs, expectations, and perceptions” [18]. Each of these domains can be meas‐
ured in two dimensions, objective assessments of functioning status and subjective perceptions
of health as reported by the individual. The patient’s subjective attitudes and expectations
convert that objective assessment into the actual quality of life [10].
Within this context, health is defined as not only the absence of disease and infirmity but also
the presence of physical, mental, and social well-being [11].
3. Measuring health-related quality of life
Adequate HRQOL measurement instrument should capture all the effects that disease and its
treatment have on the physical, emotional, social, and mental dimensions of an individual [19].
An ideal instrument would be comprehensive, reliable, and of proven validity and would
facilitate comparisons between groups of subjects with different illnesses and within the same
group receiving different modes of treatment. The extracted HRQOL measures must be
converted into a numerical value for proper utilization.
There is no one ideal tool of measuring HRQOL, and therefore, multiple different instruments
have been developed.
Most of these instruments use a series of questions to assess quality of life indirectly. These
questions are defined as “items.” Each item is then given a numerical value, based on a
predetermined scale. Most researchers measure each quality-of-life domain separately, by
asking specific questions pertaining to its most important components.
HRQOL instruments can be subdivided into categories based on whether the tool is global or
domain specific. Three major domains comprise global HRQOL: the physical domain, the
social domain, and the psychosocial or mental domain.
Many schemes have been developed to assess QOL in individuals with end-stage renal disease.
Here, we will briefly describe the most common tools used in assessing HRQOL in studies
involving patients under treatment by OL-HDF.
Domain Meaning of low score Meaning of high score Number of

questions
Physical functioning Severe limitations in physical activity, Performs vigorous activity without 10
(PF) including bathing and dressing limitations
Role-physical (RP) Limited ability to work because of Physical health does not limit work or 4
physical health other activities
Bodily pain (BP) Severe limiting pain No pain or limitations due to pain 2
General health (GH) Perceives health as poor Perceives health as excellent 5
Vitality (VT) Feels tired and worn out all the time Feels full of pep and energy all the time 4
Social functioning (SF) Physical and emotional symptoms No physical or emotional limits to 2
severely limit normal social activities normal social activities
Role-emotional (RE) Emotions limit daily function and Emotions do not interfere with daily 3
work function or work
Mental health (MH) Feels nervous and depressed all the Feels peaceful, happy, and calm all the 5
time time
Ref. [25].
Table 1. Components of the Short Form-36 (SF-36).

http://dx.doi.org/10.5772/64591
3.1. Kidney Disease Quality of Life (KDQOL) Short Form-36 (SF-36)
The Kidney Disease Quality of Life (KDQOL) instrument is a self-report questionnaire

consisting of 134 items [20]. It has the SF-36 as its generic core and is supplemented with items
of relevance to the HRQOL of dialysis patients. Disease-specific items assess symptoms/
problems, effects of kidney disease on daily life, burden of kidney disease, cognitive function,
work status, sexual function, quality of social interaction, and sleep. Included are also items
relating to social support, encouragement from dialysis staff, patient satisfaction with care,
and a global rating of health. A more practical shorter version, the KDQOL-SF, was developed
later in view of the length of the original one. The KDQOL-SF includes the SF-36 supplemented
with 43 disease-specific items from the domains identified in the original version [21].
The KDQOL-SF is easy to administer and has been validated and used widely with hemo‐
dialysis (HD) patients. KDQOL-SF became the most widely used QOL measure for ESRD
patients. It was developed in the USA for dialysis patients and has been translated into several
languages, to be used in several studies involving dialysis patients [22–24].
The SF-36 Health Survey can be self-reported or obtained with the help from a health profes‐
sional in patients unable to complete the survey. The SF-36 contains only 36 items, through
which it evaluates eight health concepts of HRQOL. The eight health concepts are physical
functioning (ten items), role limitations resulting from physical problems (four items), role
limitations caused by emotional or personal problems (three items), social functioning (two
items), bodily pain (BP) (two items), energy/fatigue (four items), emotional well-being (five
items), and general health (GH) perceptions (five items). In addition, there is one single item
that provides an indication of perceived change since 1 year. Two additional components can
be calculated from the SF-36, and they are the physical component summary (PCS) and the
mental component summary (MCS). A higher score is associated with a more favorable health
status. Components of the SF-36 are depicted in Table 1.
3.2. The Kidney Disease Questionnaire (KDQ) of Laupacis et al. (Canada) [26]
In 1992, Laupacis developed this tool which is disease-specific designed for use in chronic HD
patients. The KDQ consists of 26 items in five dimensions: physical symptoms (six items),
fatigue (six items), depression (five items), relationships (six items), and frustration (three
items). The physical symptoms dimension of the KDQ is patient specific. The six physical
symptoms that are most important to each subject are identified and used to assess that
dimension. Patients are asked to identify their specific physical problems, next to questions
regarding frustration, depression, and well-being. Patients are asked to grade their complaints
on a scale ranging from one (severe) to seven (none). The KDQ is designed for use only in
patients with ESRD on HD treatment.
3.3. The Euro Quality of Life Group (EQ-5DTM) questionnaire
The EQ-5DTM measures health-related quality of life in five dimensions: mobility, self-care,
usual activities, pain/discomfort, and anxiety/depression. Scores for the five dimensions are
converted into preference weights by using country-specific value sets drawn from the general
population [27].
This instrument is rather new; therefore, only few country-specific value sets are available.
3.4. The CHOICE Health Experience Questionnaire (CHEQ) [28]
This is a patient-reported measure of HRQOL developed for use in the Choices for Healthy
Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study [29]. The authors have
defined it as “the value assigned to duration of life as modified by the impairment, functional
states, perceptions, and social opportunities that are influenced by disease, injury, or policy.”
This instrument was developed to evaluate the effectiveness of alternative dialysis prescrip‐
tions. It supplements SF-36 survey in measuring HRQOL for patients with ESRD. It is sensitive
to differences in dialysis modality and dialysis dose. The selection of HRQOL domains to be
utilized was based on literature review, analysis of focus groups, and survey of dialysis
providers and patients. In order to arrange domains and items identified, a representative
sample of 136 dialysis patients rated each item for frequency and distress. The survey yielded
22 HRQOL domains that included 96 items: eight generic domains in the SF-36 (health
perceptions, physical, social, physical and emotional role functions, pain, mental health, and
energy), eight additional generic domains (cognitive functioning, sexual functioning, sleep,
work, recreation, travel, finances, and general quality of life), and six ESRD-specific domains
(diet, freedom, time, body image, dialysis access, and symptoms).
4. Trials on quality of life in HDF
The results of studies on HRQOL in OL-HDF are often inconclusive. The studies used different
questionnaires to assess HRQOL which probably explain some of the differences among
studies.
Reference Country Comparison Quality-of-life Timing of Study result

