The incidence of kidney disease is rapidly increasing worldwide,1 and maintenance hemodialysis (HD) has become an established protocol for treating patients with end-stage renal disease (ESRD). Remarkable improvements have been made in the technologies used for dialysis treatment, and they are matched by the evolution of various modalities for renal supportive treatments. Better outcomes achieved by convective treatment have encouraged the use of synthetic high-flux membranes in clinical setups,2 and hemodiafiltration (HDF) and volume-controlled high-flux HD are now regarded as preferred forms of convective therapy.
High-flux HD adequately clears mid-size solutes without sterile fluid infusion, because forward filtration exceeding desired volume removal is compensated for by backfiltration (BF)3; thus, HD has been entitled to a simplest form of dialysis treatment. The convective dose delivered during high-flux HD has been shown to reduce mortality in patients at risk, as defined by a serum albumin level of <4 g/dl,4 but overall patient survival remains comparable to that of low-flux HD.5 This is presumably due to the limited amount of internal filtration involved. In contrast, HDF, which describes an intermittent renal supportive therapy of combined simultaneous diffusive and convective solute transport, is characterized by a large filtration volume that far exceeds the desired amount. Hence, this modality has been reported to improve middle-to-large size molecular removal, allow better erythropoietin control, and reduce oxidative stress and inflammation.6–9 It has been even reported to have a positive influence on the survival.10 However, the far higher filtration volumes during HDF must be compensated for by external substitution in real time.
Despite various modifications of HDF techniques based on infusion modes, the inevitable complexities associated with the requirement for the exogenous substitution infusion are still unavoidable. Therefore, efforts have been continued to propose novel HDF strategies that do not require external infusion. This is achieved by spontaneous fluid reinfusion at a rate that matches convection. These modifications can be classified into three developmental categories: 1) to increase the internal filtration rate by increasing pressure gradients along the hemodialyzer, 2) to use independent domains of ultrafiltration and diffusion, and 3) to alternate forward and backward filtration procedures.
In this review, therefore, the trials on substitution-free HDF are described. Technical aspects, including in vivo and in vitro efficacies and applicability to clinical use, are discussed in detail.
Internal Filtration–Enhanced HDF
Internal filtration is defined as the total water flux across membranes within the closed blood and dialysate compartments of a dialyzer.11 Volume-controlled high-flux HD uses the internal filtration phenomenon, and convective mass transfer during HD is governed by the balance of forward and backward filtration. Thus, augmenting internal filtration provides a straightforward means of achieving enhanced convection, which is termed iHDF. The amount of internal filtration is directly regulated by pressure gradients through the hemodialyzer. A pressure drop (ΔP) is inevitable as fluid flows through a cylindrical tube, and it is expressed by Poiseuille’s equation:
where µ is the fluid viscosity, L and d are the length and diameter of the flow path, respectively, and Q is the flow rate. However, because blood and dialysate flow in opposite directions, these pressure drops occur with opposing gradients, and in some regions hydraulic blood and dialysate pressures overlap (Figure 1). In a normal countercurrent dialysis setup, the sum of hydraulic and osmotic pressures and transmembrane pressure (TMP) is positive in the proximal region of a hemodialyzer, which leads to forward filtration. However, fluid movement occurs in the opposite direction in the distal region because TMP becomes negative.
