**2.2 Double high-flux HDF**

Solute removal during extracorporeal hemodialysis, particularly for low-flux HD, is mainly facilitated by diffusion which is driven by the concentration gradient across membrane. Thus, solute clearances are highly dependent on their molecular weights. On the other hand, hemofiltration (HF) is purely convective. Thus, it could be speculated that HF delivers higher middle- to large-size solutes clearances than HD, but poorer small-size mass transfer. The additional advantages of this convective treatment include better maintenance of cardiovascular instability in ESRD patients or in ICUs. These benefits of hemofiltration encouraged investigations aimed at compensating for the inferior diffusive clearances of HF, and a hybrid configuration based on multiple membranes was introduced (Cheung et al., 1982).

Double high-flux HDF was first introduced in the early 1980's as a means of combining HD and HF. This technique was particularly aimed at significantly increasing small (diffusion) and middle-size molecular removal (convection) in order to shorten overall treatment time, and therefore, much larger surface areas were used by arranging two high-flux hemodialyzers in series, in conjunction with a extremely high blood (400-500 ml/min) and dialysate flow rate (800-1000 ml/min) and a bicarbonate dialysate (Miller et al., 1984, von Albertini et al., 1984).

This arrangement of two hemodialyzers enabled flow resistances through the two hemodialyzers to be manipulated, which permitted TMP gradients (both positive and negative) to be adjusted. A flow restrictor, placed on the intermediate blood line of two hemodialyzers, serves as a means of increasing blood pressures in the arterial-side hemodialyzer, which cause positive TMPs through this dialyzer and ultrafiltration (Fig. 2). On the other hand, blood pressure drops below dialysate pressures at the venous-side dialyzer and TMPs become negative, which leads to backfiltration (Shinzato et al., 1982).

ml/min by Doppler ultrasonography, but only 11.1 ml/min for a standard 195 mm dialyzer (Sato et al., 2003). Doppler ultrasonography is straightforward, non-invasive, and easily used at bedside (Mineshima, 2011). However, the method is still incapable of measuring blood flow velocity precisely, particularly blood velocity deep within the membrane fiber bundle. In other words, this method is based on velocities measured in peripheral membranes, which are quite different from velocities within centrally located fibers, and as

Other techniques have also been explored in an effort to quantify the filtration phenomena, or to visualize flow distributions inside hemodialyzers, these techniques include magnetic resonance imaging (Hardy et al., 2002), computed tomography (Frank et al., 2000, J. C. Kim et al., 2008) and a computerized scanning technique (Ronco et al., 2000, 2002). However, the quantification of internal filtration using these techniques is not available clinically, due to

Summarizing, internal HDF can provide a means of convective treatment by increasing internal filtration rates using specifically designed hemodialyzers, and at the same time spontaneous backfiltration compensates for fluid loss, and hence, this technique is simpler than other modalities. The hemodialyzer design for internal HDF must be optimized based on specified structural factors and on the filtration characteristics of membrane fibers. The literature suggests superior dialysis outcomes for iHDF, but the precise quantification of

Solute removal during extracorporeal hemodialysis, particularly for low-flux HD, is mainly facilitated by diffusion which is driven by the concentration gradient across membrane. Thus, solute clearances are highly dependent on their molecular weights. On the other hand, hemofiltration (HF) is purely convective. Thus, it could be speculated that HF delivers higher middle- to large-size solutes clearances than HD, but poorer small-size mass transfer. The additional advantages of this convective treatment include better maintenance of cardiovascular instability in ESRD patients or in ICUs. These benefits of hemofiltration encouraged investigations aimed at compensating for the inferior diffusive clearances of HF, and a hybrid configuration based on multiple membranes was introduced (Cheung et al.,

Double high-flux HDF was first introduced in the early 1980's as a means of combining HD and HF. This technique was particularly aimed at significantly increasing small (diffusion) and middle-size molecular removal (convection) in order to shorten overall treatment time, and therefore, much larger surface areas were used by arranging two high-flux hemodialyzers in series, in conjunction with a extremely high blood (400-500 ml/min) and dialysate flow rate (800-1000 ml/min) and a bicarbonate dialysate (Miller et al., 1984, von

This arrangement of two hemodialyzers enabled flow resistances through the two hemodialyzers to be manipulated, which permitted TMP gradients (both positive and negative) to be adjusted. A flow restrictor, placed on the intermediate blood line of two hemodialyzers, serves as a means of increasing blood pressures in the arterial-side hemodialyzer, which cause positive TMPs through this dialyzer and ultrafiltration (Fig. 2). On the other hand, blood pressure drops below dialysate pressures at the venous-side dialyzer and TMPs become negative, which leads to backfiltration (Shinzato et al., 1982).

a result, deviations from true values are unavoidable.

concerns of patient safety and technical requirements.

internal filtration remains to be determined.

**2.2 Double high-flux HDF** 

1982).

Albertini et al., 1984).

Fig. 2. Schematic Pressure Profiles during Double HDF, when a flow restrictor is placed on blood tube (upper) and on dialysate tube (below) of the two hemodialyzers.

TMP regulation is also achieved by regulating dialysate pressure. Flow resistance applied to the dialysate tubing between the two dialyzers promptly increases dialysate pressures at the venous dialyzer because blood and dialysate flow in opposing directions. Hydraulic dialysate pressures exceed blood pressures, which leads to backfiltration in the venous dialyzer. However, dialysate pressures rapidly fall in the arterial dialyzer due to flow restriction, which causes ultrafiltration in the arterial dialyzer. In addition, the high blood and dialysate flow rates used are also associated with larger pressure gradients. Hence, ultrafiltration at the arterial dialyzer at levels of exceeding those required can be promptly compensated for by backfiltration at the venous dialyzer, and thus, exogenous replacement infusion is not required for this method.

