Technical aspects of hemodiafiltration

INTRODUCTION — Hemodiafiltration (HDF) is a form of kidney replacement therapy (KRT) that utilizes convective in combination with diffusive clearance. Compared with conventional hemodialysis, HDF removes more middle-molecular-weight solutes. Some, but not all, studies have shown improved survival with HDF compared with conventional hemodialysis, provided that adequate convection volumes are achieved.

However, HDF is more complex than conventional hemodialysis and places increased demands on the user and outpatient dialysis center. HDF is available in the United States but not commonly used. In Europe, Japan, and some other countries where HDF is commonly used, most clinicians use a specific type of HDF termed online HDF (ol-HDF). In ol-HDF, the substitution fluid is produced by the dialysis machine, which enables large convection volumes.

This topic will review the technical aspects of HDF. Dosing recommendations and clinical outcomes for HDF are discussed elsewhere. (See "Chronic intermittent high-volume hemodiafiltration".)

PRINCIPLES OF HEMODIAFILTRATION

Solute removal — In conventional hemodialysis, solutes are removed mostly by diffusion, which is the random movement of solute molecules down a concentration gradient. Such movement results from the thermal kinetic energy of the molecules; at the same temperature (and, therefore, energy), larger molecules move more slowly than smaller molecules. As a result, hemodialysis clears smaller solutes more effectively than larger solutes, even if both are small enough to pass through the pores in the dialysis membrane unimpeded. (See "Overview of the hemodialysis apparatus", section on 'Diffusive transport'.)

By contrast, in hemofiltration, solutes are carried through the membrane pores by fluid flow, also known as convection. As long as the solute can easily pass through the membrane pores, the rate of transfer by convection is independent of the molecular size. This enables higher clearances of larger solutes with hemofiltration compared with hemodialysis. (See "Overview of the hemodialysis apparatus", section on 'Convective transport'.)

By combining hemodialysis and hemofiltration, HDF leverages the enhanced larger solute clearance of hemofiltration, while also providing the high clearance of small solutes obtained with hemodialysis. A meta-analysis of 69 studies found that the average clearance of beta2-microglobulin (a middle-molecular-weight solute) was 87 mL/min with convective therapies (hemofiltration or HDF) compared with 49 mL/min with conventional high-flux hemodialysis [1]. Since small solutes, such as urea, are efficiently cleared by diffusion, any increase from convective clearance will be relatively small. (See 'Calculating solute clearance' below.)

Replacement of ultrafiltrate — HDF requires the infusion of significant amounts (at least 20 and up to 100 L) of fluid, called replacement fluid or infusate, into the patient to replace the fluid lost through ultrafiltration. This replacement fluid must be sterile and nonpyrogenic since it is directly infused into the blood. (See 'Online preparation of dialysate and replacement fluid' below.)

The replacement fluid is either provided by the manufacturer terminally-sterilized in bags or generated by filtering the dialysis fluid within the dialysis machine:

●Continuous kidney replacement therapy (CKRT) with HDF, such as is used for treatments in intensive care units, utilizes fluid provided in bags by the manufacturer. When infusate is administered from bags, the rate of infusion is regulated independently from the rate of ultrafiltration. This requires accurate control of the infusion and ultrafiltration rates to avoid fluid balance errors (figure 1). The use of bags effectively limits the convective volume that can be achieved.

●When HDF is used for chronic kidney replacement therapy (KRT), infusate is usually generated by the dialysis machine, which is much less expensive than using bagged fluid. This is referred to as online HDF (ol-HDF). Ol-HDF is less limiting regarding convective volume than bagged fluid, and the infusate can also be used for priming, washback, and, in heparin-free dialysis, for periodic flushing. For ol-HDF, the infusion pump drives both ultrafiltration and replacement infusion and therefore cannot induce fluid balance errors. (See 'Online preparation of dialysate and replacement fluid' below.)

