Alternative kidney replacement therapies in end-stage kidney disease

INTRODUCTION — Despite improvements in technology and general medical care, the mortality rate of patients on maintenance dialysis remains high [1,2]. In an attempt to improve outcomes, it was postulated that a higher dialysis dose than commonly provided during conventional dialysis may increase survival among patients undergoing kidney replacement therapies [3].

However, this hypothesis was refuted in two large, well-designed studies in patients on hemodialysis or on peritoneal dialysis:

●The Hemodialysis (HEMO) Study found no improvement in patient survival when per-session hemodialysis dose was increased above the Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations [4]. (See "Prescribing and assessing adequate hemodialysis".)

●In the Adequacy of Peritoneal Dialysis in Mexico (ADEMEX) study, no reduction in mortality was seen with peritoneal dialysis doses greater than a weekly Kt/V of 1.7 [5]. (See "Prescribing peritoneal dialysis".)

In the wake of these negative trials, more attention has turned to alternative dialysis schedules, including long intermittent hemodialysis, short daily hemodialysis, and nocturnal hemodialysis. Each of these approaches is discussed in detail separately. (See "Technical aspects of nocturnal hemodialysis" and "Short daily hemodialysis".)

In addition, new and innovative forms of chronic kidney replacement therapy have emerged. These include hemodiafiltration, sorbent hemodialysis, and the use of bioartificial membranes. These alternative approaches to the treatment of end-stage kidney disease (ESKD) will be discussed in this topic review.

OVERVIEW OF UREMIC TOXINS — To better understand the possible role for alternative kidney replacement therapies, it is worthwhile to briefly review the physical properties of known uremic toxins and how effectively conventional hemodialysis removes these substances. (See "Uremic toxins".)

Uremic toxins — The uremic syndrome results largely from the accumulation of toxins, which include molecules that are normally filtered, excreted, or catabolized by the normal kidney. Of the large number of solutes retained in kidney failure, 146 were designated as uremic toxins by the European Uremic Toxin Work Group [6]. Although the mode of classification of uremic toxins is evolving [7], we will follow the molecular weight (MW)-based approach.

Solutes can be divided according to molecular weight as follows [8]:

●Low-MW toxins (MW <500 D)

●Middle-MW toxins (500 to 15,000 D), referred to collectively as "middle molecules" (MMs)

●Large solutes (>15,000 D), frequently classified as large-molecular-weight proteins (LMWPs)

Low-MW molecules, exemplified by urea, contribute to the uremic syndrome since uremic symptoms are improved with conventional hemodialysis using low-flux membranes that principally remove such toxins. In addition, the clearance of urea (as measured by Kt/V urea) correlates with patient outcomes [9].

The question of the relative contributions of retained MMs to uremic symptoms has been debated. However, there is little doubt that several of these compounds are toxic (beta-2 microglobulin, parathyroid hormone [PTH], and others). Beta-2 microglobulin levels, for example, are associated with the development of dialysis-related amyloidosis (DRA) and, possibly, reduced survival. It seems likely that beta-2 microglobulin is a marker for overall MM clearance, including more toxic and as yet unidentified solutes. (See "Dialysis-related amyloidosis".)

Lastly, evidence is accumulating that larger or protein-bound toxins contribute to the high prevalence of cardiovascular disease in ESKD. (See "Uremic toxins".)

Toxin removal — Solute removal during conventional hemodialysis occurs by three different mechanisms:

●Passive diffusion down a favorable concentration gradient

●Convection, where the frictional forces between water and solutes results in the transport of small- and large-MW solutes in the direction of ultrafiltration (ie, solvent drag)

●Adsorption of solutes to the dialysis membrane

The clearance of small solutes during conventional hemodialysis is dependent upon their size, as well as the concentration gradient across the dialysis membrane. As the MW of a solute (including those that are protein bound) increases, removal by diffusion becomes less efficient.

Removal of middle- and large-MW solutes depends upon their plasma concentration, MW, protein binding, length of dialysis, membrane permeability, and the presence of convective transport. Convective dialysis regimens have therefore been developed to exploit the ability of convection to remove larger MW solutes.

CONVECTIVE THERAPIES

Overview of convection — The rate of convective solute transport during dialysis depends upon the sieving coefficient of the solute for a given membrane and the ultrafiltration rate, which in turn depends on the transmembrane pressure (TMP). The sieving coefficient is the ratio of the concentration of the solute in the ultrafiltrate over the plasma. It ranges from 0 (no removal) to 1 (complete removal). As an example, the sieving coefficient for small molecules is 1, while the coefficient for beta-2 microglobulin is 0.6 across high-flux membranes and approaches 1 with some of the newer membranes.