The flow resistance placed on the dialysate stream was originally made from a gauge needle assembled with a bypass line in parallel. A clamp on the bypass line forced the dialysate into the gauge needle, and created flow resistance in dialysate stream. The flow resistance in this configuration is fixed, and the amounts of ultrafiltration and backfiltration cannot be adjustable externally. Hence, the means of creating resistance to dialysate flow was improved in the advanced version, termed convection-controlled double high-flux HDF, in which variable and controllable flow resistances were integrated (Pisitkun et al., 2004).

Therefore, together with these features, this modality achieved unmatched depurative outcomes, as demonstrated by far higher uremic molecular clearances regardless of molecular size (Cheung et al., 1982, Shinzato et al., 1982, von Albertini et al., 1985). Furthermore, increased clearances allowed treatment times to be shortened (Miller et al.,

Pulse Push/Pull Hemodialysis: Convective Renal Replacement Therapy 121

promptly decreases along the dialyzer length due to diffusion, and in this situation, solute concentrations in ultrafiltrate are reduced. Likewise, diffusive mass transfer is also disrupted by the presence of convection. High filtration rates throughout the entire membrane causes the formation of protein gel layer, which acts as secondary resistance; that is, the membrane fouling decreases membrane permeability and filtration rates, and consequently, convective clearances are substantially diminished. Furthermore, molecular sieving coefficients are also reduced because of protein binding, which eventually reduces membrane diffusivity (Morti & Zydney, 1998). In the PFD technique, however, convection occurs in a separate region from diffusion and theoretically, no interference between

In addition, independent convection allows ultrafiltrate volume to be regulated. The total amount of ultrafiltration surpasses desired volume removal, and sterile replacement fluid is administered at the mid-point between the hemofilter and hemodialyzer shown in the Fig. 3. In addition, desired net-volume removal by PFD can be achieved either by balancing ultrafiltration and reinfusion through the hemofilter, or by balancing internal filtration in

Likewise, as for other convective treatments, simultaneous but separate convection of PFD permitted higher depurative outcomes than standard HD mode, and even allowed treatment times to be reduced (Vanholder et al., 1991). Dialysis times could be reduced to as little as 150 minutes per session in patients with a body weight of < 61 kg without compromising dialytic tolerance and efficiency (Botella et al., 1991). PFD also achieves dialytic efficiencies comparable with HDF despite significantly lower filtration rates (40 versus 75 ml/min, respectively) (Bufano et al., 1991), which is primarily due to minimal interference between diffusion and convection. However, β2M removal is smaller than in HF mode (Marangoni et al., 1992). Other benefits of PFD may include the minimal use of backfiltration in the hemodialyzer and superior biocompatibility (Panichi et al., 1998). Since convection is achieved at the hemofilter, dialysis can be accomplished with minimal internal

Fig. 3. PFD (left) and HFR (right)

diffusion and convection occurs.

filtration and pressure gradients.

the hemodialyzer.

1984, von Albertini et al., 1984). Solute removal in a relatively short time (e.g., 2 hours) may cause greater rebound of uremic solute levels after post-dialysis equilibrium, thus solute removal rates in trials of double HDF far surpassed the removal rates desired during hemodialysis, achieving two and half times higher clearances over 2 hours as was achieved over 4 hours in conventional HD mode. These results were also confirmed by comparing treatment modalities. Double high-flux HDF attained significantly greater β2M reduction and Kt/VUREA values than high-flux HD, and showed comparable β2M clearance to that of on-line HDF (Susantitaphong et al., 2010, Tiranathanagul et al., 2007). Furthermore, the beneficial effect of this technique on patient survival was also suggested in a long-term assessment. In this study, double high-flux HDF was compared with high-efficiency or highflux HD modes in terms of treatment time, Kt/V and standardized mortality ratio over 6 years. Kaplan-Meier Survival analysis revealed a significantly lower mortality ratio for double HDF versus USRDS (0.41 and 1, respectively) despite the shortened treatment time (Bosch et al., 2006).

However, concerns have been raised regarding the use of two hemodialyzers in this double HDF technique, such as, possible increases in treatment cost and system complexity. One possible way of overcoming these issues involves the reuse of dialyzers, although regulatory guidelines on renal replacement practices in some countries do not permit reuse. Another concern arises from the large amount of cross-membrane flux. In particular, a large quantity of backfiltration should be assured by the strict and regular verification of water quality (Bosch & Mishkin, 1998. One positive aspect is that the venous dialyzer acts as a final barrier to pyrogen transfer.

Double high-flux HDF emerged as a result of an effort to increase treatment efficiencies and shorten treatment times by maximizing both diffusive and convective mass transfer. Many observations have confirmed the high solutes clearances across a wide spectrum of molecular weights, which are the results of the unique features of this method. In particular, the unique control of hydraulic pressures possibly gives this unit the ability to regulate convective dose. However, the widespread implementation of this technique may require the identification of patients capable of tolerating treatment and the overcoming of the above-mentioned underlying concerns.

### **2.3 Paired filtration dialysis with endogenous reinfusion (HFR)**

Another two-chamber technique for obtaining short and efficient HDF treatment is the socalled paired filtration dialysis (PFD). Like double HDF, PFD is also a strategy of simultaneous HD and HF treatment aimed at increasing both diffusive and convective clearances, but its design principles separate convection from diffusion (Ghezzi et al., 1989, 1987, Ronco et al., 1990). A hemofilter with a relatively small surface area is combined with a hemodialyzer in this sequence (Fig. 3). Ultrafiltration purely occurs at the hemofilter and then blood is dialyzed continually through the hemodialyzer.