Resulting TMP gradients can be readily increased by increasing blood or dialysate pressure drops.12,13 Poiseuille’s equation shows that the pressure drop is inversely proportional to the fourth power of tube diameter. Hence, many investigations of iHDF have focused on using hemodialyzers with smaller membrane diameters so as to increase blood pressure drop. In early clinical studies, a 175 µm lumen diameter dialyzer enhanced beta-2 microglobulin (β2M) clearances by two and four times, respectively, over 200 and 250 µm diameter hemodialyzers.11 Clearances of inulin and vitamin b12 were also significantly greater with 175 µm dialyzer than a 200 µm dialyzer, without changing the clearances of low-molecular-weight solutes.14 These results were also confirmed by an analytical model, in which myoglobin clearance was increased by 34% when a membrane of diameter 150 µm, rather than 200 µm, with the same surface area was used at the same blood flow rates.15,16 These dialytic benefits afforded by reducing membrane lumen diameter allow internal filtration–enhanced hemodialyzers to be used clinically.17,18 However, the underlying risk of hemoconcentration due to high levels of forward filtration may not be negligible. Pressure-driven filtration causes large volume losses from blood and promptly increases blood viscosity, which deteriorates membrane sieving and hydraulic capabilities, and inevitably diminishes membrane efficiency.
Dialysate pressure is also regulated by increasing the flow resistance on the dialysate stream, such as, increasing membrane packing density, lengthening the hemodialyzer, or physically restricting flow. In one study, β2M and alpha-1 microglobulin were shown to be better cleared by a 250-mm dialyzer than a 195-mm dialyzer.19 Analytical and experimental studies also revealed that myoglobin clearances were slightly improved when using a hemodialyzer with 71.3% packing density versus 52% or 60.1%.16 However, high packing densities cause substantial degrees of dialysate channeling and flow mismatch between blood and dialysate, which eventually leads to a loss of effective surface area and impairs the diffusion process.20 Flow visualization studies in a dialyzer with a high packing density (75%) reconfirmed this disproportionate flow pattern of dialysate and consequent reductions in urea clearance.21,22
The convective efficiency of iHDF may be quantified by evaluating internal filtration rates. The flux across a membrane can be expressed by the product of membrane hydraulic permeability and TMP. However, the flow dynamics inside the hemodialyzer are so complex that precise determinations of internal filtration rates are not available clinically, and thus, fluxes and permeabilities become parameters beyond the operator’s control. Alternatively, a semiempirical model has been developed to determine internal filtration rates. Using this model, internal filtration volumes and reinfusion rates were determined during iHDF and postdilution HDF modes and revealed that differences between total convections (4.1 and 5.4 L/h for iHDF and HDF, respectively) well reflected differences between β2M clearances (123 ± 11 and 149 ± 26 ml/min for iHDF and HDF, respectively).17 In a study conducted to verify this semiempirical model, the model was found to show excellent accuracies of around 97% and a prediction error of only 3%.23
In addition to the mathematical model, methods for performing indirect measurements of the internal filtration have been proposed. Changes in nonpermeable molecular concentrations occur in response to the water content of blood, and thus, the kinetics of water transport across membrane can be evaluated by measuring the cumulative concentration changes of nonpermeable molecules.24 Radiolabeled albumin has been used to determine the amounts of convection for hemodialyzers with reduced fiber diameters or physical flow restriction of the dialysate stream.14,25 A series of in vitro experiments proved that this scintigraphic method was accurate for measuring internal filtration rates, but despite its precision, its clinical application is not plausible due to the safety concerns with the use of radiolabeled molecules and the added complexity required for the procedures and equipment. Another approach to determine internal filtration is offered by Doppler ultrasonography. In the absence of net filtration, blood volume depletion in the proximal portion of a hemodialyzer leads to a reduction in blood flow velocity, and after the lowest point has been reached, the blood velocity gradually increases due to BF. Thus, changes in blood velocity along a dialyzer provide information on blood volume changes. In one study, the internal filtration rate of a 250 mm dialyzer was found to be 37.7 ml/min, but only 11.1 ml/min for a standard 195 mm dialyzer.19 Doppler ultrasonography is noninvasive and easily used at bedside,26 but the method is still incapable of measuring blood flow velocity precisely; i.e., this method is based on velocities measured in peripheral membranes, which differ from velocities within centrally located fibers, and as a result, deviations from true values are unavoidable. Other techniques have also been explored in an effort to quantify the filtration phenomena or to visualize flow distributions inside hemodialyzers, such as magnetic resonance imaging,27 computed tomography,28,29 and a computerized scanning technique.30,31 However, the quantification of internal filtration using these techniques is not available clinically, due to concerns of patient safety and technical requirements.