COMPONENTS AND TECHNOLOGY OF ONLINE HDF — Online HDF (ol-HDF) refers to a form of HDF in which all fluids required for treatment, including the dialysate, replacement fluid (or infusate), and priming and washback solutions, are prepared during treatment by the dialysis machine (figure 2). (See 'Replacement of ultrafiltrate' above.)

Online HDF leverages the advances that have already been made to make conventional hemodialysis safer. These advances include improved hardware for managing fluid balance and maintaining a hygienic fluid pathway, as well as improved software to monitor and control all aspects of the machine's function. The software is capable of initiating safety-critical functions, including safety checks and disinfection. The move to near universal implementation of high-flux dialysis during the 2000s and the recognition that microbial contaminants in the dialysis fluid could harm patients on dialysis have motivated improvements in dialysis hardware to deliver ultrapure dialysis fluid. (See "Ultrapure dialysis fluid".)

Compared with conventional high-flux hemodialysis, ol-HDF requires more complex hardware and software. This results in potentially higher costs in purchase and maintenance. However, the additional complexity is relatively small, as modern machines already implement much of this technology for high-flux hemodialysis. The increased cost of ol-HDF may be offset by eliminating the need for purchasing sterile fluids for priming, washback, and bolus infusions. The automated priming and washback process also has the potential to reduce preparation time. (See 'Online preparation of dialysate and replacement fluid' below.)

Machines used for ol-HDF — Machines used for online HDF (ol-HDF) are similar to modern machines used for conventional hemodialysis but have a few distinct differences. Nearly all manufacturers of dialysis machines offer versions that are capable of ol-HDF.

Machines capable of ol-HDF are equipped with the technology to produce and deliver sterile, nonpyrogenic dialysate and replacement fluid (infusate) during the treatment. In order for this to occur, the dialysis machine must have the following additional three components:

●A series of sterilizing ultrafilters to produce sterile replacement fluid from dialysate. (See 'Online preparation of dialysate and replacement fluid' below.)

●A pump for infusing the replacement fluid into the patient. (See 'Modes of infusion of replacement fluid' below.)

●A hygienic port to deliver the sterile fluid into the disposable blood line. The port is sterilized along with the machine's fluid pathways. It is designed to prevent environmental contaminants or blood from entering the machine.

In general, dialyzers used in conventional high-flux hemodialysis can also be used for ol-HDF. High-flux dialyzers with certain design features, such as a larger surface area and fiber diameter and a shorter fiber length, may be favorable for ol-HDF. (See "Chronic intermittent high-volume hemodiafiltration", section on 'Dialyzers'.)

The external appearance of a dialysis machine capable of ol-HDF is almost identical to that of a modern conventional dialysis machine. The machine will have at least two pumps visible at the front. For ol-HDF, the second pump is used for the replacement fluid, whereas for high-flux dialysis, the second pump is used occasionally for single-needle dialysis. The presence of the infusate port on the front surface of an ol-HDF-capable machine may be the only distinguishing feature. The ultrafilters are accessed from the rear of the machine, sometimes inside a closed compartment (picture 1).

Online preparation of dialysate and replacement fluid — In ol-HDF, all fluids required for treatment, including the dialysate, replacement fluid (or infusate), and priming and washback solutions, are prepared during treatment (online) by the dialysis machine using only a supply of purified water, electricity, sodium bicarbonate powder, and a liquid concentrate.

Since this fluid will be directly infused into the patient's blood, the dialysis machine must be capable of producing infusate that is sterile and nonpyrogenic. In ol-HDF, this is achieved by filtering standard dialysis fluid through one or more bacterial and endotoxin-retentive ultrafilters (figure 2 and picture 1). A portion of the ultrafiltered fluid is then drawn through at least one additional ultrafilter to render it sterile for infusion. The remainder of the dialysis fluid flow is delivered to the dialyzer. These ultrafilters are reused between treatments and are disinfected and tested (eg, by pressure holding test or bubble test) automatically by the machine before each use. (See "Ultrapure dialysis fluid".)