The convection, which is not connected with diffusion, can minimize interactions between diffusion and convection (Ghezzi et al., 1987). Total resulting clearances during HDF are always lower than the sum of convective and diffusive clearances, which is attributed to the reciprocal interactions of these two processes (Gupta & Jaffrin, 1984, Sprenger et al., 1985). As diffusion and convection occur within the same membranes, the contribution made by convection to total clearances is diminished by the presence of diffusion, particularly for highly diffusive molecules. This is because the concentrations of these molecules

```
Fig. 3. PFD (left) and HFR (right)
```
1984, von Albertini et al., 1984). Solute removal in a relatively short time (e.g., 2 hours) may cause greater rebound of uremic solute levels after post-dialysis equilibrium, thus solute removal rates in trials of double HDF far surpassed the removal rates desired during hemodialysis, achieving two and half times higher clearances over 2 hours as was achieved over 4 hours in conventional HD mode. These results were also confirmed by comparing treatment modalities. Double high-flux HDF attained significantly greater β2M reduction and Kt/VUREA values than high-flux HD, and showed comparable β2M clearance to that of on-line HDF (Susantitaphong et al., 2010, Tiranathanagul et al., 2007). Furthermore, the beneficial effect of this technique on patient survival was also suggested in a long-term assessment. In this study, double high-flux HDF was compared with high-efficiency or highflux HD modes in terms of treatment time, Kt/V and standardized mortality ratio over 6 years. Kaplan-Meier Survival analysis revealed a significantly lower mortality ratio for double HDF versus USRDS (0.41 and 1, respectively) despite the shortened treatment time

However, concerns have been raised regarding the use of two hemodialyzers in this double HDF technique, such as, possible increases in treatment cost and system complexity. One possible way of overcoming these issues involves the reuse of dialyzers, although regulatory guidelines on renal replacement practices in some countries do not permit reuse. Another concern arises from the large amount of cross-membrane flux. In particular, a large quantity of backfiltration should be assured by the strict and regular verification of water quality (Bosch & Mishkin, 1998. One positive aspect is that the venous dialyzer acts as a final barrier

Double high-flux HDF emerged as a result of an effort to increase treatment efficiencies and shorten treatment times by maximizing both diffusive and convective mass transfer. Many observations have confirmed the high solutes clearances across a wide spectrum of molecular weights, which are the results of the unique features of this method. In particular, the unique control of hydraulic pressures possibly gives this unit the ability to regulate convective dose. However, the widespread implementation of this technique may require the identification of patients capable of tolerating treatment and the overcoming of the

Another two-chamber technique for obtaining short and efficient HDF treatment is the socalled paired filtration dialysis (PFD). Like double HDF, PFD is also a strategy of simultaneous HD and HF treatment aimed at increasing both diffusive and convective clearances, but its design principles separate convection from diffusion (Ghezzi et al., 1989, 1987, Ronco et al., 1990). A hemofilter with a relatively small surface area is combined with a hemodialyzer in this sequence (Fig. 3). Ultrafiltration purely occurs at the hemofilter and

The convection, which is not connected with diffusion, can minimize interactions between diffusion and convection (Ghezzi et al., 1987). Total resulting clearances during HDF are always lower than the sum of convective and diffusive clearances, which is attributed to the reciprocal interactions of these two processes (Gupta & Jaffrin, 1984, Sprenger et al., 1985). As diffusion and convection occur within the same membranes, the contribution made by convection to total clearances is diminished by the presence of diffusion, particularly for highly diffusive molecules. This is because the concentrations of these molecules

(Bosch et al., 2006).

to pyrogen transfer.

above-mentioned underlying concerns.

**2.3 Paired filtration dialysis with endogenous reinfusion (HFR)** 

then blood is dialyzed continually through the hemodialyzer.

promptly decreases along the dialyzer length due to diffusion, and in this situation, solute concentrations in ultrafiltrate are reduced. Likewise, diffusive mass transfer is also disrupted by the presence of convection. High filtration rates throughout the entire membrane causes the formation of protein gel layer, which acts as secondary resistance; that is, the membrane fouling decreases membrane permeability and filtration rates, and consequently, convective clearances are substantially diminished. Furthermore, molecular sieving coefficients are also reduced because of protein binding, which eventually reduces membrane diffusivity (Morti & Zydney, 1998). In the PFD technique, however, convection occurs in a separate region from diffusion and theoretically, no interference between diffusion and convection occurs.

In addition, independent convection allows ultrafiltrate volume to be regulated. The total amount of ultrafiltration surpasses desired volume removal, and sterile replacement fluid is administered at the mid-point between the hemofilter and hemodialyzer shown in the Fig. 3. In addition, desired net-volume removal by PFD can be achieved either by balancing ultrafiltration and reinfusion through the hemofilter, or by balancing internal filtration in the hemodialyzer.

Likewise, as for other convective treatments, simultaneous but separate convection of PFD permitted higher depurative outcomes than standard HD mode, and even allowed treatment times to be reduced (Vanholder et al., 1991). Dialysis times could be reduced to as little as 150 minutes per session in patients with a body weight of < 61 kg without compromising dialytic tolerance and efficiency (Botella et al., 1991). PFD also achieves dialytic efficiencies comparable with HDF despite significantly lower filtration rates (40 versus 75 ml/min, respectively) (Bufano et al., 1991), which is primarily due to minimal interference between diffusion and convection. However, β2M removal is smaller than in HF mode (Marangoni et al., 1992). Other benefits of PFD may include the minimal use of backfiltration in the hemodialyzer and superior biocompatibility (Panichi et al., 1998). Since convection is achieved at the hemofilter, dialysis can be accomplished with minimal internal filtration and pressure gradients.