In summary, iHDF can provide a straightforward means of convective treatment by increasing internal filtration rates using specifically designed hemodialyzers, and hence, this technique is simpler than other modalities. The literature suggests superior dialysis outcomes for iHDF versus standard HD mode, but the precise quantification of internal filtration remains to be determined. This information allows the comparison of this unit with other HDF techniques with respect to their convective capacities.
Double High-Flux HDF
Double high-flux HDF was first introduced in the early 1980s as a means of combining HD and hemofiltration (HF).32 This technique was particularly aimed at significantly increasing small (diffusion) and middle-size molecular removal (convection) 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.33,34 This arrangement of two hemodialyzers enabled flow resistances through the two hemodialyzers to be manipulated, which permitted TMP gradients to be adjusted. Flow resistance applied to the dialysate tubing between the two dialyzers promptly increases dialysate pressures at the venous dialyzer (Figure 2). Hydraulic dialysate pressures exceed blood pressures, which leads to BF in the venous dialyzer. However, dialysate pressures rapidly fall in the arterial dialyzer due to flow restriction, which causes ultrafiltration in the arterial dialyzer. Hence, ultrafiltration at the arterial dialyzer can be promptly compensated for by BF at the venous dialyzer. In addition, the high blood and dialysate flow rates used are associated with larger pressure gradients of this technique.
Therefore, together with these features, this modality achieved unmatched depurative outcomes, as demonstrated by far higher uremic molecular clearances regardless of molecular sizes.32,35–37 Furthermore, increased clearances allowed treatment times to be substantially shortened.33,34 These results were also confirmed by comparing treatment modalities. Double high-flux HDF attained significantly greater β2M reduction and Kt/V values than standard high-flux HD and showed comparable β2M clearance to that of online HDF.38,39 Furthermore, the beneficial effect of this technique on patient survival was also suggested in a long-term assessment. In this study, double HDF was compared with high-efficiency or high-flux 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 US Renal Data System (0.41 and 1, respectively) despite the shortened treatment time.40
However, concerns have been raised regarding the use of two hemodialyzers in this 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 the reuse. Another concern arises from the large amount of cross-membrane flux. In particular, a large quantity of BF should be assured by the strict and regular verification of water quality.41
Double high-flux HDF emerged as an effort to increase treatment efficiencies and shorten treatment times by maximizing 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 unit. 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 previously mentioned underlying concerns.
Paired Filtration Dialysis With Endogenous Hemofiltrate Reinfusion
Another two-chamber technique for obtaining efficient HDF treatment is the so-called 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 principle separates convection from diffusion.42–44 A hemofilter with a small surface area is combined in a circuit with a hemodialyzer as shown in Figure 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 and enable the precise quantification of convective clearance.45
However, PFD still requires the exogenous substitution infusion, which is administered at the midpoint between the hemofilter and hemodialyzer, because of the ultrafiltrate exceeding those required. One unique feature of PFD is that the ultrafiltrate is not mixed with dialysate. However, the replacement fluid must possess a physiologic balance of electrolytes after taking into account preexisting deficits or excesses. These features of ultrafiltrate and infusate encouraged the regeneration of ultrafiltrate to replace exogenous infusate, and ultrafiltrate for replacement purposes was successfully regenerated using an uncoated charcoal column.46,47 As ultrafiltrate passes through the adsorbent column, solutes with a wide spectrum of molecular weights are adsorbed except for some small molecules (e.g., urea and phosphate), but electrolytes and bicarbonate freely pass through the column. In addition, because uncaptured small molecules can be removed by diffusion at the hemodialyzer, the regenerated ultrafiltrate is successfully applied as replacement fluid.48 Adsorption capacities were further increased by combining hydrophobic styrene-based resin along with uncoated charcoal, because the resin has a high binding affinity for several mid-molecular-weight species, such as β2M49 and homocysteine,50 or free immunoglobulin light chains.51
The other benefits of this regenerated ultrafiltrate include a better acid-base balance due to the reinfusion of endogenous bicarbonate52 and also the considerable advantage of combining high convection without 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 and amino acids,53 and regeneration of ultrafiltrate allows these beneficial nutrients to be reinfused.54 In terms of plasma amino acid levels, no significant changes in their intradialytic levels occur during hemofiltrate reinfusion (HFR), whereas a ~25% reduction occur during acetate-free biofiltration.55
