**4. Site of fluid reinfusion**

Online HDF modalities are classified according to the location at which the replacement fluid is administered in the extracorporeal circuit. The replacement fluid has traditionally been reinfused either before (pre-dilution) or after (post-dilution) the dialyser. Simultaneous preand post-dilution HDF techniques (mixed- and mid-dilution) have gained popularity in recent years. Each has relative advantages and disadvantages (**Table 4**). Other novel hybrid modal‐ ities have been proposed including 'pre-dilution on demand' and 'backflush on demand'.


**Table 4.** Relative advantages and disadvantages of fluid reinfusion site.

#### **4.1. Post-dilution HDF**

inbuilt infusion pump diverts a proportion of ultrapure dialysate through another safety filter prior to being directly infused into the patient's bloodstream as replacement fluid (**Figure 5**).

Beyond the actual production of ultrapure dialysate, frequent disinfection of the water treatment system and dialysis machine, Thermochemical destruction of the biofilm, regular change of filters and maintenance of a permanent circulation of water are essential. Microbio‐

Several clinical studies have confirmed the safety of online HDF provided that appropriate CE marked and certified HDF machines are used and the best clinical practices are applied [21]. The three largest RCTs comparing HDF to HD did not demonstrate any higher incidence of

Online HDF modalities are classified according to the location at which the replacement fluid is administered in the extracorporeal circuit. The replacement fluid has traditionally been

**Figure 5.** Conversion of ultrapure water to ultrapure dialysate.

**4. Site of fluid reinfusion**

34 Advances in Hemodiafiltration

logical and endotoxin monitoring must also be carried out.

infectious complications using online fluid generation [4, 8, 9].

Post-dilution HDF is regarded as the most efficient form of HDF in terms of solute clearance and is the most common format used in contemporary clinical practice. By reinfusing fluid after the dialyser, a continuous concentration gradient is maintained along the entire course of the dialyser (**Figure 6**). This approach has been shown to be superior to both high-flux HD and pre-dilution HDF in terms of small-solute and middle-molecule clearance [11, 22].

The efficiency of solute clearance in this system occurs at the expense of escalating haemo‐ concentration, which increases the risk of filter clotting, membrane pore occlusion and a subsequent increase in TMP. In extreme cases, red cell damage and protein denaturation may occur. There is also an increased risk of albumin loss as a result of the high TMP. The potential for haemoconcentration means that the filtration fraction must be limited which in turn necessitates a high blood flow rate to achieve adequate convection (typically >350 ml/min). Therefore, in patients with poor vascular access, inadequate blood flow may compromise the ability to achieve satisfactory clearances. Similarly, the risk of filter clotting means that patients with high haematocrit, cryoglobulinemia or gammopathy should be preferentially managed with pre-dilution or mixed-dilution HDF.

#### **4.2. Pre-dilution HDF**

In pre-dilution HDF, the substitution fluid is reinfused before the entry of blood into the dialyser (**Figure 6**). This avoids complications relating to haemoconcentration which extends filter life and lowers TMP. Because of the lower risk of clotting, heparin dose can be minimised and heparin-free dialysis for high-risk patients is possible [23]. In Japan, where this technique is used most widely, improvements in shear stress, blood pressure and haematological parameters (especially neutrophil and lymphocyte function) have also been reported [24, 25]. This same group have described improvements in dialysis-related symptom burden including itch, restless legs syndrome and insomnia compared to the post-dilution HDF.

Pre-dilution HDF has obvious deleterious effects on the efficiency of solute clearance. The reduced efficiency of this system means that ultrafiltration rates must be at least twofold higher than those in post-dilution HDF to achieve equivalent solute clearance. In fact, ultrafiltration rates of up to 100% of the blood flow rate are often used.

**Figure 6.** Post-dilution HDF and pre-dilution HDF.

#### **4.3. Mixed-dilution HDF**

In mixed-dilution HDF, fluid is simultaneously reinfused both before and after the dialyser in a ratio that is automatically regulated by the TMP and ultrafiltration feedback (**Figure 7**). An internal feedback mechanism maintains the TMP between 250 and 300 mmHg and ensures a maximum filtration fraction after considering the blood and dialysate flow, internal pressure and hydraulic permeability of the dialyser. Convection volume tends to be 30–40 L/session. TMP is calculated according to the pressure measured at four points in the system: blood entry into the dialyser entry (Pblood in), blood exit from the dialyser (Pblood out), dialysate entry into the dialyser (Pdialysate in) and dialysate exit into the dialyser (Pdialysate out).

**Figure 7.** Representation of the mixed-dilution and mid-dilution HDF.

This same group have described improvements in dialysis-related symptom burden including

Pre-dilution HDF has obvious deleterious effects on the efficiency of solute clearance. The reduced efficiency of this system means that ultrafiltration rates must be at least twofold higher than those in post-dilution HDF to achieve equivalent solute clearance. In fact, ultrafiltration

In mixed-dilution HDF, fluid is simultaneously reinfused both before and after the dialyser in a ratio that is automatically regulated by the TMP and ultrafiltration feedback (**Figure 7**). An internal feedback mechanism maintains the TMP between 250 and 300 mmHg and ensures a maximum filtration fraction after considering the blood and dialysate flow, internal pressure and hydraulic permeability of the dialyser. Convection volume tends to be 30–40 L/session. TMP is calculated according to the pressure measured at four points in the system: blood entry

itch, restless legs syndrome and insomnia compared to the post-dilution HDF.

rates of up to 100% of the blood flow rate are often used.