instrument used assessment
Moura et al. Portugal Four age KDQOL-SF One time at Women >56 years old had decrease in
[38] quartiles version 1.3 for baseline work status, patient satisfaction, and
(<56 years, Portuguese role-physical. Men had decreasing
57–68 years, 69–75 patients physical functioning, with increasing
years, >75 years age. Compared to women, men
old) generally had higher scores in all
quartiles on variable combinations of
physical functioning and pain, patient’s
satisfaction, symptoms/problem list,
work status, role-physical, emotional
http://dx.doi.org/10.5772/64591

well-being, work status, energy/fatigue,
and quality of social interactions
Karkar et al. Saudi Arabia HF-HD and OL- Modified 24 months OL-HDF was associated with
[32] HDF KDQOL-SF improvement in general mood, body
version 1.3 energy, dialysis compliance, sexual
performance, social activity, and
patient’s satisfaction
Moura et al. Portugal Access type: KDQOL-SF One time at Patients with CVC had a decrease in
[43] AVF vs. CVC version 1.3 for baseline scores of physical functioning,
Portuguese emotional well-being, role emotional,
patients and energy/fatigue domains when
compared with those with AVF.
Patients with CVC also showed a
decline in cognitive function and
quality-of-social interaction domains.
Nondiabetic patients generally scored
better than diabetic patients with
similar vascular access
Mazairac et The OL-HDF and KDQOL-SF-36 At baseline At baseline, mean PCS and MCS were
al. [37] Netherlands, LF-HD version 1.3 and Q similar in both groups. In both groups,
Canada, and 3 months for multiple HRQOL domain scores
Norway a median of declined over time. Overall health
2 years domain improved in HDF patients. A
trend to a worse MCS and an improved
effect of kidney disease on daily life in
patients on HDF
Kantartzi et Greece LF-HD vs. OL- IQOLA SF-36 Q 3 months OL-HDF and HDF had better score in
al. [33] HDF and HDF Greek version for 1 year bodily pain and role limitations due to
(with prepared emotional functioning. There were no
bags) differences between the two types of
hemodiafiltration
Knezevic et Serbia OL-HDF vs. HF- KDQOL-SF-36 One time at No difference in general health domain.
al. [31] HD and LF-HD baseline Patients on HDF had better score in
most of the domains compared with
patients on HD, especially compared
with low-flux HD patients. No
differences between high-flux HD and
low-flux HD
Age, economic status, dialysis modality,
and ischemic heart disease were

