characteristics of diffusion (left) and convection (right). Diffusion is a function of KoA (mass transfer area coefficient) of the dialyzer , Qb (blood flow), and Qd (dialysate flow); whereas convection is a function of UF rate (ultrafiltration and sieving of the dialyzer membrane)
While urea removal was the leading concept since the 1970s (Gotch et al. 1976), later on, HD-associated morbidity and mortality were assigned to larger molecules, such as beta-2-microgobulin (β2M, MW 11.8 kilo Dalton [kD]) (Bardin et al. 1987). In an attempt to increase the amount of convective transport and to improve the sieving of larger particles, synthetic high-flux membranes were developed, which permitted the passage of molecules up to 40–50 kD (SCβ2M 0.8–0.9). To prevent unwanted fluid loss, HD machines with ultrafiltration (UF)-control devices were designed, which compensate the excess UF by backfiltration.
When convection is applied, water-soluble molecules are transported by solvent drag. The magnitude and the nature of convective transport are determined by the amount of water movement across the dialyzer per unit of time (UF rate) and the permeability of the membrane (Fig. 10.1). In standard low-flux HD, only the inter-dialytic weight gain, resulting from the intake of non-excreted drinks, is removed by UF (2.5–3.5 kg or L). During HDF , extra plasma water is ultrafiltrated during the treatment. In order to compensate for excess fluid loss, a substitution fluid is infused into the patient. This fluid can be infused either before the dialyzer (pre-dilution), after the dialyzer (post-dilution), both before and after the dialyzer (mixed-dilution), or within the dialyzer (mid-dilution) (see Fig. 10.2).
Schematic illustration of post-dilution (left top), pre-dilution (right top), mixed- dilution (left below), and mid-dilution (right below) hemodiafiltration
In pre-dilution HDF , the blood entering the dialyzer is diluted by substitution fluid. This results in a lower concentration of dissolved uremic toxins and a lower concentration gradient across the dialyzer membrane. Hence, diffusive clearance is less effective as compared to HD. Furthermore, the UF fluid consists of both substitution fluid and plasma water, reducing solute transfer.
In post-dilution HDF , UF results in a proportional increase in removal of middle molecular weight (MMW) toxins, as the substitution fluid is infused after the dialyzer. At the same time, hemoconcentration occurs inside the dialyzer , resulting in increased blood viscosity, restricting the amount of convection up to about 5–7 L/h. As the plasma solutes are not diluted before or within the dialyzer, diffusion is as effective as in HD, and the UF removed contains only plasma water.
With mixed-dilution HDF , the substitution fluid is infused with a variable rate both before and after the dialyzer, in an attempt to overcome the hemoconcentration occurring in post-dilution HDF , while retaining the superior clearance of pre-dilution. For mid-dilution HDF, special filters are used.
Online post-dilution HDF is the most widespread infusion mode and probably the most efficient in the removal of MMW substances. Data on clinical outcomes are available almost exclusively for post-dilution HDF.
10.2.3 Hemodiafiltration Equipment
10.2.3.1 Online-Hemofiltration Systems
In the early days of HDF treatment, substitution fluid was administered in bags, and fluid balance was obtained by weighing devices. In the 1980s, the first complete system for continuous online preparation of pyrogen-free substitution fluid was launched (Canaud et al. 1985; Shaldon et al. 1982). Later on various modifications, improvements, and supplementary options were introduced (Canaud and Ledebo 2016).
Each modern ol-HDF (hereinafter just HDF) system has its own merits and (dis)advantages, which cannot be discussed in detail in this chapter. Differences include their cleaning and disinfection principles, consisting of chemical, thermal, and/or citro-thermal measures to eliminate contamination and avoid biofilm formation. Furthermore, the various HDF systems offer different blood tubing sets and occasionally a cassette system. Additional therapeutic and monitoring options include citrate administration, thermal balance measurement, and the monitoring of blood volume and temperature . All HDF systems have their own risk management system, additional to safety features required by international standards. In this regard the monitoring and warning of filtration fraction , inlet and outlet pressures, and their adjustable alarm limits should be mentioned. While each machine has its own display of settings and prescribed parameters, several manufacturers offer the choice between manual and automatic handling. Connection to a hospital information system is provided by some but not by all manufacturers of HDF equipment. Likewise, the possibility to perform different modalities of HDF with one machine, such as pre-, post-, mid-, or mixed-dilution HDF is provided by some but not by all systems (Fig. 10.2). Finally, each HDF system has its own costs assessment for machines, disposables, and microbiological monitoring. For further reading see Sternby et al. 2016.