Pulse Push/Pull Hemodialysis: Convective Renal Replacement Therapy 123

closely related to inflammation and oxidative stress (Calo et al., 2007). Furthermore, plasma total antioxidant capacity (TAC) and antioxidant enzymes activities were found to be lower

However, contrary results have also been presented. For ESRD patients who undertook bicarbonate HD and then were switched to HFR, nutritional and inflammatory parameters remained unchanged over a year. Neither serum β2M nor PTH levels varied over the course of time, which led to the conclusion that although the change to HFR from bicarbonate HD is safe and tolerated, it is not associated with an improvement in nutritional or inflammatory parameters, or a reduction in β2M levels (Bossola et al., 2005). Prolonged,

More recently, a significant decrease was observed in cardiac troponin (cTnT) levels, a marker of myocardial damage and cardiac hypertrophy, throughout HFR sessions when using acetate-free dialysate, but cTnT increased after HFR using dialysate containing acetate. These results show that further explanation is required for the correlation between cTnT and acetate (Bolasco et al., 2011). However, both hemoglobin (Hb) levels and erythropoietic-stimulating agent (ESA) doses were not related to the presence of acetate. Hb levels increased, but ESA requirements tended to reduce continually during the 9-month

In summary, PFD is a HDF technique whereby ultrafiltrate is isolated from dialysate. Renal replacement therapies, facilitated by convection and diffusion, are still unsatisfactory for removing uremic toxins, and thus, adsorption as a third mechanism has been employed in HFR units. Adsorption during HFR allows convective treatments to be performed by the endogenous reinfusion of ultrafiltrate. Even if the loss of beneficial substances during HDF is inevitable, ultrafiltrate reinfusion reduces these losses to a minimum, like low-flux HD. Another feature of ultrafiltrate regeneration is the guaranteed purity of substitution fluid. Substitution is continuously obtained from ultrafiltrate, but the ultrafiltration, adsorption, and reinfusion system is totally closed during HFR, and therefore, excludes any possibility of contamination and ensures superior biocompatibility. However, despite these outstanding features, this unit has complications and associated costs. Furthermore, technical improvements in the preparation of ultrapure dialysate are expected to further cut the cost of preparing sterile, ultrapure replacement fluid, and this could increase the cost

A similar but simpler HDF strategy has been also introduced. This system relies on alternate repetitions of forward and backward filtration during dialysis treatment, and thus, it was named push/pull HDF. When the infusion-free HDF technique using a serial arrangement of two hemodiafilters was described in the early 1980's, the push/pull concept was devised to eliminate the need for two hemodiafilters. It is obvious that repetitive ultrafiltration can increase total filtration volume, but such a system also requires a means of repeating backfiltration (Usuda et al., 1982). Thus, a redundant dialysate bag is integrated downstream of the hemodialyzer, which is connected to the dialysate stream by a bidirectional peristaltic pump. The push/pull action that is accomplished by this bidirection pump is responsible for alternating the evacuation and replenishment of the bag. During normal operation, inlet and outlet dialysate flow rates are equally maintained and the desired volume removal is achieved by a separate ultrafiltration pump. In this situation, when the bidirectional pump pulls a portion of dialysate into the bag (70 ml/min for 3

for HFR than high-flux HD (Gonzalez-Diez et al., 2008).

larger-scale clinical studies for HFR are warranted.

study period (Bolasco et al., 2011).

gap between HFR and on-line HDF.

**2.4 Push/Pull Hemodiafiltration** 

However, PFD obviously requires the exogenous substitution infusion because of larger amounts of ultrafiltrate than required volume removal. One unique feature of PDF is that the ultrafiltrate is not mixed with the dialysate. In addition, the ultrafiltrate has a similar composition of plasma. On the other hand, the replacement fluid must possess a physiologic balance of electrolytes after taking into account preexisting deficits or excesses, and also should be sterile and free of pyrogenic substances. These features of ultrafiltrate and infusate enables the regeneration of ultrafiltrate to replace exogenous infusate, and ultrafiltrate for replacement purposes was successfully regenerated using an uncoated charcoal column (Ghezzi et al., 1991, 1992) (Fig. 3). As ultrafiltrate passes through the adsorbent column, solutes with a wide spectrum of molecular weights are adsorbed with the exception of some small molecules (e.g., urea and phosphate), but electrolytes and bicarbonate freely pass through the column. In addition, since small molecules that are not captured by the adsorbent can be removed by diffusion at the hemodialyzer, the regenerated ultrafiltrate is successfully applied as replacement fluid (Sanz-Moreno & Botella, 1995). Trace elements, such as manganese, selenium, arsenic, cadmium, mercury, lead, chromium, and zinc, also remain unaltered after passing through the adsorbent column, whereas copper is completely retained by the charcoal (de Francisco et al., 1997). Adsorption capacities were further increased by combining hydrophobic styrenic resin along with uncoated charcoal, because the resin has a high binding affinity for several mid molecular weight species, such as, β2M (Marinez de Francisco et al., 2000) and homocysteine (Splendiani et al., 2004), or free immunoglobulin light chains (Testa et al., 2010).

The other benefits of this regenerated ultrafiltrate include a better acid-base balance due to the reinfusion of endogenous bicarbonate (de Francisco et al., 1997), and also the not inconsiderable advantage of combining high convection without compromising physiologic molecule loss. Ultrafiltrate has a composition similar to that of plasma and contains huge numbers of polypeptides and other beneficial substances, such as, hormones, amino acids, and vitamins (Weissinger et al., 2004), and ultrafiltrate regeneration allows these beneficial nutrients to be reinfused (La Greca et al., 1998). In terms of plasma amino acid levels, no significant changes in their intradialytic levels occur during HFR, whereas a ~25% reduction occur during acetate-free biofiltration (Borrelli et al., 2010).