associated with PCS. Age, sex,
economic status, dialysis modality, and
vascular access are associated with MCS
Stefánsson et Sweden OL-HDF vs. LF- IQOLA SF-36 60 days With the exception of a lower score for
al. [40] HD (Swedish social functioning with HDF, there was
version) + local no significant difference in quality of
questionnaire life between HD and HDF
Schiffl [34] Germany HF-HD vs. OL- KDQ 52 weeks Patients in the two treatment groups
HDF had similar perceptions of their quality
of life. While on OL-HDF, patients had
sustained improvement in physical
symptoms. No change of this
dimension with the other mode of
therapy
Beerenhout The OL-HF vs. KDQ At baseline, Physical symptoms improved in the HF
et al. [39] Netherlands LF-HD 6 and group after 6 and 12 months, but not in
12 months the HD group. QOL for other aspects
(frustration, depression, well-being) did
not change in any treatment group
Lin et al. [44] Taiwan OL-HDF vs. HF- Patients’ score of Weekly Interdialytic symptomatic hypotensive
HD (different subjective well- episodes and interdialysis physical
combinations) being, work well-being and symptoms improved
tolerance, and when frequency of HDF is increased to
mental alertness three times per week
Ward et al. Germany OL-HDF vs. HF- The Kidney 26 and Both groups had similar perceptions of
[41] HD Disease 52 weeks their quality of life. Patients’ assessment
Questionnaire of physical symptoms improved during
the course of the study independent of
mode of therapy
Verzetti et al. Italy AFB vs. BHD in Patients’ score of Monthly Subjective report of well-being
[42] patients with their degree of increased when patients switched from
diabetic ESRD subjective well- traditional HD to AFB
being
Abbreviations: AFB, acetate-free biofiltration; AVF, arteriovenous fistula; BHD, bicarbonate hemodialysis; CVC, central
venous catheter; HDF, hemodiafiltration; HF, hemofiltration; HF-HD, high-flux hemodialysis; IQOLA, International
Quality of Life Assessment; KDQOL, Kidney Disease Quality of Life; KDQ, Kidney Disease Questionnaire; LF-HD,
low-flux hemodialysis; MCS, mental component summary; OL-HDF, online hemodiafiltration; OL-HF, online
hemofiltration; PCS, physical component summary; SF-36, Short Form-36.
Table 2. Summary of studies assessing QOL in patients treated with convective therapy.
http://dx.doi.org/10.5772/64591
The following is the description of trials that examined HRQOL in patients under treatment
of OL-HDF, hemofiltration (HF), and acetate-free biofiltration (AFB) in comparison to low-flux
hemodialysis (LF-HD) or high-flux hemodialysis (HF-HD). Summary of these trials is
presented in Table 2.
4.1. Moura et al.
Moura et al. performed an evaluation of 322 ESRD under OL-HDF from five dialysis units in
north Portugal in which patients reported HRQOL utilizing the Kidney Disease Quality of Life
Short Form (KDQOL-SF). Patients showed a mean (±SD) of 53.17 % (±15.31 %) in SF-36 total
score, 50.17 % (±9.51 %) in the SF-36 mental component summary (MCS), and 49.75 % (±9.44
%) in the SF-36 physical component summary (PCS). Red cell distribution width (RDW), female
gender, and diabetes were found as significant predictors of SF-36 total score of HRQOL, which
accounts for 12 % of the total explained variance. Patient satisfaction, RDW, body mass index,
and gender were identified as predictors for the PCS, which accounts for 22 % of total explained
variance. Furthermore, patient satisfaction and dry weight were found as predictors for MCS.
These predictors accounted for 28 % of the total explained variance. The authors concluded
that the coexistence of diabetes, female gender, and anemia are predictors of HRQOL in
patients under OL-HDF and suggest that more attention should be given to these issues in
order to improve HRQOL [30]
4.2. Knezevic et al.
Knezevic et al. examined whether hemodialysis modality and membrane flux, independent of
membrane biocompatibility, make differences in quality of life in 124 patients from Serbia. The
patients were divided, based on therapy, into three groups: online HDF, high-flux hemodial‐
ysis, and low-flux hemodialysis. Health-related quality of life was assessed using the Short
Form-36 questionnaire combined with special questionnaire, which included demographic
and clinically related questions. Health-related quality of life was better in patients on HDF
compared with patients on hemodialysis, especially compared with low-flux hemodialysis
patients in most of the scales and in both dimensions: physical component scale and mental
component scale. There were no differences in Short Form-36 domains between high-flux
hemodialysis and low-flux hemodialysis. The conclusion was that HDF has a potential positive
influence on quality of life, which is sufficient to justify further research in prospective and
longitudinal study design [31].
4.3. Karkar et al.
Karkar et al. investigated the effect of online HDF vs. high-flux hemodialysis (HF-HD) on a
patient’s health-related satisfaction level. The study involved 72 patients from Saudi Arabia
on regular low-flux HD who were randomized to HF randomized to HF-HD and to HDF
(n = 36) and followed up for 24 months. Satisfaction level was assessed using modified
questionnaires of the Kidney Disease Quality of Life Short Form (KDQOL-SF) version 1.3. The
HDF group achieved a higher satisfaction level than the HD group (P < 0.0001) with less
cramps, itching, joint pain, and stiffness. There was an improvement in general mood, sexual
performance, and social activity. The investigators concluded that high-efficiency postdilution
online HDF significantly improved patients’ satisfaction level and quality of life [32].
4.4. Kantartzi et al.
Kantartzi et al. reported a prospective crossover study involving 24 patients. Each patient
received HD, OL-HDF, and HDF with prepared bags of substitution fluid for 3 months, with
the dialysis modality subsequently being altered. Quality of life was measured by the Short-
Form Health Survey with 36 questions (SF-36), and subscale scores were calculated. There were
statistical significant differences in QOL for the total SF-36, bodily pain score, and role
limitations due to emotional functioning in favor of online HDF over low-flux HD [33].
4.5. Schiffl
Schiffl studied 76 clinically stable patients on low-flux conventional HD (LF-HD) in a pro‐

spective crossover clinical evaluation of high-flux ultrapure hemodialysis (HF-HD) and OL-
HDF. They were randomized to HF-HD or OL-HDF (24 months) and switched to the
alternative treatment (24 months). Online HDF had a greater clearance of urea, phosphate, and
β2-microglobulin. Both OL-HDF and high-flux ultrapure HD significantly improved nutri‐
tional status and the response to erythropoietin. Disease-related quality of life was determined
after 52 weeks of each study period using the KDQ. The KDQ determines quality of life in five
dimensions: physical symptoms, fatigue, depression, relationship with others, and frustration.
The patients in the two treatment groups had similar perceptions of their quality of life.
However, the patients’ assessment of their physical symptoms showed a sustained improve‐
ment during treatment with OL-HDF. There was no change of this dimension with the other
modes of therapy (P < 0.05). None of the other dimensions of the Kidney Disease Questionnaire
showed a change during the course of the study [34].
4.6. Mazairac et al.
Mazairac et al. analyzed data of 714 patients from the Convective Transport Study [35, 36] with
a median follow-up of 2 years to assess the effect of HDF on quality of life compared with HD
in patients with ESRD. Quality of life was assessed with the KDQOL-SF. There were no
significant differences in changes of HRQOL over time between patients treated with HD
(n = 358) or hemofiltration (n = 356) [37].
4.7. Moura et al.
Moura et al. evaluated the influence of aging on patients’ perception of HRQOL in 305 ESRD
patients under OL-HDF. Data about comorbidities, hematological data, iron status, dialysis
adequacy, and nutritional and inflammatory markers were collected from patient’s records.
Quality of life was assessed by using the KDQOL-SF. Analysis of the data showed significant
decrease with increasing age in some parameters evaluated by the KDQOL-SF instrument,
namely, for work status, physical functioning, and role-physical (RP) [38].
http://dx.doi.org/10.5772/64591
4.8. Beerenhout et al.
Beerenhout et al. examined the effects of LF-HD and predilution online HF (OL-HF) on
cardiovascular and nutritional parameters, interdialytic levels of uremic toxins, and quality of
life. The KDQ of Laupacis [26] was used for QOL assessment. At 1 year, 27 patients were eligible
for analysis (HF, 13 patients; HD, 14 patients). QOL for physical symptoms improved in the
HF group (4.2 ± 1.2–5.0 ± 1.1), P < 0.05 within the HF group, but not in the HD group (4.0 ± 1–
4.4 ± 1.4) [39].
4.9. Stefánsson et al.
Stefánsson et al. performed a prospective, randomized, and patient-blinded crossover study