10.2.3.2 Dialyzers for Hemodiafiltration
A prerequisite to perform HDF efficiently and safe is the selection of an adequate dialyzer. Criteria for selection include the material of the membrane, its biocompatibility profile, its hydraulic permeability (UF coefficient [KUF] generally expressed in mL/h/mmHg/m2), the magnitude of the membrane surface area, its cutoff point for molecular size, and its physical strength to resist the intra-dialyzer transmembrane forces (Ronco et al. 2016). In addition, the material and structure of the membrane should be resistant to chemical and physical sterilizing agents. High adsorptive properties may contribute to the solute removal capacity of some membranes (Sombolos et al. 1997).
In HDF, dialyzer membrane wall thickness should be small enough (<45 μm) to permit diffusion but also strong enough to resist the high transmembrane pressure (TMP) needed for large convection volumes and to prevent rupturing of the membrane and leakage of blood. The hydraulic permeability of the dialyzer membrane should be sufficient (KUF >30 mL/h/mmHg/m2) to allow the passage of uremic toxins up to 40–50 kD but simultaneously minimize albumin (66.4 kD) loss (SCalbumin <0.001). As indicated in the KUF formula, the surface area of the membrane is an important determinant of UF rate. Various technical options have been applied to optimize the distribution of blood and dialysis flow in the central parts of the dialyzer and in peripheral areas, to obtain the most favorable exchange of uremic toxins (Vienken and Ronco 2001). Finally, a beneficial biocompatibility profile and an optimal endotoxin retaining capacity are fundamental aspects of the filter.
Dialyzers for HDF in Clinical Practice
Only a few studies provided information from clinical practice. In the multicenter Convective Transport Study (CONTRAST), dialyzers were used with a membrane surface area between 1.7 and 2.2 m2, KUF between 56 and 85 mL/h/mmHg/m2, capillary lumen diameters between 185 and 215 μm, and capillary lengths between 225 and 280 mm (Chapdelaine et al. 2014). Regardless of these differences, achievement of a high convection volume was above all dependent of treatment time and blood flow , while the type of membrane and its surface area was not determining. Nonetheless, in a comparative crossover study with four different membranes, the highest convection volumes were achieved by a dialyzer with the largest surface area (2.2 m2), a high KUF (85 mL/h/mmHg/m2), and capillaries with a wide lumen (215 μm) and a short length (200 mm) (Albalate et al. 2011). Since high convection volumes (>29 L/5 h) could also be obtained with a special designed 1.4 m2 dialyzer, these investigators raised the question whether a smaller membrane surface area than usual would induce fewer bio-incompatible side effects and less fouling and clotting (Maduell et al. 2014, 2015).
With respect to bio-incompatibility, even less studies have been performed. From a sub-study in patients from CONTRAST, it appeared that alterations in platelet activation, as measured by CD62p expression and platelet numbers, was more pronounced during HDF than during HD, most probably due to a higher TMP and increased hemoconcentration (Gritters-van den Oever et al. 2009). Electron microscopic evaluation revealed that the surface area of platelets was considerably reduced (Schoorl et al. 2011). In CONTRAST and in the Turkish HDF study (THDFS), the dose of heparin and low-molecular-weight heparin (LMWH) was 10%, respectively, 25% higher in HDF patients as compared to those who were treated by HD (de Roij van Zuijdewijn et al. 2014; Ok et al. 2013). Since high-volume (HV) HDF is associated with a significantly better clinical outcome than both standard HDF and HD, it appears that these potential harmful side effects are counterbalanced by dominant beneficial effects, such as a better intradialytic hemodynamic stability and/or a superior clearance of MMW uremic toxins (see next paragraph).