A number of clinical studies on ESRD patients have revealed that HFR remarkably improve dialytic efficiencies and solute removal over a wide molecular weight ranges, such as, the removal of uremic marker molecules (β2M, leptin and free immunoglobulin light chains) (Bolasco et al., 2006, S. Kim et al., 2009, Testa et al., 2006), cardiovascular risk factors (homocysteine) (Splendiani et al., 2004), inflammatory cytokines (CRP, IL-1, IL-6), and biomarkers of oxidative stress (ox-LDL, IL-1β) (Calo et al., 2011, Testa et al., 2006). In a comparison between HFR and on-line HDF, both were found to be highly biocompatible and to considerably reduce inflammatory markers, such as, CRP and IL-6 (Panichi et al., 2006). One technical variance of HFR is the repositioning of convection and diffusion. The change of sequence during HFR significantly enhanced reductions in urea and β2M, possibly due to the less saturated use of adsorbents, and also reduced cytokine levels, e.g., IL6 and TNFα, more than conventional HFR (Meloni et al., 2004, 2005).

In addition, HFR appears to be more beneficial at reducing oxidative stress and the risk of atherosclerotic cardiovascular disease than standard HD mode. A comparative study of HFR and low-flux bicarbonate HD revealed that HFR reduced not only the plasma level of oxidized low-density lipoprotein (LDL), but also the mRNA production of p22phox and PAI-1 (palsminogen activator inhibitor 1), whose protein expressions are known to be

However, PFD obviously requires the exogenous substitution infusion because of larger amounts of ultrafiltrate than required volume removal. One unique feature of PDF is that the ultrafiltrate is not mixed with the dialysate. In addition, the ultrafiltrate has a similar composition of plasma. On the other hand, the replacement fluid must possess a physiologic balance of electrolytes after taking into account preexisting deficits or excesses, and also should be sterile and free of pyrogenic substances. These features of ultrafiltrate and infusate enables the regeneration of ultrafiltrate to replace exogenous infusate, and ultrafiltrate for replacement purposes was successfully regenerated using an uncoated charcoal column (Ghezzi et al., 1991, 1992) (Fig. 3). As ultrafiltrate passes through the adsorbent column, solutes with a wide spectrum of molecular weights are adsorbed with the exception of some small molecules (e.g., urea and phosphate), but electrolytes and bicarbonate freely pass through the column. In addition, since small molecules that are not captured by the adsorbent can be removed by diffusion at the hemodialyzer, the regenerated ultrafiltrate is successfully applied as replacement fluid (Sanz-Moreno & Botella, 1995). Trace elements, such as manganese, selenium, arsenic, cadmium, mercury, lead, chromium, and zinc, also remain unaltered after passing through the adsorbent column, whereas copper is completely retained by the charcoal (de Francisco et al., 1997). Adsorption capacities were further increased by combining hydrophobic styrenic resin along with uncoated charcoal, because the resin has a high binding affinity for several mid molecular weight species, such as, β2M (Marinez de Francisco et al., 2000) and homocysteine

(Splendiani et al., 2004), or free immunoglobulin light chains (Testa et al., 2010).

occur during acetate-free biofiltration (Borrelli et al., 2010).

IL6 and TNFα, more than conventional HFR (Meloni et al., 2004, 2005).

The other benefits of this regenerated ultrafiltrate include a better acid-base balance due to the reinfusion of endogenous bicarbonate (de Francisco et al., 1997), and also the not inconsiderable advantage of combining high convection without compromising physiologic molecule loss. Ultrafiltrate has a composition similar to that of plasma and contains huge numbers of polypeptides and other beneficial substances, such as, hormones, amino acids, and vitamins (Weissinger et al., 2004), and ultrafiltrate regeneration allows these beneficial nutrients to be reinfused (La Greca et al., 1998). In terms of plasma amino acid levels, no significant changes in their intradialytic levels occur during HFR, whereas a ~25% reduction

A number of clinical studies on ESRD patients have revealed that HFR remarkably improve dialytic efficiencies and solute removal over a wide molecular weight ranges, such as, the removal of uremic marker molecules (β2M, leptin and free immunoglobulin light chains) (Bolasco et al., 2006, S. Kim et al., 2009, Testa et al., 2006), cardiovascular risk factors (homocysteine) (Splendiani et al., 2004), inflammatory cytokines (CRP, IL-1, IL-6), and biomarkers of oxidative stress (ox-LDL, IL-1β) (Calo et al., 2011, Testa et al., 2006). In a comparison between HFR and on-line HDF, both were found to be highly biocompatible and to considerably reduce inflammatory markers, such as, CRP and IL-6 (Panichi et al., 2006). One technical variance of HFR is the repositioning of convection and diffusion. The change of sequence during HFR significantly enhanced reductions in urea and β2M, possibly due to the less saturated use of adsorbents, and also reduced cytokine levels, e.g.,

In addition, HFR appears to be more beneficial at reducing oxidative stress and the risk of atherosclerotic cardiovascular disease than standard HD mode. A comparative study of HFR and low-flux bicarbonate HD revealed that HFR reduced not only the plasma level of oxidized low-density lipoprotein (LDL), but also the mRNA production of p22phox and PAI-1 (palsminogen activator inhibitor 1), whose protein expressions are known to be closely related to inflammation and oxidative stress (Calo et al., 2007). Furthermore, plasma total antioxidant capacity (TAC) and antioxidant enzymes activities were found to be lower for HFR than high-flux HD (Gonzalez-Diez et al., 2008).

However, contrary results have also been presented. For ESRD patients who undertook bicarbonate HD and then were switched to HFR, nutritional and inflammatory parameters remained unchanged over a year. Neither serum β2M nor PTH levels varied over the course of time, which led to the conclusion that although the change to HFR from bicarbonate HD is safe and tolerated, it is not associated with an improvement in nutritional or inflammatory parameters, or a reduction in β2M levels (Bossola et al., 2005). Prolonged, larger-scale clinical studies for HFR are warranted.