The sterile, nonpyrogenic infusate is delivered to a port on the front of the machine. A single-use line (usually part of the blood line set) is connected to this port (figure 2).

Control systems within the dialysis machine monitor the disinfection process and the integrity of the ultrafilters and fluid pathway. The infusate generated by the HDF system can be used for priming, washback, and flushing, which may offset the cost of the filters. (See 'Microbiological safety' below.)

Modes of infusion of replacement fluid — Once the replacement fluid is produced by the machine, it may be delivered into the tubing upstream of the dialyzer (predilution) or downstream of the dialyzer (postdilution). Infusion both upstream and downstream of the dialyzer (mixed-dilution) or into the middle of the dialyzer blood pathway (mid-dilution) is less commonly used (figure 1 and figure 2).

●Postdilution – Postdilution HDF is used in the majority of HDF treatments. Postdilution infusion maximizes clearance for a given volume of infusate.

In postdilution HDF, the high rate of ultrafiltration causes significant increases in the hematocrit and serum protein concentration as blood flows through the dialyzer. This increases viscosity and oncotic pressure in the blood compartment. Protein tends to be deposited on the membrane surface (membrane fouling), reducing the permeability of the membrane to fluid and solutes. These factors limit the rate of ultrafiltration to around 30 percent of blood flow rate.

Membrane fouling causes an increase in transmembrane pressure (TMP), which can be detected by the machine. The machine may automatically regulate the ultrafiltration rate to maximize clearance, avoiding excessive fouling.

The probability of fouling is increased when blood flow is interrupted. For that reason, a reliable vascular access is required for HDF. In intermittent treatments, extracorporeal blood flow rates of at least 350 mL/min in adults and 5 to 8 mL/min/kg body weight or 150 to 240 mL/min/m² body surface area in children are recommended [2]. HDF also requires adequate anticoagulation throughout the procedure and the absence of any condition that increases blood viscosity (such as high hematocrit, cryoglobulinemia, gammopathies). (See "Chronic intermittent high-volume hemodiafiltration", section on 'Anticoagulation'.)

●Predilution – For patients who cannot undergo postdilution HDF, predilution or mixed-dilution HDF combined with feedback control of TMP may be used [3].

In predilution HDF, the infusion dilutes the blood components before ultrafiltration takes place. This reduces the risk of fouling and allows much higher ultrafiltration rates (typically over 60 percent of blood flow rate).

Despite higher ultrafiltration rates, clearance rates are lower with predilution HDF compared with postdilution HDF. This is because solute concentrations in blood and ultrafiltrate are reduced by the upstream infusion, which reduces clearance by both diffusion or convection. Infusion rates have to be much higher in predilution HDF compared with postdilution to achieve the same clearance rate [4,5].

●Mixed-dilution – In mixed-dilution HDF, the replacement fluid is delivered into the tubing both upstream and downstream of the dialyzer. This combines the effects of both predilution and postdilution to optimize the clearance rate. The system may vary the rates of ultrafiltration, upstream, and downstream infusions, depending on the measurements of pressure at various points, to achieve maximum clearance without clotting or excessive pore blockage [6].

●Mid-dilution – In mid-dilution HDF, special dialyzers are used. Replacement fluid enters the blood through an additional port in the dialyzer halfway down the dialyzer blood pathway. This system has been proposed to combined the benefits of both pre- and postdilution [7].

In addition to these methods of delivering infusate, modifications to the fluid pumps have been described that cause variations in dialysis fluid pressure, resulting in alternating filtration and back-filtration of dialysate across the dialyzer membrane [8]. This is called push-pull HDF. In push-pull HDF, the dialysis fluid acts as infusate and is filtered across the dialyzer membrane. Push-pull HDF provides some of the effects of predilution on clearance and coagulation, similar to mixed- or mid-dilution HDF. In addition, the intermittent back-filtration may remove protein deposition on the blood side of the membrane, making this technique suitable for prolonged treatments (eg, continuous treatment for acute kidney injury, nocturnal dialysis). Push-pull HDF is generally not available in standard HDF systems.