10.2.3.3 Water Treatment Systems
During standard HD, 500 mL/h of dialysis fluid flows through the water compartment of the dialyzer , which is separated from the blood compartment by the membrane of the dialyzer only. Depending on the concentration of the contaminant, the characteristics of the membrane, and the mode of HD, water-soluble contaminants may cross the membrane from the dialysis fluid into the blood. In Table 10.1, a number of low-molecular-weight substances are shown which are commonly found in drinking water and are toxic to HD patients. The recommendations for dialysis water are around tenfold lower than allowed for drinking water. Water treatment systems to produce water for dialysis, including HDF , consist of nonspecific purification steps, such as softeners and carbon filtration, which are centered around a reverse osmosis (RO). To achieve high-quality dialysis fluid, both prevention of bacterial entry to the system and controlling of bacterial growth within the system, especially slime-producing pseudomonas species, are important. To prevent biofilm formation, the material of the distribution systems must allow disinfection with hot water or water containing ozone.
Standards for drinking water and dialysis water
WHO recommendations for drinking water (mg/L) (World Health Organization 2011)
ISO 13959:2014 standards dialysis water (mg/L) (International Organization for Standardization 2014a)
Considering the entry of viable bacteria or their products, current HDF machines use a validated two-stage process. The first stage generates ultrapure (UP) dialysis fluid, and the second step reduces endotoxin levels further by a factor 100. Since it is not possible to verify the required purity, the validated process is automatically controlled and monitored by the dialysis machine. With respect to bacterial-derived products in the dialysis water, both diffusion and convection to the bloodstream of the patients may play a role: diffusion in low-flux and high-flux HD and convection by backfiltration in high-flux HD. Since bacteria and most bacterial-derived products, such as endotoxins and DNA fragments, which vary widely in size and composition, are too large for diffusion but not for convective transport, bacteriological safety requirements for high-flux HD (ultrapure [UP] dialysis fluid) are more stringent than for low-flux HD ( standard dialysis fluid) (see Table 10.2).
Maximum allowable levels of microbiological contaminants in dialysis fluids
Standard dialysis fluid
Ultrapure dialysis fluid
Sterile, pyrogen-free infusion fluid
Dialysis and Substitution Fluid for Hemodiafiltration
Similar to HD, HDF patients are exposed to 120–240 L of dialysis fluid during treatment. Purified RO water enters the machine and is mixed with bicarbonate and acid concentrate. In HDF, however, a considerable amount of plasma water is extracted from the patients on top of the UF requirements. To maintain volume balance, a similar amount of fluid is dispensed directly into the bloodstream of the patients. This substitution is produced online from dialysis fluid. While the fresh RO water passes upstream through an ultrafilter to ensure microbial purity and enters the ECC, the redirected substitution fluid passes through a downstream final filtration system to remove residual pyrogens and endotoxins before administering to the patients. This substitution fluid must not only be free of chemical contaminants, as in HD, but also highly pure, that is sterile and pyrogen-free (Table 10.2). The intravenous administration of large amounts of substitution fluid necessitates levels of microbiological quality far below detection limits.
10.2.4 Purity of HDF in Clinical Practice
Only little data are available on the water quality of HDF in clinical practice. Pyrogenic reactions were not reported in 4.284 HDF sessions over a 6-year period (Pizzarelli et al. 1998). In a crossover study in 27 patients, C-reactive protein (CRP) and tumor necrosis factor α (TNFα) did not differ between patients who were treated with HDF and low-flux HD (Vaslaki et al. 2005). From another study it appeared that the levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and TNFα were lower during HDF than during HD (Panichi et al. 2006). Since in this study the two arms differed not only in the type of treatment (low-flux HD versus [low-volume] HDF) but also in the bacteriological quality of the dialysis fluid, the exact reason for these differences is not completely clear. Yet, the nature of these findings was confirmed in a large study on 11.258 HDF sessions in 97 CONTRAST patients (Penne et al. 2009a). From this study it appeared that the UP dialysis fluid was compliant with bacteriological and endotoxin reference levels in 99.3% and 98.8% of the samples, respectively. Clinical reactions did not occur. Moreover, from another report from the CONTRAST group in 405 patients, who were followed for 3 years on average, it appeared that both CRP and IL-6 levels were significantly lower in HDF patients as compared to individuals who were treated with low-flux HD (den Hoedt et al. 2014a). Finally, from a recent meta-analysis based on the individual participant data of four recent major randomized controlled trials (RCT), comparing HDF with HD, it appeared that hospital admissions because of infections were not different between HDF and HD patients (Peters et al. 2016).