Convective transport is also influenced by secondary membrane formation and concentration polarization [10]:

●Secondary membrane formation is related to the adsorption of proteins on the surface of the membrane and offers resistance to the transfer of both water and solutes.

●Concentration polarization constitutes a layer of increased concentration of a high-molecular-weight (MW) solute close to the membrane, which is created as the specific solute is left behind during ultrafiltration due to its slower transfer rate. As this creates a concentration gradient and flux away from the membrane and towards the center of the hollow fiber, it impedes the convection of other solutes. At the same time, however, it increases the concentration gradient of that particular solute across the membrane, thereby facilitating its removal. Concentration polarization is more prominent with high ultrafiltration rates, low blood flow rates (less washout of the increased concentration layer), and the use of postdilution (rather than predilution) techniques (see below).

High TMP is necessary for convection to take place. The relationship between TMP and ultrafiltration is linear at moderate TMP levels. However, ultrafiltration plateaus or reverses at higher TMP, thereby decreasing convective clearance while increasing the risk to the patient.

Hemofiltration and hemodiafiltration — Intermittent hemofiltration and intermittent hemodiafiltration are two principal chronic kidney replacement modalities that provide substantial removal of larger MW uremic toxins via convection. Daily convective therapy has also been used [11]. (See 'Daily hemofiltration/hemodiafiltration' below.)

●Hemofiltration – With hemofiltration, fluid is removed by the dialysis machine through increased TMP, and the replacement solution is infused intravenously at equal volume, minus the desired fluid volume removal. The clearance for a particular solute is dictated by the ultrafiltration volume and the sieving coefficient. As the sieving coefficient for low-MW unbound solutes equals 1, the clearance for small molecules is equal to the ultrafiltrate volume. Although hemofiltration is relatively effective in the removal of the larger MW solutes, it is relatively less effective (compared with diffusive clearance) in the removal of small molecules as it is restricted by the ultrafiltration volume.

●Hemodiafiltration – In general terms, hemodiafiltration is a combination of hemodialysis and hemofiltration and therefore leverages the enhanced middle molecule (MM) clearance of hemofiltration, while also providing better clearance of small solutes by adding a diffusive component. The EUropean DIALysis (EUDIAL) group proposed a more formal definition for hemodiafiltration that further highlights the central role of replacement fluid.

Hemodiafiltration is a blood purification therapy that combines diffusive and convective solute transport using a high-flux membrane characterized by an ultrafiltration coefficient greater than 20 mL/hour per mmHg/m² and a sieving coefficient (S) for beta2-microglobulin of greater than 0.6. Convective transport is achieved by an effective convection volume of at least 20 percent of the total blood volume processed. Appropriate fluid balance is maintained by external infusion of a sterile, nonpyrogenic solution into the patient's blood [12]. (See "Technical aspects of hemodiafiltration".)

Chronic hemofiltration and hemodiafiltration schedules are similar to conventional dialysis regimens, with three sessions per week of three to five hours' duration. A typical conservative (or high-dose) regimen for hemodiafiltration includes a postdilution configuration with a blood flow of 300 mL/min (500 mL/min for high dose), a dialysate flow of 500 mL/min, a substitution fluid infusion rate of 60 mL/min (120 mL/min for high dose), and a high-flux dialyzer of 1.4 m² (2.2 m² for high dose) [13].

Continuous kidney replacement therapies utilizing convection are also used in the intensive care setting for the treatment of acute kidney injury (AKI). These modalities are discussed separately. (See "Continuous kidney replacement therapy in acute kidney injury", section on 'Definition of CKRT modality'.)

Substitution fluid infusion methods — Replacement fluid can be infused before (predilution mode) or after the dialyzer (postdilution mode) in both hemofiltration and hemodiafiltration. A combination of the two configurations, mid-dilution, provides better results than predilution and is technically more feasible than postdilution hemodiafiltration. [14,15]. A large ultrafiltrate volume is generated across a membrane with high hydraulic permeability.

There are important trade-offs with the pre- and postdilution substitution fluid infusion modes [11]. These are discussed elsewhere. (See "Technical aspects of hemodiafiltration", section on 'Modes of infusion of replacement fluid'.)

Other configurations — A number of alternate configurations have been described:

●Hemofiltration with back-filtration consists of two filters in series: one for fluid removal and one for fluid reinjection [16].

●In the "push-pull" hemodiafiltration technique, the same filter is used for ultrafiltration and back-filtration sequentially [17,18]. The rate of ultrafiltration has to be much higher to compensate for the time lost during back-filtration.