Control of fluid balance — Modern dialysis machines implement fluid balancing systems so that the amount of fluid removed from the patient is accurately controlled. The balancing system controls the rate at which fluid is pumped to and from the dialyzer. Any difference in these two rates drives the rate at which fluid filters across the dialyzer membrane.

●In continuous kidney replacement therapy (CKRT), the flow rate of the infusate and dialysis fluid pumps are controlled by the machine to achieve the desired fluid balance. Some systems are gravimetric, with fluid balance informed by the weights of the bags containing fresh and used fluid. Others are volumetric, depending on accurate pumping chambers.

●In conventional hemodialysis, the fluids are not retained within the machine and, therefore, cannot be weighed. Instead, fluid balance is monitored by the rates or volumes pumped.

●In ol-HDF, fluid balance is controlled by the same balancing system as used in conventional hemodialysis. The infusion fluid is pumped from the dialysis fluid between the balancing system and dialyzer (figure 2). This reduces dialysis fluid flow into the dialyzer, reducing pressure in the dialysate compartment and driving additional filtration from the blood in the dialyzer at the exact same rate as is being infused. Thus, the addition of convection in ol-HDF has no effect on fluid balance (figure 3).

Microbiological safety — For CKRT, replacement fluid is supplied in bags and the manufacturer is responsible for its quality as long as it is stored and used under the conditions defined by the manufacturer. For ol-HDF, the situation is much more complex.

The purity of ultrapure dialysis fluid can be monitored by testing for microbial counts and endotoxin. These should be undetectable. However, for the replacement fluid (infusate), there is no routine test that can provide evidence that the fluid is sterile and nonpyrogenic. Even if there were such a test, failures could not be detected rapidly enough to prevent infusion. Instead, ol-HDF depends on systems and operating procedures that reduce the risk of infusing contaminated fluid to an acceptably low level. An acceptable risk would be equivalent to that accepted for intravenous infusions or standard high-flux dialysis.

Standard dialysis fluid contains a significant amount of viable microorganisms (up to 100 colony forming units [CFU]/mL) and bacterial fragments (up to 0.5 endotoxin units [EU]/mL). These contaminants may originate from the treated water and concentrates used to prepare the dialysate, from the external connections on the machine, or may arise from bacterial growth within the fluid pathways. For high-flux hemodialysis, the dialysis fluid pathway is regularly disinfected, and the fluid is passed through one or more ultrafilters to render it ultrapure (<0.1 CFU and <0.03 EU/mL [ie, undetectable by routine tests]). The membrane in a high-flux dialyzer presents a final barrier to inhibit the transfer of any remaining contaminants entering the blood. In ol-HDF, the second stage of ultrafiltration needs to be at least as effective a barrier to the contaminants as the dialyzer membrane. Compared with the dialyzer membrane, the ultrafilter membranes can be thicker and have fewer pores and, therefore, are potentially more effective at blocking and absorbing contaminants. Some systems implement multiple ultrafilters for the infusate.

The fluid pathways inside the dialysis machine are disinfected regularly (at least once for each day of use). The machine monitors the process to ensure that the disinfecting conditions (eg, low pH, high temperature) are maintained for sufficient time. Repeated cycles of use and disinfection will eventually degrade the ultrafilter membranes, so they need to be replaced after a specified number of cycles or period of time (eg, 100 uses or three months). The time or number of uses allowable before replacement will depend upon the chemicals used. The dialysis machine may detect and record disinfections and ultrafilter changes, warning of or disallowing treatment if actions are overdue.