36 Advances in Hemodiafiltration

**Figure 6.** Post-dilution HDF and pre-dilution HDF.

**4.3. Mixed-dilution HDF**

$$TMP = 0.5 \times \left[ (P\_{blood \, in} + P\_{blood \, out}) - (P\_{dialys\, in} + P\_{d \, display \, out \, out}) \right]^2$$

If the TMP rises beyond its maximum tolerated value, a fraction of infused dialysate is diverted from post- to pre-dilution, which decreases haemoconcentration and lowers the risk of membrane pore occlusion. Similarly, if the TMP falls below the target range, fluid is redirected towards the post-dilution mode to increase system efficiency.

Mixed dilution HDF has been shown to be non-inferior to post-dilution HDF in terms of small and protein-bound solute clearance and superior to post-dilution and pre-dilution HDF in terms of β2−microglobulin clearance (β2−M) [26–29]. Whilst these were relatively small rando‐ mised trials which require larger studies to confirm their findings, mixed-dilution HDF appears to offer an attractive balance between efficiency of solute removal and minimisation of haemoconcentration-related complications. Specifically, it may be suitable for patients in whom target convection volumes are not achieved by post-dilution HDF because of high haematocrit, high plasma protein, or inadequate vascular access and blood flow rate.

#### **4.4. Mid-dilution HDF**

Mid-dilution HDF similarly combines pre- and post-dilution fluid reinfusion into a hybrid system (**Figure 7**). It does so by utilising a specialised haemodiafilter, the Nephros OLpur MD 190. This filter is constructed in such a way that blood enters through the central core fibres of the dialyser and returns in the opposite direction peripherally. This model effec‐ tively comprises two dialysers in series. Substitution fluid is incorporated at the midpoint of the system, which creates an initial post-dilution stage followed by a pre-dilution stage. This enables a high-concentration gradient and encourages movement of small solutes in the first stage and maximal ultrafiltration of plasma water and convective removal of larger mole‐ cules in the second stage. Reinfusion rates up to 10–12 L/h are possible.

Unfortunately, due to the nature of the specialised dialyser, mid-dilution HDF is associated with higher costs. There is also a higher degree of albumin loss, which is not insignificant. Concerns exist regarding generation of a high TMP, which could compromise membrane permeability. A TMP of up to 1000 mmHg has been reported as necessary to achieve the required minimum ultrafiltration of 6 L/h [30]. This high TMP is especially problematic in the first section of the dialyser where the post-dilution phase takes place and is thought to be the result of partial fibre clotting and increased resistance to blood flow due to the reduced capillary diameter in this segment [31]. Given the pro-coagulant effect of rapid convection, adequate anticoagulation is necessary to ensure device patency. Reversal of the configuration of the blood tubing (i.e. connecting the arterial line to the venous port of the dialyser and vice versa) has been successfully trialled in mid-dilution HDF without significant effect on plasma clearances if adequate infusion rates are maintained [32, 33]. Consideration should also be given to the use of larger-surface filters (e.g. Nephros OLpur MD 220) [34].

When compared to post-dilution HDF, mid-dilution HDF is associated with inferior small solute but superior middle-molecule clearance (β2M, myoglobin, prolactin, RTP) and similar clearance of protein-bound solutes [35–37]. With increasing molecular weight, differences in treatment efficiency between mid- and post-dilution HDF rise [36]. Phosphate clearance is similar between the two groups. Whilst few studies have compared mid- and mixed-dilution HDF, one small prospective randomised trial found greater small-solute and middle-molecule clearance with mixed-dilution HDF though differences in dialyser membranes may have confounded their outcomes [30]. Another small prospective crossover study compared 'simple mid-dilution' (using two dialysers in series, rather than the Nephros OLpur MD 190) and mixed-dilution HDF. They similarly found that mixed-dilution HDF provided significantly greater clearances of urea, creatinine and β2M compared To 'simple mid-dilution' HDF with equivalent phosphate clearances [38]. These outcomes require examination in larger trials.

#### **4.5. Novel systems**

Two novel systems, '*pre-dilution on demand*' and '*backflush on demand*', have recently been proposed as potential alternatives to the standard online HDF modalities [39]. These sys‐ tems utilise inbuilt automated software to balance ultrafiltration against haemoconcentra‐ tion. In pre-dilution on-demand mode, escalating TMP is managed by temporarily pausing ultrafiltration and diverting a proportion of filtered dialysate into the dialyser in pre-dilu‐ tion mode as a bolus. This produces sudden haemodilution. In backflush on demand, rising TMP results in an automatic cessation of filtration and an infusion of ultrapure dialysate in‐ to the dialyser. This creates positive pressure in the dialysate compartment, which back‐ flushes the membrane pores and reduces haemoconcentration. These modes are currently experimental but offer a novel and intuitive solution to some of the inherent technical barri‐ ers of the existing HDF modes. Of note, these machines and dialysers would carry addition‐ al expense, which would need to be considered.