More recently, a significant decrease was observed in cardiac troponin (cTnT) levels, a marker of myocardial damage and cardiac hypertrophy, throughout HFR sessions when using acetate-free dialysate, but cTnT increased after HFR using dialysate containing acetate. These results show that further explanation is required for the correlation between cTnT and acetate (Bolasco et al., 2011). However, both hemoglobin (Hb) levels and erythropoietic-stimulating agent (ESA) doses were not related to the presence of acetate. Hb levels increased, but ESA requirements tended to reduce continually during the 9-month study period (Bolasco et al., 2011).

In summary, PFD is a HDF technique whereby ultrafiltrate is isolated from dialysate. Renal replacement therapies, facilitated by convection and diffusion, are still unsatisfactory for removing uremic toxins, and thus, adsorption as a third mechanism has been employed in HFR units. Adsorption during HFR allows convective treatments to be performed by the endogenous reinfusion of ultrafiltrate. Even if the loss of beneficial substances during HDF is inevitable, ultrafiltrate reinfusion reduces these losses to a minimum, like low-flux HD. Another feature of ultrafiltrate regeneration is the guaranteed purity of substitution fluid. Substitution is continuously obtained from ultrafiltrate, but the ultrafiltration, adsorption, and reinfusion system is totally closed during HFR, and therefore, excludes any possibility of contamination and ensures superior biocompatibility. However, despite these outstanding features, this unit has complications and associated costs. Furthermore, technical improvements in the preparation of ultrapure dialysate are expected to further cut the cost of preparing sterile, ultrapure replacement fluid, and this could increase the cost gap between HFR and on-line HDF.

### **2.4 Push/Pull Hemodiafiltration**

A similar but simpler HDF strategy has been also introduced. This system relies on alternate repetitions of forward and backward filtration during dialysis treatment, and thus, it was named push/pull HDF. When the infusion-free HDF technique using a serial arrangement of two hemodiafilters was described in the early 1980's, the push/pull concept was devised to eliminate the need for two hemodiafilters. It is obvious that repetitive ultrafiltration can increase total filtration volume, but such a system also requires a means of repeating backfiltration (Usuda et al., 1982). Thus, a redundant dialysate bag is integrated downstream of the hemodialyzer, which is connected to the dialysate stream by a bidirectional peristaltic pump. The push/pull action that is accomplished by this bidirection pump is responsible for alternating the evacuation and replenishment of the bag. During normal operation, inlet and outlet dialysate flow rates are equally maintained and the desired volume removal is achieved by a separate ultrafiltration pump. In this situation, when the bidirectional pump pulls a portion of dialysate into the bag (70 ml/min for 3

Pulse Push/Pull Hemodialysis: Convective Renal Replacement Therapy 125

side chamber, the dialysate compartment begins to expand, and the dialysate compartment becomes depressurized, which leads ultrafiltration. However, despite the large amount of ultrafiltration, blood flow in the venous line is maintained, because the ultrafiltrate removed

Furthermore, the reciprocating movement of the piston is regulated by pressure differences between the two chambers of the cylinder pump (i.e., Pb-Pd). The rotation torque of the driving motor attached to the piston can be expressed in accord with TMP (i.e., torque = TMPxSxLxsinθ). Voltage applied to the motor is adjusted so that the TMP is set at 400 mmHg during forward filtration, but at -400 mmHg during the backward filtration phase, that is, pressure-controlled push/pull HDF can maintain transmembrane pressures at the maximum permissible level throughout treatment (Shinzato et al., 1994). In addition, contrary to the original push/pull HDF, in which one cycle of filtration and backfiltration takes approximate 4~5 minutes, the pressure controlled push/pull HDF unit can repeat one

This optimized use of transmembrane pressure and more frequent alternations of forward and backward filtration in the revised push/pull HDF unit are obviously accompanied with a markedly larger total filtration volumes and higher solutes clearances (Shinzato et al., 1994). Push/pull HDF tends to relieve symptoms like arthralgia (joint pain), irritability, pruritus, and insomnia more rapidly than conventional HD (Maeda et al., 1990, Maeda & Shinzato, 1995, Shinzato et al., 1995). Furthermore, the optimal maintenance of membrane permeabilities by prompt backfiltration has the added benefit of considerably inhibiting albumin loss in addition to increasing convection and diffusion (Shinzato et al., 1996). Albumin loss is inevitable when using membranes with high water permeabilities and sieving characteristics (Combarnous et al., 2002). Since convective therapy is based on larger amounts of fluid exchange and solvent drag during fluid exchange occurs randomly, albumin permeation becomes more worrisome during convective treatments (Ahrenholz et al., 2004). In addition, filtration-induced elevated albumin concentration at the inner membrane wall also aggravates the albumin loss (Miwa & Shinzato, 1999). Protein concentration polarization develops quickly after sudden TMP development and the hydraulic permeabilities of the membrane decrease rapidly in about 2 seconds. However, during push/pull HDF, backward flushing of dialysate takes place within the time frame required for the protein layer to fully develop (i.e., 1.5~1.7 seconds), and thus, it can effectively wash out the inner lumen and inhibit

However, this modality still requires the use of a separate device so that dialysate pressures are regulated instantaneously. In addition, no clinical observation has been conducted to examine the long-term clinical effect of pressure-controlled push/pull HDF versus on-line HDF. Push/pull HDF is based on repetitive dilution at a rate of approximate 15 ml per 1.7s cycle, which exceeds blood flow rates (3.3~5 ml/s). Hence, push/pull HDF is assumed to be close to pre-dilution mode HDF (Shinzato & Maeda, 2007). Even though post-dilution HDF is more efficient in terms of solute removal, the substantial amount of total filtration and the optimal use of membrane offered by the push/pull HDF technique probably translate to