The ultrafilters are included in the pressure holding tests the machine initiates to test for leaks. The machine may also test for integrity of the ultrafilter membranes by opening a valve to allow air to enter on one side of the membrane. Surface tension will render the membrane impermeable unless there are physical defects.

The infusate port, where the external single-use infusate line is connected to the machine, is a point where contamination of the sterile segment can occur (figure 2). It may contain a valve to prevent ingress of contaminants into the internal pathway. The infusate port and associated connector and line required for ol-HDF increase the complexity and potential for contamination and errors compared with conventional dialysis. These risks may be reduced by integrating most of the lines and connectors into a single cassette (figure 4).

The patient's blood does not enter any of the fluid pathways within the machine, and, therefore, disinfection of the machine between treatments is generally not necessary. The procedure to disinfect the external parts of the port between treatments varies by type of HDF machine.  

QUANTIFICATION OF HDF

Assessing adequacy of HDF

●Dialysis adequacy – Dialysis adequacy in HDF can be assessed using the same urea-based measures (eg, Kt/V, urea reduction ratio) and their targets used for conventional high-flux hemodialysis. These are discussed in more detail elsewhere. (See "Prescribing and assessing adequate hemodialysis".)

●Quantifying convection – As discussed above, the addition of convective clearance in HDF increases the clearance of larger solutes. The most important measurement for quantifying the convective component of HDF is the effective convection volume, which is the total volume of fluid ultrafiltered during the treatment, including that removed for weight loss. The effective convection volume is calculated differently for postdilution HDF and for pre-, mid-, and mixed-dilution HDF, as discussed elsewhere. (See "Chronic intermittent high-volume hemodiafiltration", section on 'Effective convection volume'.)

Achieving a certain effective convection volume per HDF session has been shown in some studies to improve clinical outcomes [9]. This issue is discussed in more detail separately. (See "Chronic intermittent high-volume hemodiafiltration", section on 'All-cause and cardiovascular mortality'.)

Calculating solute clearance — The clearance of solutes other than urea is generally not measured and can be difficult to do so. If required for scientific purposes, total solute clearance for a particular solute can be calculated from the diffusive clearance (K_d) and convective clearance (K_c) and multiplying by a dilution factor (DF).

Diffusive clearance is calculated from the effective blood water flow rate (Q_be), the dialysis fluid flow rate (Q_d), and the solute-specific dialyzer mass transfer area coefficient (K_oA). Convective clearance is calculated from the diffusive clearance, the effective blood water flow (Q_be), and the ultrafiltration rate (Q_f), taking the sieving coefficient (S) into account.

The clearance of any solute by HDF therefore depends on the K_oA, Q_be, Q_d, Q_f, and S. Calculations are shown below:

●Dialyzer mass transfer coefficient (K_oA) – The K_oA is specific for solute and dialyzer combination. The K_oA for a range of solutes dissolved in water can be calculated from clearance values quoted in the dialyzer datasheet [10].

The clearance values in the datasheet were obtained by measurements "in vitro" using water as the solvent, not blood. To predict clearance in blood, the K_oA values should, in theory, be adjusted by multiplying by a factor 0.72 to take account of the increased viscosity of plasma compared with water. K_oA is proportional to the diffusion factor (D), which is inversely proportional to viscosity [11]. Limited measurements in vivo support this reduction [12,13].

●Effective blood water flow (Q_be) – For solutes other than urea, the effective blood flow is the plasma water flow [12]. (See 'Urea and nonurea solute kinetics' below.)

Where Q_b is blood flow rate, Q_u is upstream (predilution) infusion rate (if any), Hct is hematocrit, fpw is fraction of plasma water (approximately 0.93). A more accurate approximation for fpw can be calculated from plasma total protein [14].

Where Tprot is plasma total protein concentration in g/L.