involving 20 patients from Sweden on chronic HD. The patients received either HD for
2 months followed by postdilution HDF for 2 months or in opposite order. Online postdilution
HDF was used, and the replacement volume was standardized to 25–30 % of the total blood
volume treated. The two treatments were similar with respect to dialysis-related complica‐
tions, quality of life, and the biomarkers of oxidative stress and inflammation. Interviews for
assessment of quality of life were double blinded. Patients answered health-related questions
in two separate questionnaires. The first one was the Swedish version of the standardized
quality-of-life questionnaire, SF-36. The second one was generated by the study designers and
specifically concerned 12 symptoms and health-related conditions occurring during the
previous 4 weeks. With the exception of a lower score for social functioning with HDF (P < 0.05),
there was no significant difference in quality of life between HD and HDF [40].
4.10. Ward et al.
Ward et al. tested the hypothesis that HDF provides better solute removal than HF-HD in a
prospective, randomized clinical trial. Twenty-four patients were randomized to online
postdilution HDF, and twenty-one patients were allocated to HF-HD for a period of 12 months.
Removal of both small (urea and creatinine) and large (β2-microglobulin and complement
factor D) solutes was significantly greater for HDF than for HF-HD. Pretreatment plasma β2-
microglobulin concentrations decreased with time (P < 0.001); however, the decrease was
similar for both therapies. The patients’ assessment of their quality of life was determined after
26 and 52 weeks of the study. A single interviewer administered the questionnaire to all
patients. The patients in both groups had similar perceptions of their quality of life as assessed
by the KDQ. The patients’ assessment of their physical symptoms showed a significant
improvement during the course of the study which was independent of the treatment
modality. None of the other dimensions of the KDQ showed a change over the course of the
study [41].
4.11. Verzetti et al.
Verzetti et al. performed a study to compare standard bicarbonate hemodialysis (BHD) with
acetate-free biofiltration (AFB) in a group of 41 stable diabetic patients on dialysis treatment
for 25 ± 22 months. Twenty-four type II and seventeen type I diabetic patients, all requiring
insulin therapy, were included and were followed up for 1 year in a 6-month crossover
randomized study for both methods. The analysis was carried out on dialysis symptoms,
interdialysis symptoms, and nutritional status. On a monthly basis, patients were also required
to score their degree of subjective well-being. All the clinical events occurring during the study
period, together with the number of hospitalizations and mortality rates, were recorded. AFB
significantly reduced dialytic and extra-dialytic symptoms (P = 0.003 and 0.001, respectively).
Cardiovascular collapses decreased by 43 %, and other dialysis symptoms showed a similar
trend (−35 %). The interdialysis symptoms decreased by 28 % and were accompanied by an
increase in subjective well-being (39 %) when patients were switched from traditional HD to
AFB. Acid-base control was better with AFB (P = 0.01), both at the beginning and during the
session. In comparison to traditional HD, hypotensive episodes and other dialysis symptoms
during AFB decreased by 43 % and 35 %, respectively. Interdialysis symptoms showed the
same favorable trend, decreasing by 28 %. Moreover, subjective report of well-being increased
by 39 % when the patients switched from traditional HD to AFB. The number of hospital
admissions and the mortality rate were lower during the AFB than the BHD period. The
authors concluded that AFB allows better control of some metabolic aspects, reduces intra-
and extra-dialysis symptoms, and improves patient QOL [42].
4.12. Moura et al.
Moura et al. examined the effect of vascular access type (arteriovenous fistula (AVF) vs. central
venous catheter (CVC)) on patients reported HRQOL in 322 ESRD under OL-HDF. Arterio‐
venous fistula (AVF) was used by 252 patients (78.3 %), whereas 70 patients (21.7 %) had a
central venous catheter (CVC). Patients using CVC as a vascular access presented a decrease
in four SF-36 domain scores, namely, physical functioning, emotional well-being, role-
emotional, and energy/fatigue when compared with those using AVF as a vascular access.
Additionally, these patients also showed significant decline in cognitive function and quality-
of-social interaction domains. Left-arm AVF was associated with higher scores in three SF-36
domain scores, namely, physical functioning, pain, and general health. It was also associated
with a higher score in ESRD target areas of symptoms/problem list and effects of kidney disease
and quality-of-social interaction domains. The authors concluded that ESRD patients under
OL-HDF using AVF as a vascular access had higher HRQOL scores in several domains when
compared with those using CVC. Patients using AVF in the left forearm presented with higher
HRQOL scores [43].
4.13. Lin et al.
Lin et al. compared OL-HDF (thrice, twice, and once per week) with different frequencies of
combination high-flux HD. Interdialytic symptomatic hypotensive episodes were reduced
when frequencies of online HDF were increased. Interdialysis physical well-being and
symptoms similarly improved when frequency of HDF is increased to three times per week
[44].
http://dx.doi.org/10.5772/64591
4.14. Nistor I et al.
Nistor et al. [45] conducted a systematic review of randomized controlled trials in which data
for quality of life were extractable from eight trials (988 participants), including six evaluating
HDF and one each evaluating HF or acetate-free biofiltration [33, 34, 36, 39–42, 44]. The authors
Stated that in very low-quality evidence, data for quality of life were inconsistent. Data from
the four parallel-group trials [33, 36, 39, 41] showed that there was no difference in the change
in quality of life (any domain) comparing HDF with HD in one trial [36]. Both HDF and HD
patients reported significant improvement in physical symptoms irrespective of treatment
allocation in a second trial [41]. Hemodialysis patients had lower physical well-being scores
than patients on HDF, but treatment effects on work tolerance and mental alertness were not
available in a third trial [33]. Comparative data for HF and HD were not available in a fourth
trial [39]. The remaining four studies were crossover design, and data for the end of the first
phase of treatment were not available.
5. Summary
The available data on HRQOL in patients under OL-HDF therapy is limited and of low quality.
Most parallel-group randomized clinical trials on this subject demonstrate no or limited