Push/pull HDF was developed in an effort to perform infusion-free, simultaneous HD and HF by using a single hemodialyzer. Thus, it alternates between forward filtration and backfiltration instead of dividing ultrafiltration and backfiltration regions. Pressurecontrolled push/pull HDF using a double-chambered cylinder pump can maintain TMPs at

in the hemodialyzer is replenished in the venous chamber.

excessive albumin leakage (Shinzato et al., 1996).

outstanding hemodialytic outcomes.

cycle in 1.5~1.7 seconds.

minutes), hydrostatic pressures through the dialysate compartment decrease, because the dialysate compartment is closed and has a fixed volume, and water flux occurs from blood to the dialysate compartment (ultrafiltration) at the same level as dialysate removal from the dialysate compartment. Soon after the ultrafiltration completes, the pump operates in reverse and pushes the dialysate in the bag into the dialysate stream, which causes a volume overload in the dialysate compartment. The surplus dialysate in the closed dialysate compartment is then moved to the blood compartment (backfiltration). In the same manner, another bag and an additional bidirectional peristaltic pump is also integrated into the venous chamber, and conducts the pulling and pushing of blood, although in this case, the actions of the blood-side pump are 180O out of phase with those of the dialysate side pump to keep blood flow returning to the patient constant.

When pure dialysate is pushed into the blood stream, solute concentrations in blood are immediately equilibrated and decreased by dilution. Soon after, the blood-to-dialysate pressure gradient reverses from negative to positive, and plasma fluid in blood is forced to move into the dialysate compartment, which removes various molecules from plasma. This repetitive ultrafiltration obviously contributes to convective mass transfer and increases the reductions of small-sized (urea) or mid-sized (β2M) molecules as compared with HF or HD, respectively (Shinzato et al., 1989). On the other hand, repetitive backfiltration during push/pull HDF prevents volume depletion. In addition, the repetitive backflushing of dialysate also helps prevent membrane binding (Usuda et al., 1982).

However, disposable bags and separate bidirectional peristaltic pumps make this unit complicated and increase treatment costs. Instead, a double-chamber cylinder pump was devised with two independent chambers and a reciprocal piston; that is, each chamber is connected to either dialysate or the blood stream (Tsuruta et al., 1994), as seen in Fig. 4.

Fig. 4. Push/Pull HDF and Double-Chamber Cylinder Pump

When the piston squeezes the chamber on the dialysate side, the dialysate compartment, which has a fixed volume, is pressurized and backfiltration begins. At this time, the chamber on the blood side expands and blood in the venous chamber starts flowing in the direction of the double-chambered pump. Since the blood volume that returns to the blood-side chamber of the pump is equal to the backfiltration volume, blood flow returning to patients remains constant. The piston then moves in the opposite direction and squeezes the blood-

minutes), hydrostatic pressures through the dialysate compartment decrease, because the dialysate compartment is closed and has a fixed volume, and water flux occurs from blood to the dialysate compartment (ultrafiltration) at the same level as dialysate removal from the dialysate compartment. Soon after the ultrafiltration completes, the pump operates in reverse and pushes the dialysate in the bag into the dialysate stream, which causes a volume overload in the dialysate compartment. The surplus dialysate in the closed dialysate compartment is then moved to the blood compartment (backfiltration). In the same manner, another bag and an additional bidirectional peristaltic pump is also integrated into the venous chamber, and conducts the pulling and pushing of blood, although in this case, the actions of the blood-side pump are 180O out of phase with those of the dialysate side pump

When pure dialysate is pushed into the blood stream, solute concentrations in blood are immediately equilibrated and decreased by dilution. Soon after, the blood-to-dialysate pressure gradient reverses from negative to positive, and plasma fluid in blood is forced to move into the dialysate compartment, which removes various molecules from plasma. This repetitive ultrafiltration obviously contributes to convective mass transfer and increases the reductions of small-sized (urea) or mid-sized (β2M) molecules as compared with HF or HD, respectively (Shinzato et al., 1989). On the other hand, repetitive backfiltration during push/pull HDF prevents volume depletion. In addition, the repetitive backflushing of

However, disposable bags and separate bidirectional peristaltic pumps make this unit complicated and increase treatment costs. Instead, a double-chamber cylinder pump was devised with two independent chambers and a reciprocal piston; that is, each chamber is connected to either dialysate or the blood stream (Tsuruta et al., 1994), as seen in Fig. 4.

When the piston squeezes the chamber on the dialysate side, the dialysate compartment, which has a fixed volume, is pressurized and backfiltration begins. At this time, the chamber on the blood side expands and blood in the venous chamber starts flowing in the direction of the double-chambered pump. Since the blood volume that returns to the blood-side chamber of the pump is equal to the backfiltration volume, blood flow returning to patients remains constant. The piston then moves in the opposite direction and squeezes the blood-

to keep blood flow returning to the patient constant.

dialysate also helps prevent membrane binding (Usuda et al., 1982).

Fig. 4. Push/Pull HDF and Double-Chamber Cylinder Pump

side chamber, the dialysate compartment begins to expand, and the dialysate compartment becomes depressurized, which leads ultrafiltration. However, despite the large amount of ultrafiltration, blood flow in the venous line is maintained, because the ultrafiltrate removed in the hemodialyzer is replenished in the venous chamber.

Furthermore, the reciprocating movement of the piston is regulated by pressure differences between the two chambers of the cylinder pump (i.e., Pb-Pd). The rotation torque of the driving motor attached to the piston can be expressed in accord with TMP (i.e., torque = TMPxSxLxsinθ). Voltage applied to the motor is adjusted so that the TMP is set at 400 mmHg during forward filtration, but at -400 mmHg during the backward filtration phase, that is, pressure-controlled push/pull HDF can maintain transmembrane pressures at the maximum permissible level throughout treatment (Shinzato et al., 1994). In addition, contrary to the original push/pull HDF, in which one cycle of filtration and backfiltration takes approximate 4~5 minutes, the pressure controlled push/pull HDF unit can repeat one cycle in 1.5~1.7 seconds.