A number of clinical studies on patients with ESRD have revealed that HFR remarkably improve dialytic efficiencies and solute removal, such as the removal of uremic marker molecules (β2M, leptin, and free immunoglobulin light chains),56–58 cardiovascular risk factors (homocysteine),50 inflammatory cytokines (C-reactive protein [CRP], interleukin [IL]-1, and IL-6), and biomarkers of oxidative stress (oxidized low-density lipoprotein and IL-1β).58,59 In a comparison between HFR and online HDF, both were found to be highly biocompatible and to considerably reduce inflammatory markers, such as CRP and IL-6.60 One technical variance of HFR is the repositioning of convection and diffusion. The change of sequence significantly enhanced reductions in urea and β2M, and also cytokine levels, e.g., IL6 and TNFα, more than conventional HFR, possibly due to the less saturated use of adsorbents.61,62 Contrary results have also been presented. For patients with ESRD treated with bicarbonate HD and then switched to HFR, nutritional and inflammatory parameters remained unchanged over a year. Neither serum β2M nor parathyroid hormone 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.63 Prolonged, large-scale clinical studies remain to be conducted for HFR.
More recently, a significant decrease was observed in cardiac troponin (cTnT) level throughout HFR sessions when using acetate-free dialysate, but cTnT increased after HFR using dialysate containing acetate, which requires further explanation for the correlation between cTnT and acetate.64 However, both hemoglobin levels and erythropoietic-stimulating agent doses were not related to the presence of acetate during the 9 month HFR period.65
Adsorption as a third mechanism for purifying blood has been used in HFR units. Adsorption during HFR allows convective treatments to be performed by the endogenous reinfusion of ultrafiltrate. The ultrafiltrate reinfusion minimizes the loss of beneficial substances. 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.
Push/pull (PP) systems rely on alternate repetitions of forward and backward filtration during dialysis treatment. When the HDF technique using a serial arrangement of two hemodiafilters was described in the early 1980s, the PP concept was devised to eliminate the need for two filters. It is obvious that repetitive ultrafiltration can increase total filtration volume. However, such a system also requires a means of repeating BF.66
In early trials of PP HDF, a redundant dialysate bag was integrated downstream of the hemodialyzer, which was connected to the dialysate stream by a bidirectional peristaltic pump. The pump alternated the evacuation and replenishment of the bag, which forced hydrostatic pressures through the dialysate compartment to be oscillated. Likewise, another bag and an additional pump were integrated into the venous chamber and conducted the pulling and pushing of blood. However, disposable bags and separate PP pumps make this circuit considerably complicated. Hence, a double-chamber cylinder pump was devised to achieve the PP procedures and substantially simplify the required circuit (Figure 4). The cylinder pump includes two independent chambers and a reciprocal piston. Each chamber is connected to either dialysate or the blood stream.67 When the piston squeezes the chamber on the dialysate side, the dialysate compartment is pressurized and BF begins. At this time, the blood-side chamber expands and blood is filled in the venous chamber. Because the blood volume filled in the chamber is equal to the BF volume, blood flow returning to patients remains constant. The piston then moves in the opposite direction and squeezes the blood-side chamber; the dialysate compartment begins to expand and becomes depressurized, which leads to ultrafiltration. However, blood flow in the venous line is maintained, because the ultrafiltrate removed in the hemodialyzer is replenished in the venous chamber. In addition, the reciprocating movement of the piston is regulated by pressure differences between the two chambers so that the TMP is set at maximally optimal level, i.e., 400 and −400 mm Hg during forward and backward filtration phases, respectively.68
This optimized use of TMP and frequent alternations of forward and backward filtration are obviously accompanied with markedly larger total filtration volumes and higher solutes clearances.68 The PP HDF unit tends to relieve symptoms such as arthralgia (joint pain), irritability, pruritus, and insomnia more rapidly than conventional HD mode.69–71 Furthermore, the optimal maintenance of membrane permeabilities by prompt BF has the added benefit of considerably inhibiting albumin loss in addition to increasing convection and diffusion.72 During PP HDF, backward flushing of dialysate takes place within the time frame required for the protein layer to fully develop, and thus, it can effectively wash out the inner lumen and inhibit excessive albumin leakage.