For reasons explained in the next section, "on-line" substitution fluid production is standard practice.

Substitution fluid — Initially, sterile Ringer's lactate solution was used as a substitution fluid for hemodiafiltration. More recently, bicarbonate-based solutions have been adopted. With these solutions, acetate, which is sometimes used in acid concentrates, is converted in vivo into bicarbonate.

Isotonic sodium bicarbonate has also been used in hemofiltration/hemodiafiltration (so-called acetate-free biofiltration [AFB]), with reports of improved hemodynamic stability [19-22].

With the evolution of hemofiltration/hemodiafiltration, there has been a tendency to prescribe larger substitution fluid volumes. This initially led to concerns of higher costs and greater risk of microbiologic contamination. Exposure to large fluid volume was of particular concern with back-filtration and push-pull hemofiltration techniques, in which dialysate crosses the membrane, thus increasing the risk of exposing patients to pyrogenic substances.

These concerns created the impetus to generate "ultrapure" dialysate, largely through the use of additional ultrafilters. These have been incorporated into standard hemodialysis equipment to facilitate "on-line" substitution fluid generation and are therefore available for use with conventional hemodialysis as well. These refinements are predicated on the growing concern that exposure to bacterial components not only can cause pyrogenic reactions, but also low-grade inflammation that may contribute to the atherosclerosis, malnutrition, and poor outcomes for patients on dialysis [23].

The meaning of the term "ultrapure" has evolved over the last two decades [24]. The microbiologic standards adopted by the American Association for the Advancement of Medical Instrumentation (AAMI) for water for dialysis are <200 colony-forming units (CFUs) and <0.5 endotoxin units (EU)/mL. The more stringent standards of the European Pharmacopoeia include <100 CFU and <0.25 EU/mL, respectively. (See "Ultrapure dialysis fluid".)

Subsequently adopted definitions require <0.1 CFU and <0.03 EU/mL for a solution to be considered "ultrapure." As compared with standard dialysis fluid, this translates into a threefold logarithmic difference in bacterial content and a onefold logarithmic difference in endotoxin content [24]. Some investigators suggest an even lower number for CFU and endotoxin levels for the substitution fluid to be used for hemofiltration/hemodiafiltration [24].

The technique of "on-line" fluid production (initially termed cold sterilization) has allowed the production of an unlimited volume of "pure" substitution fluid at a cost close to that of dialysate for conventional hemodialysis [25-27]. The first step of the process includes the filtration of the water after it is produced using the reverse osmosis technique. The water is then used for the production of dialysate. This step has also been adopted in several hemodialysis machines to produce dialysate of improved purity for hemodialysis. The second step includes further filtration of the dialysate. Finally, a third filtration by a disposable microfilter completes the creation of the substitution solution. The disposable microfilter is replaced at the end of dialysis. The dialysate prior to the last filtration is used for the diffusive element of hemodiafiltration. The purity achieved using this approach has been repeatedly confirmed [27,28].

In most dialysis systems, the substitution solution volume is subtracted from the produced total dialysate volume. Increasing ultrafiltration and the need for substitution solution volume therefore improves convective efficacy but decreases the diffusive efficacy of the system. A balance between the two is needed while keeping substitution volumes greater than 23 L per session [12,29-34].

Major factors that place an upper limit on exchange volumes include blood flow rate and treatment time, while albumin and hematocrit play a minor role [31,35]. The use of a dialysis catheter can limit blood flow, and high exchange volumes can therefore be achieved by increasing the dialysis time.

Membranes — Membrane properties have evolved over time. Membranes with larger pores were developed to enhance large-molecule clearance but resulted in albumin loss. Although loss of albumin can increase the removal of albumin-bound solutes [36], it is undesirable during convective therapy.

Newer technologies have led to the creation of asymmetrical membranes, which allow the removal of larger molecules (not including albumin) and molecules like phosphorus and beta-2 microglobulin [37]. In addition, the need for a narrow fiber lumen to facilitate back-filtration (and therefore add a convective element to hemodialysis) was eliminated by the development and availability of low-cost sterile substitution solutions at volumes that make back-filtration unnecessary [38]. The sieving coefficient of larger molecules has increased with newer membranes, approaching that of the glomerular membrane [39,40].