improvement in HRQOL associated with OL-HDF. However, several crossover studies
support a beneficial role of OL-HDF in enhancing quality of life in these patients. The effect of
online HDF on quality of life reported by clinical studies is variable. The inconsistency of these
results is probably related to different methods used to assess quality of life, sample size,
duration of study, and the different characteristics of the convective therapy utilized such as
blood flow rate, vascular access type and type of the dialyzer, convection volume, and
frequency of online HDF. The most widely used and tested method of assessing health-related
quality of life in patients undergoing online HDF replacement therapy is Kidney Disease
Quality of Life Short Form-36 (KDQOL-SF-36). It is easily administrable and has been vali‐
dated.
With the increased popularity of OL-HDF as a renal replacement therapy, larger better
organized studies will probably become available in the future. Such studies, hopefully, will
better clarify the issue.
Author details
Samir H. Almueilo
Address all correspondence to: smueilo@uod.edu.sa
King Fahd Hospital of the University, University of Dammam, Alkhobar, Saudi Arabia
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Chapter 9
Cost-Effectiveness of Online Hemodiafiltration
Khalid AlSaran and Khalid Mirza
http://dx.doi.org/10.5772/64679
Abstract
Care of patients with end-stage renal disease (ESRD) is essential but also resource
intense. We review several studies on online hemodiafiltration (OL-HDF), which
concluded that high-volume OL-HDF is associated with better outcome compared to
conventional hemodialysis. The cost-effectiveness of OL-HDF was shown in many
studies. For example, in the Canadian setting of the Convective Transport Study
(CONTRAST), the high-efficiency OL-HDF was shown to be cost-effective compared
with low-flux hemodialysis (LF-HD) for patients with ESRD. In our study (Al Saran et
al.), it was shown that the cost of hemodialysis was quite less in Saudi Arabia than in
other industrialized countries while maintaining a high standard of care. In our
retrospective analysis of the cost of OL-HDF in the same center, it was only 3% higher
than the conventional HD, which indicates that it is cost-effective considering the
improved hospitalization rate, the mortality rates, and the likely better quality of life
associated with it. The trend of increased practice of OL-HDF may encourage the
practice of home OL-HDF as well. It has been shown that home HD is more cost-
effective than in-center HD and we presume that the same results will be applied to
home OL-HDF as well.
Keywords: online hemodiafiltration, low-flux hemodialysis, middle molecules, cost
1. Introduction
Untreated end-stage renal disease (ESRD) carries a high mortality. The management of ESRD
is either by dialysis or by a kidney transplant. Due to insufficient number of kidney donors in
comparison with the progressive increase in the number of ESRD patients in need for dialysis,
dialysis remains the main modality of treatment. Since the care of patients with ESRD is
resource intense, it is necessary to adopt measures that render the delivery of dialysis more
cost-effective and improve the quality of care. The uremic syndrome is characterized by the
accumulation of uremic toxins due to inadequate kidney function. The European Uremic Toxin
Work Group has listed more than 90 compounds considered to be uremic toxins. Among them,
68 have a molecular weight less than 500 Da, 10 have between 500 and 12,000 Da, and 12 exceed
12,000 Da [1]. Solutes weighing less than 500 Da are considered low molecular weight solutes
and they are removed by passive diffusion down a favorable concentration gradient. Urea is
considered a marker of such toxins. Its clearance, as measured by Kt/V urea, correlates with
patient morbidity showing the evidence that such toxins contribute to the uremic syndrome
[2]. The mortality rate of patient on maintenance dialysis has been found to be 15–20% [3].
This is despite improvements in patient care and technology. In order to increase survival in
dialysis patients, it was postulated in 1983 that increasing the Kt/V in conventional dialysis
may help to reduce mortality. However, the hemodialysis (HEMO) study failed to show a
positive effect on patient survival when dialysis dose per hemodialysis session was in‐
creased above the current K/DOQI recommendations [4]. Possible explanation for this
unfavorable outcome could be in the kinetics of urea removal which is representative of small
solutes, but not of larger-sized molecules such as middle molecules, large molecular weight
proteins or protein-bound solutes, thereby making Kt/V misleading [5]. Clearance of urea
accounts for only one-sixth of physiological clearance [1]. In addition, several shortcomings
are associated with short dialysis schedules that are not captured by Kt/V index such as
extracellular fluid volume control, phosphate control, and adequate removal of middle and
larger uremic molecules compounds. Beta-2 microglobulin levels are associated with the
development of dialysis-related amyloidosis and possibly reduced survival [6]. It seems likely
that beta-2 microglobulin is a marker for overall-middle molecule clearance, including more
toxic and yet unidentified uremic compounds [7–10]. Those solutes are better removed by
high-flux membranes due to their more porous characteristics with increased permeability.
Hemodialfiltration (HDF) is the treatment modality that combines diffusion and enhanced
convection in order to facilitate removal of small molecular weight solutes. Moreover, small
molecule removal is further increased with the use of high-volume OL-HDF. HDF is thus a
more cardioprotective renal replacement therapy.
Recent randomized controlled trials (RCTs) have shown the survival advantage of HDF using
high-convective volumes (23 L/session or 69 L/week prescription). In Peters et al.’s review [11]
which is a pooled individual participant analysis of 4 RCTs, it was a observed that in patients
receiving the higher delivered convection volume (>23 L per 1.73 m2 body surface area (BSA)
per session), the longest survival benefit was seen with Hazard Ratio (HR) of 0.69 (95% CI:
0.47; 1.00) for cardiovascular disease mortality and HR of 0.78 (95% CI: 0.62; 0.98) for all-cause
mortality.
In another study by Canaud et al. [12], which was a retrospective data collection from over
2000 patients with a minimum follow-up of 2 years, the relative survival rate of OL-HDF
patients was found to increase at about 55 L–75 L/week of convection volume.
Cost-Effectiveness of Online Hemodiafiltration 143
http://dx.doi.org/10.5772/64679
2. Principles of hemodiafiltration
Ultrafiltrate volume is removed by the dialysis machine through increased transmembrane