From these studies it can be concluded first that HDF, when properly performed, does not result in an increased incidence of pyrogenic reactions . Second, these data also show that UP water can be obtained over a prolonged period of time. Third, HDF does not aggravate the micro-inflammatory state which is commonly observed in patients with ESKD. Actually the risk of infection and markers of inflammation seem to be lower in patient on HDF than in patients who were treated with HD.
10.3 Clinical Evidence on Hemodiafiltration
Clinical research on HDF has been focused both on indirect or surrogate parameters, including relevant biomarkers and the functioning of vital organs, and hard endpoints, such as mortality. The assessment of its benefits and disadvantages, however, is complicated since in many of these investigations, different HDF techniques were used (e.g., off-line HDF, pre- and post-dilution online HDF, acetate-free biofiltration, hemofiltration [HF]). Moreover, most comparative studies differed markedly in size, follow-up period, design, and methodology (e.g., observational versus RCT). As nearly all evidence on clinical endpoints is obtained from studies comparing online post-dilution HDF with other dialysis techniques, in the following section we will predominantly, but not exclusively, discuss this type of HDF.
10.3.2 Hemodiafiltration and Survival
10.3.2.1 Observational Studies
Several large observational studies on convective techniques have been published in the last decades. Apart from one Italian study (Locatelli et al. 1999), all investigations showed a reduction in the mortality risk of patients treated with HDF (Canaud et al. 2006a; Jirka et al. 2006; Mercadal et al. 2015; Panichi et al. 2008; Siriopol et al. 2015; Vilar et al. 2009). However, since the decision to treat patients with HDF in observational studies is generally based on clinical grounds and not on selection by chance, residual confounding can never be ruled out, even though extensive corrections are made to minimize selection bias.
10.3.2.2 Randomized Controlled Trials
Recently, three large RCTs, comparing mortality in HDF with HD, have been published. While in CONTRAST and the Turkish HDF study (THDFS) a modest, nonsignificant effect of treatment with HDF on all-cause mortality was shown (hazard rate [HR] 0.95 (95% CI 0.75–1.20) and HR 0.79 (95% CI 0.55–1.14), respectively) (Ok et al. 2013; Grooteman et al. 2012), in the Spanish ESHOL study a markedly reduced mortality risk was observed [HR 0.70 (95% CI 0.53–0.92)] (Maduell et al. 2013). Whereas the achieved convection volume was 20.7 L/session in CONTRAST and 19.6 L/session in THDFS, in ESHOL this figure was 22.9–23.9 L/session. Post hoc analysis of all three studies showed a significantly lower mortality in the group of patients treated with the highest convection volumes, even after extensive adjustments.
In recent years, several meta-analyses on the effects of convective therapies have been published, which, though, produced conflicting results (Mostovaya et al. 2014a; Nistor et al. 2014; Susantitaphong et al. 2013; Wang et al. 2014). At closer look, these meta-analyses differed considerably in the selection of the studies in the convective treatment arm [off-line HDF, online HDF, acetate-free biofiltration (AFB), hemofiltration (HF), and high-flux HD]. Since the magnitude of the convection volume is currently considered a key parameter for the efficacy of HDF, comparison of various low-dose convective techniques among themselves, nowadays, does not seem to be very helpful (see Table 10.3).