However, PP HDF still requires the use of a separate double-compartment piston pump to regulate dialysate pressures. Thus, a simpler strategy for achieving the PP actions has been recently introduced, which was implemented by using pulsatile devices for blood and dialysate.73–76 Respective pushing phases of blood and dialysate pulsations alternated, and TMPs cycled between positive and negative, which drove consecutive periods of ultrafiltration and BF; thus, the need for a separate double-compartment piston pump was eliminated. The hemodialytic efficiencies of the revised PP unit have been demonstrated in vitro and also in vivo, and these studies have shown that the devised PP unit substantially improves the clearances of uremic marker molecules, particularly for mid-sized molecules.73,77 Pressure profiles also showed obvious oscillations of TMPs throughout treatment, and their magnitudes were significantly larger than those observed in HD mode. More recently, due to concerns with the pulsatile circulation of blood, particularly in terms of blood supply and vascular access, this unit has been further improved by eliminating blood pulsation, but retaining the recurrent forward and backward filtration procedures, which was achieved by integrating a dual pulsatile device in the dialysate stream.78
Push/pull techniques described have been reported to deliver maximal permissible levels of volume exchange, which allows speculation on the capability of this unit in terms of convective efficiency. However, no clinical observation has been conducted to examine the long-term clinical effect of these PP techniques. In addition, the forward and backward filtration rates exceed blood flow rates,79 and the repeated BF and consequent blood dilution may translate into a dialytic efficiency drop. Nevertheless, the optimizations of PP procedures, in terms of the PP volumes and frequencies, may result in more efficient use of membranes, generate better convective efficiency, and as a result, achieve a simple but efficient substitution-free HDF.
Substitution-free HDF treatments must be accompanied by spontaneous fluid restoration, such as BF or ultrafiltrate regeneration (Table 1). A simpler way might be to increase internal filtration during HD sessions, although this can only be done to a limited extent. Much higher efficiencies can be achieved by the two-chamber techniques, which were developed in an effort to increase solute removal and shorten treatment times. However, these modalities appear to unavoidably increase overall system complexity and cost. Push/pull techniques were derived by considering phase separation for forward and backward filtration. In addition, the pulse PP scheme has adopted pulsatile devices for blood and dialysate circulation as an effort of modulating flow patterns. However, no clinical observation has been made using these PP units.
Modern dialysis machines offer HDF and HD as default therapies and are also equipped with outstanding monitoring facilities not only for patients but also for treatments.80 In particular, advances in water treatment allow ultrapure replacement fluid to be prepared in real time. These technical advancements are certainly lowering the barriers to higher convective HDF therapies. Therefore, the additional convective and diffusive clearances of these substitution-free HDF techniques should be translated into features that simplify overall dialysis treatments, such as a miniaturized unit that can be characterized as being user-friendly, light, and portable. A dialysis unit equipped with these features may also provide treatment alternatives beyond the current thrice weekly clinic dialysis for patients with ESRD.
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