pressure (TMP), whereas the replacement solution is infused intravenously at equal volume
minus the desired fluid volume removal to preserve extracellular fluid balance and isovolemic
state. The replaced solution represents substitution volume, whereas convective volume
represents the sum of substitution volume and desired fluid volume removal during the
dialysis session. The fluid can be substituted either after the dialyser as the reference mode
(post-dilution mode) or before the dialyser (pre-dilution mode) or the combination of both
(mixed dilution mode).
3. Efficacy of online hemodiafiltration
Several studies have shown online hemodiafiltration (OL-HDF) to be superior to conventional

hemodialysis in reducing all-cause mortality in hemodialysis patients. OL-HDF has been
found to reduce cardiovascular events as compared with conventional hemodialysis.
Furthermore, OL-HDF has significantly improved patients’ satisfaction and quality of life [13–
16]. OL-HDF has also shown to be a cost-effective treatment for ESRD [17]. For example, in the
prospective Convective Transport Study (CONTRAST), there was no significant difference
between treatment groups with regard to all-cause mortality (121 versus 127 deaths per 1000
person-years in the OL-HDF and LF-HD groups, respectively); (hazard ratio, 0.95; 95%
confidence interval, 0.75–1.20) after a mean follow-up of 3 years (range 0.4–6.6 years). Receiv‐
ing high-volume hemodiafiltration during the trial was associated with lower all-cause
mortality.
In the ESHOL multicentre, open-label RCT [14], patients on OL-HDF compared with those on
HD had a 55% lower risk of infection-related mortality (HR, 0.45; 95% CI, 0.21–0.96; P = 0.03),
a 33% lower risk of cardiovascular mortality (HR, 0.67; 95% CI, 0.44–1.02; P = 0.06), and a 30%
lower risk of all-cause mortality (HR, 0.70; 95% confidence interval [95% CI], 0.53–0.92; P =
0.01). In conclusion, high-efficiency post-dilution OL-HDF reduces all-cause mortality
compared with conventional hemodialysis. According to the Turkish OL-HF prospective RCT
[15], 782 patients undergoing thrice-weekly HD were enrolled and randomly assigned in a 1:1
ratio to either postdilution OL-HDF or high-flux HD. Using a filtration volume of 17.2 ± 1.3 L,
there was no difference in the primary outcome between the two groups (event-free survival
of 77.6% in OL-HDF vs. 74.8% in the high-flux group, P = 0.28). Also, no difference was seen
in the cardiovascular and overall survival, number of hypotensive episodes and hospitaliza‐
tion rate. However on further analysis, the patients who received higher substitution volume
(>17.4 L per session) had better cardiovascular outcome (P = 0.002) and overall survival
(P = 0.03) compared with those who received high-flux HD. The study of Karkar et al. [16]
aimed to investigate the effect of OL-HDF versus high-flux HD (HF) on a patient’s health-
related satisfaction level. A higher satisfaction level was achieved by the OL-HDF group
compared with HF group (p < 0.0001). In the OL-HDF group, there was less itching (9 ± 10 vs.
48 ± 10), less cramps (3 ± 5 vs. 55 ± 8), less joint pain and stiffness (24 ± 10 vs. 83 ± 8) with
improvement in sexual performance (57 ± 10 vs. 5 ± 5), social activity (82 ± 9 vs. 15 ± 8), and
general mood (94 ± 9 vs. 28 ± 16). High-efficiency postdilution online HDF versus high-flux
HD significantly improved patients’ satisfaction and quality of life, including social, physical,
and professional activities.
4. Cost-effectiveness of OL-HDF
4.1. Review of the literature

In spite of the several studies which investigate the efficacy of OL-HDF, there were fewer
studies which assessed the cost-effectiveness of this procedure. One of them was the CON‐
TRAST [17] in which the cost-effectiveness of high-efficiency OL-HDF was compared with LF-
HD for patients with ESRD based on the Canadian (Centre Hospitalier de l’Universite de
Montreal) arm of a parallel-group RCT. Over a period of 74 months, an economic evaluation
was conducted. To simulate costs and health benefits over lifetime, a Markov state transition
model was constructed. A total of 130 patients were randomly allocated to OL-HDF (n = 67)
and LF-HD (n = 63). The primary outcome was costs per quality-adjusted life-year (QALY)
gained. The cost-utility ratio of OL-HDF versus LF-HD was Can$53,270 per QALY gained over
lifetime, and it was fairly robust in the sensitivity analysis. It was concluded that in a Canadian
setting, high-efficiency OL-HDF can be considered as a cost-effective treatment for ESRD.
In Mazairac et al. study [18], a cost-utility analysis was performed using a Markov model. It
included data from the CONTRAST. Probabilistic sensitivity analyses were performed to study
uncertainty, and costs were estimated using a societal perspective. Total annual costs for HDF
and HD were €88,622 ± 19,272 and €86,086 ± 15,945, respectively (in 2009 euros). The incre‐
mental cost per quality-adjusted life year (QALY) of HDF versus HD was €287,679 when
modeled over a 5-year period. Even under the most favorable assumptions like a high-
convection volume (>20.3 L), this amount will not fall below €140,000 using sensitivity
analyses. They concluded that HDF cannot be considered a cost-effective treatment for patients
with end-stage renal disease at present. This was based on accepted societal willingness-to-
pay thresholds.
Various factors may responsible for the true differences in the cost of dialysis provision
between various studies. These factors may include variable standards of care, different
management protocols, differences in the methodologies used, the older population of patients
with more comorbid illness (especially in the United States), different import duties and
shipping charges, local labor costs, dates of the studies, the differences in countries in which
the analyses were carried out, nurse/patient and physician/patient ratios and the number of
dialysis sessions. Direct comparisons may not be very informative. Finally, the comparison
between countries in the cost of dialysis must take into consideration the morbidity and
mortality outcomes in these patients, as well as perceived quality of life [19, 20].
We have previously [21] assessed the cost of hemodialysis according to the treatment protocols
based on the current Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines. The
http://dx.doi.org/10.5772/64679
cost data, which included direct and overhead costs, were analyzed during the period from 1
January 2007 to 30 June 2010. Direct cost included items related to dialysis treatment such as
dialysis disposables, dialysis related drugs, medical personnel, outpatient medications,
laboratory, and other ancillary survives.
The category The cost/session Percentage

