**2. Diffusive versus convective therapy**

Physical removal of solutes across a dialysis membrane occurs via diffusion (passive move‐ ment down a concentration gradient) and/or convection (obligatory "dragging" of solutes by

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fluid removal across the dialysis membrane, i.e. solvent drag) [4]. Some solutes, especially proteins, may also be removed to a limited extent by adsorption to the dialysis membrane.

In conventional low-flux haemodialysis, solute clearance predominantly occurs via diffusion across the dialysis membrane in a counter-current set up whereby blood flows in one direction and the dialysate flows in the other (Figure 1). Solutes move across the semi-permeable dialysis membrane down a concentration gradient. The factors that lead to a higher rate of diffusive exchange are 1) larger concentration gradient; 2) larger membrane pore size; 3) smaller solute molecular size; 4) larger exchange surface area; 5) higher blood flow rate; and, 6) higher dialysate flow rate. Diffusion represents the main mechanism for removal of low molecular weight molecules (<500 Daltons), such as urea (60 Da) and creatinine (113 Da), but is relatively inefficient at removing middle molecules (500 – 60,000 Daltons) [5], such as β2-microglobulin (11,500 Da), and does not appreciably remove large molecules (>60,000 Da), such as albumin (66,500 Da). This limitation can be overcome to a certain extent by the use of high-flux dialysis membranes with a larger pore size. High-flux dialysers permit increased blood water transfer across the membrane at the proximal end of the dialyser, compensated by the phenomenon of backfiltration, in which dialysate flows across the membrane at the distal end of the dialyser under a hydrostatic pressure gradient. Concentration of plasma proteins in the blood com‐ partment will also exert osmotic pull, further contributing to backfiltration [6]. This process results in "internal" convection of up to 5-10L per dialysis treatment, and improves clearance of middle molecules compared to low-flux dialysis. Figure 1. Conventional haemodialysis. A solute, shown dissolved in blood, moves across the semi-permeable dialysis membrane by diffusion, into the dialysate, with blood and dialysate flowing in opposite directions (countercurrent). The rate of diffusion is dependent on the initial concentration in the blood, the blood flow rate, the permeability of the membrane for the solute, and the dialysate flow rate. Removal of water (ultrafiltration) is determined largely but the pressure across the membrane.

**Figure 1.** Conventional haemodialysis. A solute, shown dissolved in blood, moves across the semi-permeable dialysis membrane by diffusion, into the dialysate, with blood and dialysate flowing in opposite directions (countercurrent). The rate of diffusion is dependent on the initial concentration in the blood, the blood flow rate, the permeability of the membrane for the solute, and the dialysate flow rate. Removal of water (ultrafiltration) is determined largely but the pressure across the membrane.

In contrast to haemodialysis, haemofiltration clears solutes primarily via convection, allowing water and solutes up to 20 kDa to cross the membrane and achieving more efficient removal of middle and large molecular weight solutes (Figure 2). The factors that lead to a higher rate of convective removal of solute are 1) volume of ultrafiltration, 2) a higher sieving coefficient (solute concentration in the ultrafiltrate divided by plasma concentration) and 3) a higher transmembrane pressure (which leads to a higher ultrafiltration rate) [7]. Given that haemo‐ filtration is dependent upon large volume ultrafiltration, replacement fluid needs to be infused back into the patient to prevent excessive fluid removal. However, although haemofiltration provides efficient clearance of middle and large molecular weight molecules, it is less efficient at removing small molecular weight solutes than conventional haemodialysis. Figure 2. Haemofiltration (convection). Movement of water across the more water-permeable membrane 'drags' solute across, and leads to production of a filtrate which contains the solute. Solute removal is largely dependent on the ultrafiltration rate, but is limited by haemoconcentration and so 'pure' haemofiltration is not practical without replacement of fluid.

fluid removal across the dialysis membrane, i.e. solvent drag) [4]. Some solutes, especially proteins, may also be removed to a limited extent by adsorption to the dialysis membrane.