Overview of meta-analyses on convective therapies
First author and year of publication
No of RCTsa
No of patientsa
Effect on all-cause mortality
Effect on cardiovascular mortality
HR (95% CI)
HR (95% CI)
HF, HDF, AFB
lfHD, hf HD
HF, HDF, AFB, hfHD
lfHD, hf HD
HF, HDF, AFB
lfHD, hf HD
HF, HDF, AFB
lfHD, hf HD
lfHD, hf HD
To avoid doubtful conclusions from meta-analyses on aggregated patient data from individual studies, which include low-dose convective therapies—such as high-flux HD—as well, the individual participant data (IPD) from CONTRAST, THDFS, ESHOL, and the French HDF study (Morena et al. 2017). French HDF study were combined. After collecting the mortality data for patients who were censored alive in the individual studies—352 out of a total of 355 censored patients were traced—the IPD base encompassed 2793 patients (Peters et al. 2016; Davenport et al. 2015). From this IDP meta-analysis, which includes only RCTs with a mean convection volume around 19 L/session, now it appeared that the risk of all-cause and cardiovascular (CVD) mortality was significantly reduced in the HDF group (HR 0.86 [95% CI 0.75-0.99]),HR 0.77 (95% CI 0.61–0.97) respectively. Post hoc analysis in tertiles of the achieved convection volume (<19, 19–23, >23 L body surface area [BSA] adjusted) suggested a minimum necessary volume of 23 L/1.73 m2 BSA/session, which was recently confirmed in a large observational study (Canaud et al. 2015). In an Editorial to the meta-analysis, it was speculated that effects on the hemodynamic stability during treatment could be the main mechanism of the beneficial effect (Daugirdas 2016).
10.4 How to Achieve High-Volume Hemodiafiltration?
Actually, “convection volume” is the key parameter in HDF prescription, as it determines the magnitude of the convective transport and has been related to the reduced mortality in clinical trials (Peters et al. 2016; Tattersall and Ward 2013). From the IPD meta-analysis of four European RCTs on post-dilution HDF, it appeared that a convection volume >23 L/1.73 m2 BSA/session is necessary to reduce mortality (adjusted HR 0.78 [0.62–0.98]), as compared to patients treated with HD (Peters et al. 2016). Obviously, in this respect dose targeting bias might play a role (Daugirdas 2013): ESKD patient characteristics which have been associated with an improved survival [such as the presence of an AV fistula (Slinin et al. 2010)] may enhance the chance of achieving a high convection volume. Yet, in the three recently published RCTs, comparing HDF with HD, the association between a high convection volume and survival remained after extensive correction for confounders. In clinical practice, a substitution volume of >21 L/session, which corresponds to >23 L of convection when UF volume is included, could be achieved in 81.5% of the sessions in 3315 patients (Marcelli et al. 2015).
10.4.2 Determinants of the Convection Volume in Post-dilution Hemodiafiltration
In CONTRAST, treatment-related factors (including treatment time, blood flow rate, and filtration fraction [FF]) were far more important in determining the convection volume than patient-related factors (such as comorbidity, vascular access, albumin , hematocrit, age, and body size) (Chapdelaine et al. 2014; Penne et al. 2009b). The convection volume is defined by three treatment parameters: treatment time , blood flow rate, and filtration fraction . A sufficient treatment time and high blood flow rate result in a high processed blood volume:
10.4.2.1 Treatment Time
Treatment time is highly practice dependent. Worldwide, treatment times during standard HD differ from 4 h 16 min in the Australia/New Zealand area to 3 h 34 min in the United States (Tentori et al. 2012). Even within countries, treatment time differs widely: in some centers participating in CONTRAST, treatment time was 4 h for all patients, whereas in other centers, It varied between 2.5 and 4 h (Chapdelaine et al. 2014). ‘From a Dutch feasibility study which aimed to optimize the convection volume as much as possible, it appeared that none of the patients was willing to increase their treatment time (de Roij van Zuijdewijn et al. 2016). Hence, to achieve a high convection volume, it seems wise to start immediately with sessions of at least 4 h in incident HDF patients.