(I) Direct cost USD SR
(1) Dialysis disposables (including tubing, dialyzer, acid concentrate, needles, normal 40.53 152 13.64
saline, dressing set, heparin and bed sheets)
(2) Medical equipments and maintenance 13.6 51 4.58
(3) The meals 7.12 26.7 2.40
(4) Personnel:
a. Administrative 32 120 10.77
b. Medical 90.13 338 30.34
(5) Intravenous medications
a. ESA 16.8 63 5.66
b. Vitamin D 1.06 4 0.36
c. Iron 0.8 3 0.27
d. Albumin and dextrose 0.53 2 0.18
(6) Vascular access creation and revision* 10.24 38.4 3.45
(7) Laboratory tests 10.19 38.2 3.43
(8) Imaging investigations 0.11 0.7 0.06
(9) Out-patient and crash cart medications 17.87 67 6
Total direct cost 241 904 81.15
(II) Indirect cost
(1) Non-medical equipments with maintenance and housekeeping 15.55 58.3 5.23
(2) Medical records 0.5 1.86 0.17
(3) Building** 29 109 9.78
(4) Disposal of medical waste 0.71 2.66 0.24
(5) Meals for personnel 7.12 26.7 2.40
(6) Suit for personnel 0.22 0.83 0.07
(7) Automobile maintenance and fuel 1.28 4.8 0.43
(8) Utility bills (electricity, water and phone) 1.56 5.85 0.53
Total indirect cost 56 210 18.85
Total 297 1114 100
Calculated based on the mean half-life of the access and on the mean frequency rate of re-insertion or revision.
*
Calculated based on the current cost for the land and construction divided by 20 years for the construction and by
**
10 years for the land (investment rate).
Table 1. The unit cost of the categories associated with hemodialysis provision at the King Salman Center for kidney
diseases.
Over head (indirect) cost included building, maintenance and engineering costs, housekeeping
and administrative personnel. The mean total cost per HD session was calculated as 297 US
dollars (USD) [1114 Saudi Riyals (SR)], and the mean total cost of dialysis per patient per year
was 46,332 USD (173,784 SR). Out of the total cost, the direct cost was the major part (81.15%)
(Table 1). The total cost was well below the average cost in the industrialized countries
although a high standard of care was maintained.
The category Hemodialysis Hemodiafiltration

(I) Direct cost
(1) Dialysis disposables (include tubing, dialyzer, acid concentrate, needles, 40.53 50.53
normal saline, dressing set, heparin and bed sheets)
(2) Medical equipments and maintenance 13.6 13.6
(3) The meals 7.12 7.12
(4) Personnel
a. Administrative 32 32
b. Medical 90.13 90.13
(5) Intravenous medications
a. ESA 16.8 16.8
b. Vitamin D 1.06 1.06
c. Iron 0.8 0.8
d. Albumin and dextrose 0.53 0.53
(6) Vascular access creation and revision 10.24 10.24
(7) Laboratory tests 10.19 10.19
(8) Imaging investigations 0.11 0.11
(9) Out-patient and crash cart medications 17.87 17.87
Total direct cost 241 251
(II) Indirect cost
(1) Nonmedical equipments with maintenance and housekeeping 15.55 15.55
(2) Medical records 0.5 0.5
(3) Building** 29 29
(4) Disposal of medical waste 0.71 0.71
(5) Meals for personnel 7.12 7.12
(6) Suit for personnel 0.22 0.22
(7) Automobile maintenance and fuel 1.28 1.28
(8) Utility bills (electricity, water, and phone) 1.56 1.56
Total indirect cost 56 56
Total 297 307
Table 2. Comparison of the cost/session between hemodialysis and hemodiafiltration in US dollar.