In conventional low-flux haemodialysis, solute clearance predominantly occurs via diffusion across the dialysis membrane in a counter-current set up whereby blood flows in one direction and the dialysate flows in the other (Figure 1). Solutes move across the semi-permeable dialysis membrane down a concentration gradient. The factors that lead to a higher rate of diffusive exchange are 1) larger concentration gradient; 2) larger membrane pore size; 3) smaller solute molecular size; 4) larger exchange surface area; 5) higher blood flow rate; and, 6) higher dialysate flow rate. Diffusion represents the main mechanism for removal of low molecular weight molecules (<500 Daltons), such as urea (60 Da) and creatinine (113 Da), but is relatively inefficient at removing middle molecules (500 – 60,000 Daltons) [5], such as β2-microglobulin (11,500 Da), and does not appreciably remove large molecules (>60,000 Da), such as albumin (66,500 Da). This limitation can be overcome to a certain extent by the use of high-flux dialysis membranes with a larger pore size. High-flux dialysers permit increased blood water transfer across the membrane at the proximal end of the dialyser, compensated by the phenomenon of backfiltration, in which dialysate flows across the membrane at the distal end of the dialyser under a hydrostatic pressure gradient. Concentration of plasma proteins in the blood com‐ partment will also exert osmotic pull, further contributing to backfiltration [6]. This process results in "internal" convection of up to 5-10L per dialysis treatment, and improves clearance

blood

semi‐permeable dialysis membrane

**Figure 1.** Conventional haemodialysis. A solute, shown dissolved in blood, moves across the semi-permeable dialysis membrane by diffusion, into the dialysate, with blood and dialysate flowing in opposite directions (countercurrent). The rate of diffusion is dependent on the initial concentration in the blood, the blood flow rate, the permeability of the membrane for the solute, and the dialysate flow rate. Removal of water (ultrafiltration) is determined largely but the

solute

Removal of water (ultrafiltration) is determined largely but the pressure across the membrane.

A solute, shown dissolved in blood, moves across the semi-permeable dialysis membrane by diffusion, into the dialysate, with blood and dialysate flowing in opposite directions (countercurrent). The rate of diffusion is dependent on the initial concentration in the blood, the blood flow rate, the permeability of the membrane for the solute, and the dialysate flow

dialysate

pressure across the membrane.

of middle molecules compared to low-flux dialysis.

200 Updates in Hemodialysis

Figure 1.

rate.

Conventional haemodialysis.

**Figure 2.** Haemofiltration (convection). Movement of water across the more water-permeable membrane 'drags' solute across, and leads to production of a filtrate which contains the solute. Solute removal is largely dependent on the ultra‐ filtration rate, but is limited by haemoconcentration and so 'pure' haemofiltration is not practical without replacement of fluid.

The distinct and separate advantages of haemofiltration (efficient middle and large molecule clearance) and haemodialysis (efficient small solute clearance) are combined by the technique of HDF, which provides both diffusive and convective clearances (Figure 3). This theoretically offers better overall clearance of small, middle and large molecular weight substances. HDF can produce convective volumes of greater than 20L per session, and this can be achieved by several different means:


**3.** Online HDF: A form of HDF whereby substitution fluid is produced by the dialysis machine, creating ultrapure dialysate that is sterile, non-pyrogenic, continuous and unlimited while the machine is in operation [4]. Figure 3.

As discussed later in the chapter, convective volume, and therefore enhanced removal of larger uraemic toxins, has emerged as an important parameter in outcomes relating to convective therapies. Convective dose is defined as the total ultrafiltered volume, which equates to the sum of volume gained/lost and substitution fluid given [7]. Convective dose has been proposed as the key quantifier of online-HDF by the European Dialysis (EUDIAL) group [8]. Haemodiafiltration (HDF). HDF combines dialysis and filtration across a semi-permeable membrane but uses much larger volumes of dialysate. Extra ultrapure water can be added either pre-dilution or post-dilution to replace the filtrate. Small solutes are removed largely by diffusion whereas larger solutes (middle molecules) are removed by convection. Water removal (ultrafiltration) is regulated by varying the volume of replacement fluid.

**Figure 3.** Haemodiafiltration (HDF). HDF combines dialysis and filtration across a semi-permeable membrane but uses much larger volumes of dialysate. Extra ultrapure water can be added either pre-dilution or post-dilution to replace the filtrate. Small solutes are removed largely by diffusion whereas larger solutes (middle molecules) are removed by convection. Water removal (ultrafiltration) is regulated by varying the volume of replacement fluid.

