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. Chronic intermittent high-volume HDF is not widely available in the United States but is commonly used in Europe, Japan, and other countries. Most clinicians use a specific type of HDF termed online HDF, in which the substitution fluid is produced by the dialysis machine.

This topic reviews the technical aspects of HDF. Other aspects of HDF, including patient selection, dosing recommendations, and clinical outcomes, are discussed elsewhere. (See "Prescribing chronic intermittent high-volume hemodiafiltration" and "Outcomes associated with chronic 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 'Assessing 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.

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).

Dialyzers — A membrane with a high hydraulic permeability (ie, a high-flux dialyzer) is required for ol-HDF and certain design features, such as a larger surface area and fiber diameter and a shorter fiber length, are preferred. Many dialyzers used in conventional high-flux hemodialysis can also be used for ol-HDF.

However, specific information on the performance of different dialyzer membranes in postdilution online HDF is scarce. In the multicenter Dutch Convective Transport Study (CONTRAST), dialyzers were used with membrane surface areas between 1.7 and 2.2 m², ultrafiltration coefficients between 56 and 85 mL/hour/mmHg/m², capillary lumen diameters between 185 and 215 microm, and capillary lengths between 225 and 280 mm [2]. Despite these differences in dialyzer characteristics, the convection volume was determined by treatment time and blood flow and not the type of membrane and its surface area.

By contrast, a crossover study that tested four different dialyzers showed that the highest convection volumes and filtration fraction were achieved by the dialyzer membrane with the largest surface area, a high ultrafiltration coefficient, a wide capillary lumen diameter (≥200 micrometer), and a capillary length of 200 mm [3]. Increasing the dialyzer surface area from 1.4 to 1.8 m² in a crossover study resulted in higher convection volumes [4]. Hence, a dialyzer surface area of at least 1.7 to 1.8 m² seems advisable. Further research on this subject is warranted.

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. This ratio is often called the "filtration fraction."

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 [5]. 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 "Prescribing chronic intermittent high-volume hemodiafiltration", section on 'Patient evaluation' and "Prescribing 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 [6].

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 (often twice as high) in predilution HDF compared with postdilution to achieve the same clearance rate [7,8].

●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 [9].

●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 [10].

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 [11]. 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 dialysis fluid can be monitored by testing for microbial counts and endotoxin. The "ultrapure" standard for dialysis fluid is defined as a microbial count of <0.1 colony forming units (CFU)/mL and an endotoxin concentration <0.03 endotoxin units (EU)/mL. The membrane in a dialyzer presents a final barrier to inhibit the transfer of any remaining contaminants entering the blood. By contrast, there is no such mechanical barrier to contamination for the replacement fluid (infusate), and there are no tests that can provide evidence that the infusate is completely sterile and free of endotoxin. 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.

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 dialysis fluid is passed through one or more ultrafilters to render it ultrapure, as defined above. In ol-HDF, the final stage of ultrafilter-mediated infusate purification needs to be at least as effective a barrier to 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.  

ol-HDF systems must be validated to produce sterile and nonpyrogenic replacement solution under specified operating conditions, which include the input fluid quality. Different machine manufacturers might specify a different input fluid quality depending on the design of their system. It is important that the user is aware of the specified input fluid quality for a particular machine and understand that they are responsible for ensuring that specification is met under routine operation.

QUANTIFICATION OF HDF

Assessing adequacy

●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 "Prescribing chronic intermittent high-volume hemodiafiltration", section on 'Calculation of effective convection volume'.)

Achieving a certain effective convection volume per HDF session has been shown in some studies to improve clinical outcomes [12,13]. This issue is discussed in more detail separately. (See "Outcomes associated with chronic hemodiafiltration", section on 'Mortality'.)

Assessing solute clearance — Since the reason for using HDF rather than hemodialysis is to increase the clearance of middle molecules (MMs; molecular weight 500 to 60,000 daltons), it would make sense to quantify HDF in terms of MM clearance, instead of urea clearance. Beta2-microglobulin (beta2-m) is considered as a key MM, and its clearance in vitro is quoted in manufacturer datasheets for dialyzers intended for HDF.

Unfortunately, measurement of in vivo MM clearance (including that of beta2-m) is difficult and is not usually done in clinical practice. Unlike urea, MMs do not easily pass through cell membranes, and there is no significant clearance of MM from erythrocyte water as blood flows through the dialyzer [14]. MM concentrations in plasma water are significantly lower than that of blood water in samples taken at the blood outlet and in the postdialysis blood sample. Because postdialysis rebound for MMs is significantly greater than that of urea [15], MM reduction ratios measured from pre- and post-dialysis blood samples do not adequately reflect clearance from the whole body.

However, measurement of beta2-m concentrations in predialysis blood samples could be a useful and practical marker of total clearance [16]. The predialysis beta2-m concentration is equal to its generation rate divided by its total clearance (ie, clearance by residual renal function + nonrenal clearance + continuous equivalent clearance by dialysis). Higher predialysis beta2-m concentrations are associated with higher mortality [17]. In an individualized dialysis prescription, HDF could be used to reduce predialysis beta2-m to below a maximum target level.

When clearance of an MM is measured in vivo for scientific purposes, the following factors need to be taken into account:

●Erythrocyte water is not cleared of the MM to a significant extent as blood passes through the dialyzer. Thus, clearance can be calculated using plasma water flow rate and the concentrations in plasma water at the inlet and outlet. The sample from the outlet or venous line requires special handling to prevent or account for the rise in concentration in the plasma component as solute diffuses from erythrocytes after drawing. Rapid cooling and separation of the sample has been suggested [14]. Alternatively, the sample from the dialyzer outlet can be left to stand until it has equilibrated, before separation. In that case, clearance can be calculated from whole blood water flow and concentrations in plasma water.

●Clinical laboratories typically report concentrations as mass/volume of whole plasma. Clearance calculations require concentration as mass/volume of plasma water. Sometimes the concentration is actually measured in plasma water, then adjusted by the laboratory to estimate concentration in whole plasma. Knowledge of the methods used to measure and report concentration is required for accurate calculation of clearance in vivo. Where conversion to concentration in water is required, changes in the nonwater plasma components (due to concentration by ultrafiltration) should be taken into account [18].

If predicting in vivo clearance from blood or plasma water flow, dialysate flow, and the mass transfer-area coefficient (KoA) quoted in the dialyzer datasheet calculated from in vitro beta2-m clearance (eg, by the Michaels equations [19]), the following principles should be considered:

●Clearance by diffusion is inversely proportional to the viscosity of the solution [20]. Therefore, the in vitro KoA should be reduced to take account of the higher viscosity of plasma compared with water and the fact that the ultrafiltration in HDF further increases the plasma viscosity.

●Ultrafiltration in vivo causes a layering of protein on the blood side of the membrane, potentially further reducing KoA.

●Any predilution infusion of replacement fluid reduces the concentration in the blood compartment of the dialyzer, thereby proportionally reducing concentration gradients that drive clearance by diffusion. Concentrations in the ultrafiltrate are also proportionally reduced, thereby reducing clearance by ultrafiltration.

●Clearance by diffusion cannot simply be added to clearance by ultrafiltration. This is because each component adversely affects the other. The combination of clearance and ultrafiltration has been studied and modeled in hemodialysis (with its relatively low ultrafiltration rates) [16] and for HDF in vitro [5]. However, these models have not been fully validated in HDF in vivo.

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.)