http://dx.doi.org/10.5772/64679
4.2. Retrospective comparison between HD and OL-HDF
In our retrospective analysis of the cost of OL-HDF in the same center, the cost of the OL-HDF
was only 3.4% higher than the conventional HD (10 US dollar difference per session). This
difference in cost was in the category of dialysis disposables (Table 2). It is attributed to (1) the
cost of the water purification filter at the back of online HDF dialysis machine which cost an
average of 1.95 USD/session, (2) the cost of tubing extension used for OL-HDF which cost 7.8
USD/session, (3) the cost of the treated water used as substitution fluid (its volume in our center
was 30 L/session), which cost 0.25 USD/session. This little difference in the cost of water
treatment between the two modalities may be attributed to the fact that we are using ultrapure
water for the two modalities in order to minimize the risk of micro-inflammation associated
with HD. We need to emphasize that in some centers that have the latest manufactured dialysis
machine, there will be no extra cost for the tubing as it will be the same tubing in both
modalities. Finally, there was no difference in the cost for using high-flux dialyzer as its price
nowadays is almost the same as for low-flux dialyzer. In conclusion, this minor cost difference
between HD and OL-HDF indicates that OL-HDF is cost-effective considering the advantages
of the OL-HDF and the better quality of life associated with it. The possible presumed decrease
in the cost of medications and hospitalization is another supportive factor for the cost-
effectiveness of OL-HDF. In addition, OL-HDF may not be indicated for all the dialysis
patients. In our center, OL-HDF was only performed for certain indications such as severe
hyperphosphatemia, severe resistant hypertension, and resistant anemia.
4.3. The cost-effectiveness of home HD and home OL-HDF
The trend of increased practice of OL-HDF may encourage the practice of home OL-HDF as
well. More intensive and/or frequent hemodialysis may provide clinical benefits to patients
with ESRD; however, these dialysis treatments are more convenient to the patients if provided
in their homes. It has been shown that home HD is more cost-effective than in-center HD, and
we presume that the same results will be applied to home OL-HDF as well. In Komenda et al.
[22] review of data from Australia, Canada, and the United Kingdom, it was noted that the
cost of the first year for all hemodialysis modalities were higher than in subsequent years, and
the cost for conventional home hemodialysis was lower than in-center hemodialysis in
subsequent years. Their conclusions were similar to previous studies that home-based
conventional and more frequent hemodialysis may provide clinical benefit at reasonable costs.
In another study for Komenda et al. [23], they described a comprehensive funding model for
a large centrally administered but locally delivered home hemodialysis program in British
Columbia, Canada. There were 122 patients, of which 113 were still in the program at study
end. In this two-year retrospective study, the majority of patients performed home nocturnal
hemodialysis, and it was found that the total cost for home hemodialysis was higher in the
first two years and it was lower by about 10,500 per year in the subsequent years. So their study
explained a valid, comprehensive funding model delineating reliable cost estimates of starting
as well as maintaining a large home-based hemodialysis program. Therefore, when designing
budgets for home hemodialysis, consideration of hidden costs is important for administrators
and planners.
McFarlane et al. [24] assessed the cost-effectiveness of home nocturnal hemodialysis (HNHD)
in relative to in-center hemodialysis (IHD). In this Canadian one-year prospective study which
was done at two centers in Toronto in the year 2000, HNHD had a higher mean number of
treatments per week (5.7 vs. 3.0, P = 0.004). In the cost categories, staffing was found to be less
expensive for HNHD (weekly $210 vs. $423, P < 0.001, PMA $4179 vs. $12,393). There was a
trend toward lower costs for hospital procedures and admissions (weekly $23 vs. $134,
P = 0.355, PMA $1173 vs. $6997), for the capital costs (weekly $118 vs. $17, P < 0.001, PMA $6139
vs. $871) and the cost of direct hemodialysis materials (weekly $318 vs. $126, P < 0.001, PMA
$16,587 vs. $6575). On the other hand, there was a trend toward higher cost for laboratory tests
(weekly $33 vs. $26, P = 0.094, PMA $1744 vs. $1364). Physician costs were the same at $128
per week (PMA $6650). The projected mean annual costs were more than $10,000 lower
($56,394 vs. $68,935). The weekly mean total cost for health care delivery was 20% less for
HNHD ($1082 vs. $1322, P = 0.006). Their conclusion was that HNHD provides about three
times as many treatment hours at nearly a one-fifth lower cost. The savings were evident even
when only program and funding specific costs were considered.
5. Conclusion
OL-HDF seems to be cost-effective and much better than conventional hemodialysis for the
patient’s satisfaction, quality of life, patient’s survival, dialysis-related mortality and morbid‐
ity, and cardiovascular outcomes. However, more prospective studies are needed on the cost-
effectiveness of this procedure.
Acknowledgements
The authors are grateful to Engineer Fahad Alderh for his contribution in cost calculation.
Author details
Khalid AlSaran1,2,3* and Khalid Mirza4
*Address all correspondence to: Khalid_aln@yahoo.co.uk
1 Pediatric Nephrology Department, King Saud Medical City, Riyadh, Saudi Arabia
2 College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
3 King Salman Kidney Center, Riyadh, Saudi Arabia
4 King Saud Medical City, Riyadh, Saudi Arabia

http://dx.doi.org/10.5772/64679
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Chapter 2 Principles of Haemodiafiltration: Rationale for Improved

Chapter 3 Fluid Convection, Generation and Reinfusion in

Chapter 4 The Effect of Convective Dialytic Modalities on Arterial

Chapter 5 Effectiveness of Ultrafiltration in Patients with Congestive

Chapter 6 Update on Clinical Evidence Supporting Hemodiafiltration

Chapter 7 Home Haemodialysis and Haemodiafiltration

Chapter 8 Quality of Life on Online Hemodiafiltration (HDF)

Chapter 9 Cost-Effectiveness of Online Hemodiafiltration

Hemodiafiltration (HDF) is an advanced renal replacement

Additional information is available at the end of the chapter

Figure 1. Major milestones in the development of online HDF.

Address all correspondence to: aymankarkar@yahoo.com

Ministry of Health, Riyadh, Saudi Arabia

Principles of Haemodiafiltration: Rationale for Improved

Goran Imamović, Bernard Canaud,

Additional information is available at the end of the chapter

Keywords: haemodialysis, haemodiafiltration, convection, ultrafiltration, mortality

The uremic syndrome is characterised by an accumulation of uremic toxins due to inadequate

In an attempt to improve patients’ outcomes, alternative renal replacement therapies have

Figure 1. Mimicking native kidney function to enhance middle-molecule removal.

3. Technological principles of haemodiafiltration

3.1. Dilution modes

Figure 4. Dilution modes in haemodiafiltration; HDF, haemodiafiltration.

Post-dilution HDF Pre-dilution HDF Mixed-dilution HDF

High solute clearance and removal Haemodilution Avoids the drawbacks

Reduced consumption of substitution volume Decreased viscosity and oncotic Cons

Post-dilution HDF Pre-dilution HDF Mixed-dilution HDF

Haemoconcentration Preserved hydraulic

Increased viscosity and oncotic pressure Reduced membrane stress

Fibres and membrane fouling Cons

Reduced hydraulic and solute membrane Reduced solute clearance

Increased transmembrane pressure Increased consumption of

Reduced sieving coefficient

Increasing membrane stress

Potential albumin leakage

Table 1. Pros and cons of dilution modes.

4. Water for dialysis

5. Rational for improved patients’ survival on high-volume

effect of post-dilution oHDF over HD in reducing all-cause and cardiovascular mortality

5.1. Limiting factors for high-volume on-line haemodiafiltration

5.1.1. Blood viscosity as a limiting factor for high-volume on-line haemodiafiltration

Figure 6. Increased filtration fraction in plasma water.

5.1.2. Filter performance as a limiting factor for high-volume on-line haemodiafiltration

Correlation between ultrafiltered volume and beta-2 microglobulin elimination is linear, as

5.1.3. Blood flow as a limiting factor for high-volume haemodiafiltration

On-line monitoring of blood parameters allows adjustment of ultrafiltration rate to identify

Figure 9. The impact of blood flow on filtration fraction.

6. Towards more cardioprotective renal replacement therapy

The advanced technology of automatic adaptation by the built-in software AutoSub®,

7. Clinical effects of high-volume oHDF

8. The impact of substitution volume in haemodiafiltration on patients’

HV oHDF is a renal replacement treatment modality that is becoming increasingly employed

Goran Imamović1,2*, Bernard Canaud3,4, Nusret Mehmedović5 and Cäcilia Scholz6