This optimized use of transmembrane pressure and more frequent alternations of forward and backward filtration in the revised push/pull HDF unit are obviously accompanied with a markedly larger total filtration volumes and higher solutes clearances (Shinzato et al., 1994). Push/pull HDF tends to relieve symptoms like arthralgia (joint pain), irritability, pruritus, and insomnia more rapidly than conventional HD (Maeda et al., 1990, Maeda & Shinzato, 1995, Shinzato et al., 1995). Furthermore, the optimal maintenance of membrane permeabilities by prompt backfiltration has the added benefit of considerably inhibiting albumin loss in addition to increasing convection and diffusion (Shinzato et al., 1996). Albumin loss is inevitable when using membranes with high water permeabilities and sieving characteristics (Combarnous et al., 2002). Since convective therapy is based on larger amounts of fluid exchange and solvent drag during fluid exchange occurs randomly, albumin permeation becomes more worrisome during convective treatments (Ahrenholz et al., 2004). In addition, filtration-induced elevated albumin concentration at the inner membrane wall also aggravates the albumin loss (Miwa & Shinzato, 1999). Protein concentration polarization develops quickly after sudden TMP development and the hydraulic permeabilities of the membrane decrease rapidly in about 2 seconds. However, during push/pull HDF, backward flushing of dialysate takes place within the time frame required for the protein layer to fully develop (i.e., 1.5~1.7 seconds), and thus, it can effectively wash out the inner lumen and inhibit excessive albumin leakage (Shinzato et al., 1996).

However, this modality still requires the use of a separate device so that dialysate pressures are regulated instantaneously. In addition, no clinical observation has been conducted to examine the long-term clinical effect of pressure-controlled push/pull HDF versus on-line HDF. Push/pull HDF is based on repetitive dilution at a rate of approximate 15 ml per 1.7s cycle, which exceeds blood flow rates (3.3~5 ml/s). Hence, push/pull HDF is assumed to be close to pre-dilution mode HDF (Shinzato & Maeda, 2007). Even though post-dilution HDF is more efficient in terms of solute removal, the substantial amount of total filtration and the optimal use of membrane offered by the push/pull HDF technique probably translate to outstanding hemodialytic outcomes.

Push/pull HDF was developed in an effort to perform infusion-free, simultaneous HD and HF by using a single hemodialyzer. Thus, it alternates between forward filtration and backfiltration instead of dividing ultrafiltration and backfiltration regions. Pressurecontrolled push/pull HDF using a double-chambered cylinder pump can maintain TMPs at

Pulse Push/Pull Hemodialysis: Convective Renal Replacement Therapy 127

The hemodialytic efficiencies of PPPHD have been demonstrated *in vitro* and also *in vivo*, and these studies have shown that PPPHD substantially improves the clearances of uremic marker molecules, particularly for mid-sized molecules (Table 1) (K. Lee et al., 2008), which is believed to be due to a higher level of total filtration. Pressure profiles also showed obvious oscillations of TMPs throughout treatment, and their magnitudes were significantly

CHD - 236±3.6 420±3 161.1±4.3 127.2±3.9 37.5±6.3 25.3±5.1 PPPHD 40 234±3.1 419±3 166.2±3.8 136.9±4.2 55.7±5.0 37.8±3.9 % Increase - - 3.2 7.6 48 49 P-value NS NS 0.053 <0.05 <0.001 <0.001 Table 1. Solutes Clearances. (CHD, conventional high-flux HD; PPPHD, pulse push/pull HD; BPM, beats per minute; QB, blood flowrate; QD, dialysate flowrate; BUN, blood urea

Increased filtration volumes in the PPPHD unit may also be due to reduced membrane fouling. In an *in vivo* setup on PPPHD, one cycle of ultrafiltration and backfiltration took 3 seconds at a pulse frequency of 20 bpm (K. Lee et al., 2008). When ultrafiltration and backfiltration times were defined as the durations of positive and negative TMPs, respectively, ultrafiltration and backfiltration times for the PPPHD unit were 1.68±0.02 and 1.31±0.03 seconds, respectively. Since protein concentration polarization on the blood-side membrane develops during the forward filtration phase and it is reduced by backfiltration, membrane convective capacity might be better maintained during PPPHD than during CHD, showing smaller reductions in post-dialysis hydraulic permeabilities (K. Lee et al., 2008). Furthermore, PPPHD-treated animals were tolerably sustained and their physiologic

BUN Creatinine Vitamin b12 Inulin

larger than those observed in conventional hemodialysis (CHD) mode.

Group BPM QB QD Clearance (ml/min)

Fig. 5. T-PLS pump for the original PPPHD

nitrogen; NS, not significant)

parameters were stable.

maximal levels and the total filtration volumes achieved are far greater than that of any other treatment modality. In addition to the filtration quantity, repetitive cycles in a shorter time than the time required for a protein layer to be established ensure superior membrane use throughout treatment, which further inhibits albumin loss. However, given the advances represented by membranes with high β2M sieving coefficients (>0.8), but very small albumin sieving coefficients (<0.01) (Ronco et al., 2002), the differences between push/pull HDF and high-flux HD with respect to β2M removal may be reduced, and albumin leakage less problematic. To an extent in modern dialysis practice, albumin permeable membranes are even considered to remove non-soluble and/or much larger molecules (De Smet et al., 2007, Samtleben et al., 2003). Therefore, a prolonged prospective study on push/pull HDF may be worthwhile to determine the benefits of this modality versus other forms of convective renal replacement.