To predict urea clearance only, the erythrocyte water is added to the flow rate. The value 0.72 is an approximation of the erythrocyte water fraction:

●Diffusive clearance (K_d) – The K_d of clearance in HDF can be estimated from the Q_be, the Q_d, and the K_oA (figure 5) [10].

The effective blood water and dialysis fluid flow rates at the inlet ports of the dialyzers should be used, taking into account any infusion. In online HDF, the infusion will subtract from the dialysis fluid flow rate generated by the dialysis machine. For predilution HDF, the effective blood water flow rate includes the upstream infusion. For clearance of urea, Q_be is considered to be the blood water flow rate, while, for other solutes, Q_be is considered to be the plasma water flow. (See 'Urea and nonurea solute kinetics' below.)

●Convective clearance (K_c) – Convective clearance is closely approximated, taking the sieving coefficient (S) into account [15]. More accurate estimation methods exist but are more difficult to calculate. The convective clearance is reduced by any diffusive clearance as diffusion reduces the concentration of solute in the ultrafiltrate.

Where Q_f is ultrafiltration rate.

●Total (convective plus diffusive) clearance (Kt) – This is calculated by adding the diffusive and convective components and taking the DF into account.

For urea only, DF is calculated using blood water flow; for all other solutes, plasma water flow is used. (See 'Urea and nonurea solute kinetics' below.)

Urea and nonurea solute kinetics — Urea passes rapidly through cell membranes due to specific urea channels. Solutes other than urea transfer across cell membranes much more slowly, if at all. As an example, transfer across cell membranes is approximately 50 times slower for creatinine than urea [16]. This results in significant differences in the behavior of urea during dialysis compared with other solutes. As examples:

●Urea is cleared from both erythrocytes and plasma water (approximately 85 percent of blood flow) as blood passes through the dialyzer. Solutes other than urea are cleared from plasma water only (50 to 80 percent of blood flow, depending on hematocrit [12]).

●In blood samples, the urea concentration is similar in plasma and erythrocyte water, even in samples taken during or after dialysis. For solutes other than urea, there may be a large difference in concentration in between erythrocyte and plasma in samples taken during or after dialysis. As a result, concentrations in plasma may increase after sampling due to diffusion out of erythrocytes, which necessitates special handling for postdialysis samples. As an example, in order to obtain a valid postdialysis plasma creatinine concentration, samples should be taken into chilled tubes and separated immediately.

●During dialysis, the urea concentration in the intracellular compartment is similar to that in the blood. For solutes other than urea, dialysis may induce a large difference between the concentrations in intracellular and extracellular compartments. After dialysis, urea concentrations rebound upward approximately 10 percent and stabilize within approximately 30 minutes as urea is washed out of areas of low blood flow by the circulation. For solutes other than urea, the rebound is greater and takes longer to complete due to diffusion out of the intracellular compartment after dialysis [17].

IMPLEMENTATION OF HDF

●Clinical application – HDF is commonly used as continuous kidney replacement therapy (CKRT) in intensive care units and has also been used as intermittent treatment for end-stage kidney disease for over 30 years [18]. (See "Continuous kidney replacement therapy in acute kidney injury", section on 'Continuous venovenous hemodiafiltration (CVVHDF)' and "Chronic intermittent high-volume hemodiafiltration".)

In Europe, the use of online HDF (ol-HDF) differs among countries and regions. In 2019, ol-HDF accounted for 26 percent of dialysis treatments, and this proportion is growing [19]. The 2018 National Institute of Health and Care Excellence guidelines from the United Kingdom recommend preferential use of HDF over conventional hemodialysis for patients who are treated with in-center hemodialysis [11]. By contrast, in the United States, there are few dialysis machines available for ol-HDF, and it is rarely used there.

In the United States, continuous HDF using bagged sterile replacement fluid is used in the intensive care setting. However, the use of ol-HDF is not common. As of July 2022, only one HDF device has been approved by the US Food and Drug Administration (FDA).