10.4.2.2 Blood Flow Rate
Blood flow rate prescription varies markedly as well between countries: from 200 mL/min in Japan, via about 300 mL/min in Europe and Australia/New Zealand, to 400 mL/min in the United States (Asano et al. 2013). Also within countries , large differences exist (Chapdelaine et al. 2014; Ponce et al. 2015). Hence, again, practice patterns seem to play a significant role. As can be seen from Table 10.4, for HV-HDF a blood flow of 350 mL/min (and preferably higher) is necessary. In order to achieve high blood flow rates, a few aspects should be taken into account:
Convection volumes at different treatment times, blood flow rates, and filtration fraction
A high blood flow (350 mL/min or more) can only be achieved with a larger bore needle: 14 or 15 G. With needles of 16 and 17 G, only <20% and <5% of patients, respectively, showed blood flow rates of >350 mL/min (Gauly et al. 2011). When changing to a 1 G larger needle (i.e., needle size 1 G), blood flow rates could be increased by about 20%, which was accompanied by lower venous and arterial pressures (Mehta et al. 2002).
An adequate vascular access is required in order to achieve high blood flow rates in the ECC. Unfortunately, data on the relation between access flow rate, blood flow rate, and convection volume are not available. In some (Marcelli et al. 2015) but not all (Chapdelaine et al. 2014) studies, the presence of an AV fistula in particular was associated with a high convection volume. Data from CONTRAST, however, indicate that the achievement of HV-HDF was independent of the type of vascular access (Chapdelaine et al. 2014). Hence, a central venous catheter is not a contraindication for high-volume HDF.
10.4.2.3 Filtration Fraction
Besides treatment time and blood flow rate, the convection volume is defined by FF as well (Rabindranath et al. 2005). FF is the third treatment-related—and hence modifiable—determinant of the convection volume. In mathematical terms, FF is the ratio between the total UF volume and the plasma flow rate (FFpw = (Q conv/Q pw)*100, where FFpw = plasma water filtration fraction, Q conv = convection flow rate, and Q pw = plasma water flow rate). The plasma water flow rate depends on the blood flow rate (Q b, in mL/min or L/h), hematocrit (Ht), and total protein concentration in the plasma (TP, in g/dL) and can be calculated by the formula: Q pw = Q b*(1−Ht)*(1−0.0107*TP). At the bedside, however, it is much more convenient to consider the blood flow rate instead of the plasma water flow rate, as it is readily apparent from the prescription and the dialysis machine.
During post-dilution HDF, generally a FF of 25–30% can be easily obtained (Marcelli et al. 2015). When targeting a certain FF, several factors have to be taken into account.
Filtration Fraction as a Preset Target Parameter
On most HDF monitors, it is not possible to set FF as a separate target parameter (unlike blood flow rate, UF volume, and treatment time). Therefore, the following surrogate parameters must be prescribed, which, however, differ per machine: substitution ratio [(Q b/Q subs)*100], substitution flow rate, or target substitution volume. Regrettably, however, these parameters are only based on the substitution volume, without taking net UF into account. When net UF increases, the difference between substitution ratio and FF raises, as illustrated in Table 10.5.
The difference between filtration fraction and substitution ratio with different net ultrafiltration rates, at different blood flow rates
Blood flow rate
Net ultrafiltration rate (L/h)
Filtration fraction (%)
Substitution ratio (%)
Filtration Fraction and Blood Flow (Set and Actual)
In clinical practice, the actual or effective blood flow rate may be lower than the set blood flow rate. As FF is calculated from the set blood flow rate, the actual FF may be higher than targeted. In HDF patients with an AV fistula, the difference is generally less than 5% but may amount to 10% in patients with catheters (Canaud et al. 2002) and small needles (Mehta et al. 2002; Kimata et al. 2013).
Filtration Fraction and Hemoconcentration
Finally, when performing post-dilution HDF, blood viscosity may increase considerably when a high FF is applied. Depending on the magnitude of FF and resulting hemoconcentration , both Ht and plasma protein levels rise proportionally. At a FF of 30% and Ht of 0.35, the estimated Ht at the dialyzer outlet is as high as 0.50 (Table 10.6).
Variation of plasma water filtration fraction at given filtration fractions (based on blood flow) and hematocrit at dialyzer inlet
Filtration fraction of blood flow (%)
Hct at dialyzer inlet
Corresponding FFpw (%)
Estimated Hct at dialyzer outlet
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