BIOCHEMICAL EFFECTS OF CONVECTIVE THERAPIES — Historically, there have been three purported benefits of convective therapies over conventional hemodialysis:

●The increased removal of larger molecules

●The use of high-flux biocompatible membranes (which decreases cytokine release) [41,42]

●The use of ultrapure dialysate (which decreases cytokine release and introduces fewer impurities) [43,44]

However, high-flux membranes and ultrapure dialysate are now widely available at a minimal cost and are used for conventional hemodialysis. In addition, with conventional hemodialysis, there is an element of convection through "back-filtration" when high-flux membranes with narrow fibers are used, although the degree of convective clearance is typically less with conventional hemodialysis.

Thus, the differences between the diffusive and convective technologies have become somewhat blurred. This becomes an issue when designing studies to compare these modalities. However, the more recent move towards high-volume substitution fluid with hemodiafiltration has served to yet again differentiate convective therapies from the conventional dialysis paradigm [11].

Solute removal

Urea and creatinine — Small-molecule clearance is usually lower with hemofiltration as it is limited by the ultrafiltration volume when compared with conventional hemodialysis or hemodiafiltration. By comparison, small-molecule removal is increased with the use of high-efficiency on-line hemodiafiltration and can be similar or even higher than hemodialysis, depending on the volume of the substitution solution [45-47]. In the European Dialysis Outcomes and Practice Patterns Study (DOPPS), for example, patients on high-efficiency (15.0 to 24.9 L substitution fluid per session), thrice-weekly hemodiafiltration had higher Kt/V urea levels than those on hemodialysis [46].

Beta-2 microglobulin — A majority of studies have suggested better removal of beta-2 microglobulin with convective techniques as compared with conventional hemodialysis [13,48-54].

This has been further supported by two meta-analyses [55,56]. Whether this translates into a clinical benefit for patients is not known.

Phosphate — Increased phosphate control by convective techniques has been reported [57-60]. In one study, although urea and creatinine clearance was similar with hemodiafiltration and hemodialysis, phosphate clearance was higher on hemodiafiltration [57]. In a second report, phosphate removal increased when patients were converted from hemodialysis to hemodiafiltration [58]. There was slow phosphate mobilization from tissue compartments as predialysis serum phosphate levels did not change until a few months after the switch. In the randomized, crossover trial cited above, serum phosphate levels were lower among patients treated with hemodiafiltration compared with low-flux hemodialysis (4.6 versus 5 mg/dL, respectively), despite lower daily doses of the phosphate-binding agent, sevelamer [47]. Parathyroid hormone (PTH) levels were also shown to be lower among hemodiafiltration patients in this study (202 versus 228 pg/mL in hemodialysis patients). However, since high-flux membranes are almost universally used on conventional hemodialysis today, it is unclear if the effect is due to the membrane characteristics or the use of convective techniques.

Despite the beneficial effect on phosphate removal, patients undergoing convective therapy still require phosphate binders, although at possibly a lower dose.

Other molecules — Levels of homocysteine and complement D factor are decreased with hemofiltration [50,61]. By comparison, there are conflicting data concerning the effect of hemofiltration on levels of leptin and advanced glycation end products (AGEs) [50,61-64]. There is also evidence that convective therapies are associated with less oxidative stress, but no difference in inflammatory markers were found between hemodiafiltration and low-flux hemodialysis [65,66]. Despite high large molecule removal by hemodiafiltration, there is no significant effect on protein bound toxin concentration [67,68]. Further studies are needed to determine whether changes in serum concentration or solute removal translate into improved clinical outcomes.

CLINICAL EFFECTS OF CONVECTIVE THERAPIES

Cardiovascular effects

Hemodynamic stability — Improved hemodynamic tolerance can be an advantage of convective therapies over conventional hemodialysis. Many [69-73], but not all [74-76], studies have supported this view. Three meta-analyses and one trial have shown that convective therapies reduce hypotension [54-56,77].

Potential mechanisms for improved hemodynamic stability include:

●Salt loading via substitution fluid administration (with a loss of relatively hypotonic fluid) [78].

●Decreased core body temperature (as a result of infusion of large amounts of fluid of lower temperature), leading to vasoconstriction [79,80].

●It has been suggested that ultrapure dialysate itself is associated with improved hemodynamic stability [81,82]. This may be due to reduced vasodilatation because of the lack of inflammation or exposure to pyrogens [81,82].

In summary, convective techniques may be associated with better intradialytic stability, although the benefit may not be due to convection itself.

Hypertension — Although there were claims in the earlier literature of better blood pressure control with convective therapies [83,84], there are no convincing data from randomized, controlled studies that convective therapies offer better blood pressure control [61].