### **3. Important considerations for haemodiafiltration**

#### **3.1. Membrane**

Haemodialysis and haemodiafiltration utilise filter membranes composed of cellulose, substituted cellulose or synthetic material. The ideal membrane will provide both solute removal capability as well as biocompatibility [9]. Contact of blood with dialysis membranes elicits inflammatory response, including activation of complement system, polymorphonu‐ clear cells and mononuclear cells [10]. A biocompatible membrane is one that elicits the least amount of inflammatory response in patients exposed to it [11]. Membranes can be described in terms of their efficiency (rate of removal of small solutes) and flux (rate of removal of middle molecules).

High-flux membranes can remove molecules as large as 20kDa, which is better than a tradi‐ tional low-flux membrane, but still inferior to glomeruli, which can clear molecules up to 65kDa [12]. 'Super high-flux' or 'high cut-off' membranes have been developed to remove larger molecules of up to 50-60kDa, in an attempt to remove larger uraemic toxins and inflammatory mediators [12, 13]. Early data using these membranes have indicated enhanced clearance of free light chains and myoglobin, in patients with myeloma and rhabdomyolysis respectively, although larger clinical trials are required to demonstrate their impact on important clinical outcomes. Loss of important serum proteins such as albumin is significant, and represents a potential disadvantage of using 'high cut-off' membranes, because of the risk of protein malnutrition [12].

### **3.2. Ultrapure dialysate**

**3.** Online HDF: A form of HDF whereby substitution fluid is produced by the dialysis machine, creating ultrapure dialysate that is sterile, non-pyrogenic, continuous and

As discussed later in the chapter, convective volume, and therefore enhanced removal of larger uraemic toxins, has emerged as an important parameter in outcomes relating to convective therapies. Convective dose is defined as the total ultrafiltered volume, which equates to the sum of volume gained/lost and substitution fluid given [7]. Convective dose has been proposed

largely by diffusion whereas larger solutes (middle molecules) are removed by convection. Water removal (ultrafiltration) is regulated by varying the volume of replacement fluid.

> larger molecule solute net water movement small molecule solute

pre‐dilution fluid

post‐dilution fluid

HDF combines dialysis and filtration across a semi-permeable membrane but uses much larger volumes of dialysate. Extra ultrapure water can be added either pre-dilution or post-dilution to replace the filtrate. Small solutes are removed

as the key quantifier of online-HDF by the European Dialysis (EUDIAL) group [8].

blood

**Figure 3.** Haemodiafiltration (HDF). HDF combines dialysis and filtration across a semi-permeable membrane but uses much larger volumes of dialysate. Extra ultrapure water can be added either pre-dilution or post-dilution to replace the filtrate. Small solutes are removed largely by diffusion whereas larger solutes (middle molecules) are removed by

Haemodialysis and haemodiafiltration utilise filter membranes composed of cellulose, substituted cellulose or synthetic material. The ideal membrane will provide both solute removal capability as well as biocompatibility [9]. Contact of blood with dialysis membranes elicits inflammatory response, including activation of complement system, polymorphonu‐ clear cells and mononuclear cells [10]. A biocompatible membrane is one that elicits the least amount of inflammatory response in patients exposed to it [11]. Membranes can be described in terms of their efficiency (rate of removal of small solutes) and flux (rate of removal of middle

High-flux membranes can remove molecules as large as 20kDa, which is better than a tradi‐ tional low-flux membrane, but still inferior to glomeruli, which can clear molecules up to

unlimited while the machine is in operation [4].

Figure 3.

Haemodiafiltration (HDF).

 dialysate plus filtrate

dialysate

**3. Important considerations for haemodiafiltration**

**3.1. Membrane**

202 Updates in Hemodialysis

molecules).

convection. Water removal (ultrafiltration) is regulated by varying the volume of replacement fluid.

Convective therapies result in infusion of substantial quantities of dialysate and substitution fluid, and a major challenge in HDF is the generation of ultrapure dialysate that is sterile and non-pyrogenic. This is because dialysate contaminants can enter the blood via convection or by direct infusion as substitution fluid [14]. The European Best Practice Guidelines (ERPG), American National Standards Institute / Association for Advancement of Medical Instrumen‐ tation (ANSI/AAMI) and International Organization for Standardisation (ISO) all mandate that ultrapure fluid contains no more bacteria than 0.1 colony forming units (CFU)/mL, and endotoxins no more than 0.03 endotoxin unit (EU)/mL [14]. Previous studies indicate that ultrapure dialysate improves inflammation-related parameters such as C-reactive protein [14], albumin and haemoglobin [14-17], although endpoints such as mortality and cardiovascular events have not been adequately demonstrated in high quality trials to date.