Clinical trials are in progress in Europe to determine whether ol-HDF offers any additional benefit over conventional hemodialysis [20-22]. (See "Chronic intermittent high-volume hemodiafiltration".)

●Regulatory issues – Equipment for ol-HDF must comply with the International Electrotechnical Commission standards 60601-2-16 [23]. These standards require manufacturers to perform formal risk analysis for their equipment and implement means to reduce risk to acceptable levels. The FDA has adopted these standards.

The International Organization for Standardization (ISO) 23500-2019 E, "Quality of dialysis fluid for hemodialysis and related therapies," recommends that dialysis fluid used for high-flux hemodialysis should be ultrapure (<0.1 colony-forming unit [CFU]/mL, <0.03 endotoxin unit [EU]/mL). The infusate for HDF must be sterile and nonpyrogenic [24]. ISO recognizes that it is not possible to confirm compliance by testing the infusate, since there is no test for absolute sterility. Instead, the standards require that online replacement fluid be prepared using a process validated by the manufacturer of the equipment. (See 'Microbiological safety' above.)

The majority of manufacturers worldwide provide systems licensed for ol-HDF. In the United States, the FDA has published a pathway for licensing ol-HDF systems [5].

As with all medical equipment, the responsibility for the safe operation of HDF is shared between the operator and the manufacturer. The manufacturer is responsible for the correct functioning of the equipment, for validating the process for delivering HDF safely, and for the user instructions. The user is responsible for following the manufacturer's instructions, for maintenance, and for operation.

SUMMARY

●General principles – Hemodiafiltration (HDF) is a form of kidney replacement therapy (KRT) that utilizes convective in combination with diffusive clearance. Compared with conventional hemodialysis, HDF removes more middle-molecular-weight solutes. HDF is commonly used in Europe, Japan, and some other countries but is not commonly used in the United States. (See 'Introduction' above and 'Principles of hemodiafiltration' above.)

●Replacement of ultrafiltrate – HDF requires the infusion of significant amounts (at least 20 and up to 100 L) of fluid, called replacement fluid or infusate, into the patient to replace the fluid lost through ultrafiltration. This replacement fluid must be sterile and nonpyrogenic since it is directly infused into the blood. (See 'Replacement of ultrafiltrate' above.)

●Online HDF – Online HDF (ol-HDF) refers to a form of HDF in which all fluids required for treatment are prepared during treatment by the dialysis machine. (See 'Components and technology of online HDF' above.)

•HDF machines – Machines used for ol-HDF are similar to modern machines used for conventional hemodialysis but have a few distinct differences. They are equipped with the technology to produce and deliver sterile, nonpyrogenic dialysate and replacement fluid (infusate) during the treatment. The dialyzer used in ol-HDF is the same as that used in conventional high-flux hemodialysis. (See 'Machines used for ol-HDF' above.)

•Online preparation of fluid – All fluids required for treatment, including the dialysate, replacement fluid (or infusate), and priming and washback solutions, are prepared during treatment by the dialysis machine using only a supply of purified water, electricity, sodium bicarbonate powder, and a liquid concentrate. Production of sterile, nonpyrogenic ultrapure dialysis fluid is achieved by filtering standard dialysis fluid through one or more bacterial and endotoxin-retentive ultrafilters (figure 2 and picture 1). (See 'Online preparation of dialysate and replacement fluid' above.)

•Modes of infusion – Once the replacement fluid is produced by the HDF machine, it may be delivered into the tubing upstream of the dialyzer (predilution) or downstream of the dialyzer (postdilution). Postdilution is used in the majority of HDF treatments. Risks associated with postdilution infusion include deposition of protein on the membrane surface (fouling). Infusion both upstream and downstream of the dialyzer (mixed-dilution) or into the middle of the dialyzer blood pathway (mid-dilution) is less commonly used (figure 1 and figure 2). (See 'Modes of infusion of replacement fluid' above.)