Cardiac hypertrophy — There is conflicting evidence on the effect of convective therapies on the regression of left ventricular hypertrophy (LVH). In a multicenter, randomized, controlled trial, predilution hemofiltration (18 patients) resulted in greater regression of LVH compared with the control group (16 patients), dialyzed using low-flux hemodialysis [85]. In another randomized trial of patients on low-flux hemodialysis and predilution hemofiltration, there was no difference in cardiovascular parameters, including left ventricular mass index (LVMI), over one year [61]. However, daily hemodiafiltration may be associated with regression of LVMI, suggesting a benefit with increased frequency rather than increased convection alone [86]. (See 'Daily hemofiltration/hemodiafiltration' below.)

Hematological parameters — The effect of convection-based regimens on anemia has been variable. Several nonrandomized studies and one randomized trial found either improvement in hemoglobin or a decrease in erythropoietin (EPO) dose requirements on hemodiafiltration [48,87-90]. By comparison, two randomized, controlled trials failed to demonstrate any improvements in these parameters with hemodiafiltration [61,91].

It is conceivable that the use of ultrapure dialysate may reduce EPO resistance by improving the cytokine profile [92]. Favorable effects on serum levels of inflammatory molecules have been observed with ultrapure dialysate [93,94]. Several studies have demonstrated the need for lower doses of ESAs for maintenance of target hemoglobin levels [94,95]. This beneficial effect, however, was not seen in a randomized, controlled trial when low-flux dialyzers were used [96].

Thus, the beneficial effect of convective therapies on anemia control, beyond the benefits of the use of ultrapure dialysate, has not been proven. Larger studies are needed to better evaluate this particular outcome issue.

Platelet activation, as measured by the expression of CD62p, was more pronounced and more protracted during hemodiafiltration than during low-flux hemodialysis in the Convective Transport Study (CONTRAST) [97,98]. It is unclear if this has potentially negative effects.

Quality of life — Compared with hemodialysis, quality of life (QOL) generally appears to be superior with convective therapies [61,99,100]:

●In one randomized, controlled trial, QOL based upon the Laupacis questionnaire improved on hemofiltration versus low-flux hemodialysis [61].

●In a meta-analysis, QOL appeared to be significantly improved in patients on hemodiafiltration therapy compared with those on hemodialysis therapy when an unvalidated tool was used but did not improve when validated QOL assessment tools were used [101].

Nutrition — Conflicting data exist concerning the relative effects of convective therapies on nutrition [61,91]. In one randomized, controlled study, there was an increase in lean body mass and body weight over one year in those undergoing hemofiltration as compared with no change in the group undergoing low-flux hemodialysis, although the difference was not statistically significant [61]. In another study, there was no difference in body weight albumin, skin-fold thickness, or albumin between those undergoing low-flux hemodialysis and hemodiafiltration [91]. Therefore, further studies are needed to demonstrate improvement in the nutritional status on convective therapies. No differences were found in micronutrient loss between hemodiafiltration and hemodialysis [102]. Significant loss of vitamin C was reported on hemodiafiltration [103].

Neuropathy — Hemodiafiltration has not been shown to improve neuropathy in patients with ESKD. In the FINESSE trial, which randomly assigned 124 patients on maintenance hemodialysis with neuropathy to either hemodiafiltration or high-flux hemodialysis for 48 months, there was no difference in the progression of neuropathy between the two arms [104]. Convection volume in the hemodiafiltration arm was a median of 24.7 L (interquartile range, 22.4 L to 26.5 L).

Dialysis-related amyloidosis — Treatment with the convective therapies has not been shown to reduce the complications of dialysis-related amyloidosis (DRA), such as carpal tunnel syndrome (CTS). However, at least one retrospective study has suggested that the use of high-flux membranes (versus low flux) with conventional hemodialysis was associated with a lower risk of developing CTS over time [105].

As yet, enhanced clearance via hemofiltration/hemodiafiltration has not translated into improvements in DRA. However, it is reasonable to use convective therapies, where available, for treating this condition. No evidence-based recommendations can yet be made as to what level of beta-2 microglobulin should be considered a threshold for initiating convective therapy, where available, for the management of this condition. (See "Dialysis-related amyloidosis".)

Hospitalization rates — Limited data describing hospitalization rates and length of stay with hemofiltration/hemodiafiltration have been reported. One study that followed 45 patients for two years on hemodiafiltration failed to demonstrate any difference in hospitalization rates as compared with over 300 patients treated with hemodialysis [74], while another crossover study showed fewer (8 versus 17) hospitalizations on convective therapy as compared with hemodialysis [22]. In the Estudio de Supervivencia study de Hemodiafiltración Online (ESHOL) trial, hospitalization rates were lower in the hemodiafiltration group compared with controls [106]. Larger-scale studies will be required to address the impact of the convective therapies on hospitalization rates.