#### **3.3. Site of fluid replacement**

In HDF, ultrafiltration for convective solute clearance necessitates that replacement fluid is administered to maintain appropriate fluid balance. The site at which the replacement fluid is infused has an important impact on several dialysis variables.

In post-dilution mode, replacement fluid is added to the venous side of the circuit, distal to the filter. The convective clearance is the same as the volume of filtrate. This is the most efficient form of HDF, with respect to solute clearance, however this modality is complicated by the effects of haemoconcentration. At high ultrafiltration rates the haematocrit rises within the dialyser, increasing the risk of the filter clotting as well as membrane pore occlusion caused by adherence of plasma proteins [8]. Haemoconcentration is proportional to the filtration fraction, typically defined as the ratio of ultrafiltration rate to blood flow rate, which is usually limited to <25% in post-dilution HDF, and necessitates a high blood flow rate [6].

In pre-dilution mode, replacement fluid is given to the arterial side of the circuit, diluting blood before it is filtered. This mitigates the effect of ultrafiltration on haemoconcentration, but at the cost of reducing the efficiency of both diffusive and convective solute clearance. As a result, to achieve equivalent clearances, the ultrafiltration rate is typically set two-fold higher when performing pre-dilution HDF compared to post-dilution HDF. While many centres use postdilution HDF, dialysis centres in Japan have more experience employing pre-dilution HDF [18, 19]. From their experience, pre-dilution has comparable effects on removal of uraemic toxins, reduces shear stress and results in stable blood pressures during treatment [18].

Recently, mid-dilution HDF has been made possible with the development of specialised dialysis circuits that permit infusion of replacement fluid between an initial post-dilution and subsequent pre-dilution stage. The advantage of this design is the ability to allow higher reinfusion rates, and early studies show better clearance of urea, β2-microglobulin and phosphate compared with high-flux HD [20, 21].

Finally, mixed dilution combining pre-and post-dilution has been developed with the aim of providing the most safe and efficient clearance of solutes. A small study of ten patients suggested that mixed dilution may provide superior clearances compared to mid-dilution, citing high transmembrane pressures in the mid-dilution dialyser potentially compromising membrane permeability and therefore infusion rate [22]. While different modes of fluid replacement in HDF have demonstrated advantages and disadvantages in small pilot studies, more data from larger studies are required to convincingly demonstrate the relative efficacy and safety of each method. For now, regional availability and experience tend to dictate the method utilised.

#### **3.4. Cost effectiveness**

One important consideration when deciding whether to adopt HDF is that of cost and costeffectiveness. One French centre estimated that for each session, additional consumables (- €2.55 to+€3.35), microbiological analysis (€1.10) and water consumption (€0.15 to €0.23, based on 50.8 to 74.8 L), resulted in a cost of €-1.29 to €+4.58 per session for HDF over conventional HD [23]. Another cost analysis conducted in the United Kingdom over a 12 month period comparing HDF and high-flux HD found variable consumables costs (-£0.78 to+£1.16, de‐ pending on type of line used), similar erythropoiesis stimulating usage and less phosphate binder use (£3.8 and £5.0 weekly) in the HDF group [24].

A cost analysis of HDF versus haemodialysis was performed based on data from the CON‐ TRAST study (mentioned later in the chapter) comparing low-flux HD and HDF. It was found that the annual costs for HDF and HD were €88,722 ± 19,272 and €86,086 ± 15,945, respectively, in 2009 in Europe [25]. However, when cost-utility analysis was applied to assess difference in quality of life, the incremental cost per quality-adjusted year (QALY) of HDF over HD was €287,769. Based on this analysis, the authors concluded that HDF was not cost effective, as concurred by McBrien, et al [26].

#### **3.5. Potential role in home haemodialysis**

To date, little data has been published regarding HDF utlisation in the home setting. This is not surprising, given that it is yet to be established as the predominant method of haemodial‐ ysis. If applied in the home setting, an extra filter used to produce ultrapure dialysate may provide benefits relating to inflammatory parameters, as mentioned above.