Mortality — Mortality data comparing convective therapies with hemodialysis are conflicting. Some but not all studies report that high-dose hemodiafiltration compared with conventional hemodialysis may confer a mortality benefit in at least some patient subsets [33,46,74,86,91,98,100,101,104,106-114]. Five randomized trials have been published:

●The CONTRAST trial randomly assigned 714 patients to either hemodiafiltration with an average substitution volume of approximately 19 L or low-flux hemodialysis over three years [98]. No differences in patient mortality rates were observed. A post-hoc analysis suggested decreased mortality with substitution volume more than 20 L (hazard ratio [HR] 0.61, 95% CI 0.38-0.98).

●The Turkish OL-HDF trial randomly assigned 782 patients to either hemodiafiltration or high-flux hemodialysis over two years [111]. There were no between-group differences in all-cause or cardiovascular mortality. In a post-hoc analysis, substitution volumes of more than 17 L were associated with better cardiovascular and overall survival compared with high-flux hemodialysis (HR 0.70, 95% CI 0.46-1.08).

●The ESHOL trial randomly assigned 906 patients to either hemodiafiltration with more than 20 L of convective volume per session or high-flux hemodialysis [106]. At a follow-up of three years, patients treated with on-line hemodiafiltration had a 30 percent lower risk of all-cause mortality (HR 0.70, 95% CI 0.53-0.92), a 33 percent lower risk of cardiovascular mortality (HR 0.67, 95% CI 0.44-1.02), and a lower incidence of hypotension and rates of hospitalization.

●The FRENCHIE study randomly assigned 381 older adults (>65 years of age) to hemodiafiltration or high-flux hemodialysis and found no difference in survival between the groups [77].

●The CONVINCE study was a pragmatic trial that randomly assigned 1360 patients to either high-dose hemodiafiltration (convection volumes of at least 23 L per session) or high-flux hemodialysis [114]. At a median follow-up of 30 months, all-cause mortality was lower in the hemodiafiltration group compared with the hemodialysis group (17 percent versus 22 percent; HR 0.77, 95% CI 0.65-0.93), though the mortality benefit of hemodiafiltration was limited to patients without preexisting cardiovascular disease or diabetes mellitus. Although COVID-19 may have complicated determining the cause of death in this trial, the benefit associated with hemodiafiltration appeared predominantly due to a reduction in deaths from infection rather than from cardiovascular disease.

However, these trials had a number of methodologic issues, including the exclusion of patients with poor prognosis, which may limit their generalizability [30]. Other issues included the following:

●In ESHOL and CONVINCE, the randomized groups were imbalanced. In ESHOL, the hemodiafiltration group was younger, had a lower comorbidity index, and had a higher proportion of fistula compared with catheter use. In addition, patients who could not achieve a hemofiltration volume of more than 18 L were excluded after randomization; such patients may have had poor fistulas due to vascular disease. In CONVINCE, the hemodiafiltration group at baseline had lower rates of cardiovascular disease, diabetes mellitus, and current smoking compared with the hemodialysis group.

●In the Turkish hemodiafiltration study, the control patients were not treated with ultrapure dialysate.

●In CONTRAST and the Turkish trial, the correlation of outcomes with ultrafiltration volume was done post hoc. An additional limitation is that significant crossover and dropout rates also could have introduced bias into these trials.

In contrast to the CONVINCE trial, which did not identify a reduction in cardiovascular mortality, several meta-analyses suggested that hemodiafiltration may have a larger effect on cardiovascular mortality than on all-cause mortality [54-56,115-117]:

●One meta-analysis including 29 crossover and 36 parallel-arm studies showed that, compared with low-flux hemodialysis, high-flux hemodialysis, hemofiltration, and hemodiafiltration decreased cardiovascular mortality (relative risk [RR] 0.84, 95% CI 0.71-0.98) but not all-cause mortality [54]. However, only a small proportion of included studies directly examined hemofiltration (n = 274) and hemodiafiltration (n = 1288); most of the included studies were of high-flux hemodialysis (n = 3204). In addition, a high dropout rate introduced a significant risk of bias.

●Another meta-analysis including 35 trials that compared convective therapies (including hemodiafiltration, hemofiltration, and acetate-free biofiltration) with low- or high-flux hemodialysis found that convective therapies had little or no effect on all-cause mortality, may have reduced cardiovascular mortality (RR 0.75, 95% CI 0.58-0.97), and had an uncertain effect on nonfatal cardiovascular events [56].

●An updated Cochrane review included 40 studies published up to February 2015 [116]. Convective dialysis had no significant effect on all-cause mortality (11 studies, 3396 participants; RR 0.87, 95% CI 0.72-1.05), but significantly reduced cardiovascular mortality (six studies, 2889 participants; RR 0.75, 95% CI 0.61-0.92). Convective therapies significantly reduced predialysis levels of beta-2 microglobulin (12 studies, 1813 participants; 95% CI -9.11 to -1.98) and increased dialysis dose (Kt/V urea; 14 studies, 2022 participants; 95% CI -0.00 to 0.14) compared with diffusive therapy. The review was criticized as having combined studies with significant differences in substitution solution volumes.

Trends in utilization of convective techniques — The utilization of convective therapies has been variable. Between 1998 and 2001, approximately 14 percent of patients were on hemodiafiltration in the European countries participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) [46,118]. In Australia and New Zealand, the incidence rate of patients starting on hemodiafiltration between 2000 and 2014 was approximately 15 and 19 percent, respectively [119]. The prevalence rate in December 2019 was 36 and 21 percent, respectively [120].

There remains almost no utilization of intermittent convective therapies for chronic kidney replacement therapy in North America. The reason for the lack of penetration in North America is a combination technical complexity, cost, and limited quality of evidence [121].

Cost — Although the cost of providing convective therapies has decreased with the availability of the on-line substitution fluid production, there are only limited cost-effectiveness data comparing the convective techniques with conventional hemodialysis [122-124]. Such data will likely be a necessary prerequisite for the widespread adoption of these techniques.

Summary — The published literature suggests that there are benefits from the use of convective technologies. They include biochemical, as well as clinical, benefits:

●The main biochemical benefits over conventional hemodialysis include enhanced clearance of middle molecules (MM) such as beta-2 microglobulin, as well as phosphate, and, depending on the technique, other small molecules.

●The main clinical benefits include hemodynamic stability, possibly improved QOL, and a delay in the development of DRA. Benefits on anemia and blood pressure control are less well documented. There is some evidence that the patient mortality rates are lower on convection therapies, especially using high volume of substitution solutions (>23 L over a four-hour session), but the quality of this evidence is limited by risk of bias.

In environments with sufficient experience with these methods, they can be used as an alternative to conventional hemodialysis without much difficulty. Where available, it seems reasonable to use these therapies in the settings in which they are most likely to be beneficial, such as in patients with hemodynamic instability and, possibly, with DRA.

In North America, experience with the convective therapies is still fairly limited. In view of data showing a potential survival benefit of hemodiafiltration, it may be time to re-evaluate the role of convective techniques [11,34,125]. Availability of easy-to-use machines and decreasing cost may gradually lead to increased adoption.

DAILY HEMOFILTRATION/HEMODIAFILTRATION — Although not commonly performed for chronic therapy, daily convective therapy may provide significant benefits. Based upon theoretical models and calculations in different studies, some conclusions may be inferred regarding the relative clearance of different substances with daily convective therapy. In one study, a theoretical model was developed to predict dialysis dosing offered by short daily hemofiltration using 15 L of substitution solution [126]. This choice of fluid volume was made to allow for financially sustainable use of hemofiltration on a daily basis using a prepackaged solution at home.

The investigators used either equivalent renal urea clearance (EKR) or standardized Kt/V (stdKt/V) as the dose measure for different molecular-weight (MW) solutes (urea, creatinine, vitamin B12, inulin, and beta-2 microglobulin) and for different therapies (conventional high-flux hemodialysis, short daily hemofiltration, short daily hemodialysis, continuous ambulatory peritoneal dialysis [CAPD], and daily nocturnal hemodialysis) [126-128]. Results were as follows:

●When stdKt/V was used as a dialysis dose measure for small molecules, daily hemofiltration was equivalent to conventional hemodialysis and CAPD but inferior to short daily hemodialysis and nocturnal hemodialysis.

●When stdKt/V as a dialysis dose measure was used for the larger molecules, hemofiltration was better than all the regimens except for nocturnal hemodialysis.

●When EKR was used, daily hemofiltration was inferior to conventional or daily hemodialysis for small molecules but still better for larger molecules.

In a second study, seven times per week hemofiltration (at two hours per session) was required to achieve a predialysis urea similar to that achieved with hemodialysis performed thrice weekly for four hours [129]. This is consistent with the lower small-molecule clearance offered by hemofiltration when compared with hemodialysis. However, a six times a week, two-hour session would provide lower pretreatment beta-2 microglobulin levels than three times a week hemodialysis.

Clinical studies — Several small studies using daily hemofiltration/hemodiafiltration have been published [53,130-134]. Some of the measured outcomes included beta-2 microglobulin levels, blood pressure control, quality of life (QOL), phosphate control, and growth in children. As examples:

●One short-term study reported a 40 percent decrease in beta-2 microglobulin with daily hemofiltration [53].

●In one study in which 12 patients switched from hemodialysis to hemofiltration at home on a daily basis for one month, hemofiltration was associated with a lower blood pressure, higher caloric intake, and improved QOL, findings consistent with previous reports on short daily hemodialysis [132,134]. A trend toward a decrease in serum beta-2 microglobulin could be safely ascribed to the hemofiltration alone. The infusion volume used was 40 percent of total body water, which offered a standard Kt/V of approximately 2.

●In another study of eight patients undergoing in-center daily hemodiafiltration for six months, there were lower serum levels of predialysis blood urea nitrogen (BUN) and creatinine (which were expected by the change to a daily schedule), as well as lower levels of other solutes, including beta-2 microglobulin and homocysteine [130]. Additional benefits included improved phosphate control, discontinuation of all antihypertensive agents, and a 30 percent regression in left ventricular mass. Although some of these results can be attributed to the daily treatment schedule, the decrease in the pretreatment levels of beta-2 microglobulin and the improvement in phosphate control are clearly attributable to both convection and the increased treatment frequency.

Daily hemodiafiltration has been used successfully in children [135,136]. Clinical results have been positive, including a favorable effect on growth.

SORBENTS — The earliest sorbent technologies, developed in the 1960s, relied primarily upon activated charcoal, which needed to be separated from the blood compartment due to its incompatibility with blood. Since clearance of water, urea, and inorganic ions was limited, it could only be used as an adjunct to dialysis.

Dialysate regeneration and more elaborate sorbent systems had evolved by the 1970s in the form of the REcirculating DialYsis (REDY) System [137]. Uremic solutes were metabolized or adsorbed by a sorbent cartridge. The main advantages of this method were that there was no need for water and it was portable. It has been used in the hospital setting, as well as at home and when traveling. It represented the best choice for the military, as well as in case of natural disasters, when access to large volumes of water for dialysate production can be limited.

The sorbent cartridge included five layers:

●An activated carbon layer, which adsorbed nitrogenous waste products

●A glucose hydrous zirconium layer, which is an anion exchanger (acetate was exchanged for phosphate, fluoride, and heavy metals)

●A zirconium phosphate layer, which was a cation exchanger (Na+ and H+ were exchanged for ammonium, Ca+2, Mg+2, and K+)

●A urease layer (urease, bound to aluminum oxide, catalyzes the conversion of urea into ammonia and carbamic acid)

●A purification layer (activated carbon removes particulate matter, heavy metals, and oxidizing substances)

The REDY System was eventually abandoned because of aluminum leaching. (See "Choosing home hemodialysis for end-stage kidney disease".)

Adsorption is a physicochemical process in which molecules are bound to sorbent particles or porous surfaces either through a chemical or physical process. It is heavily dependent on pore structure. The pore size is divided into macro (>500 A), meso (20 to 500 A), and micro (<20 A) sizes.

Removal of larger-molecular-weight (MW) substances has focused on sorbents containing mesopores. Activated charcoal contains only a small number of mesopores compared with synthetic resin adsorbents, which are the preferred materials.

Newer sorbents have also been used in the form of a cartridge connected in series with a dialyzer to adsorb larger-MW toxins such as beta-2 microglobulin, angiogenin, leptin, and cytokines [138-140]. The Lixelle device has been used in Japan to adsorb beta-2 microglobulin [141]. Reduced symptoms of dialysis-related amyloidosis (DRA) as well as a limited reduction in bone cysts on radiographs and short-lived reduction of inflammatory cytokines, endotoxin, and peptidoglycans have been reported. The cost of the treatment using Lixelle is high. In Japan, coverage of this treatment is granted for up to one year. This sorbent device was also found to adsorb cytokines, endotoxin fragments, and microbial fragments.

The main clinical use of sorbents is as part of the wearable artificial kidney and sorbent-based peritoneal dialysis [142,143].

Although oral sorbents were considered in the treatment of ESKD in the past [144-146], no efficient commercial application exists to date. There is still interest in this area in the form of biochemically active microcapsules [99].

The future use of sorbents as an adjunct to the kidney replacement therapy depends upon the clinical results from ongoing studies and on the added cost of this treatment.

EXPERIMENTAL TECHNOLOGIES

Renal tubule assist device — Kidney replacement therapy in its current forms does not replace the metabolic and endocrine functions of the renal tubular cells. In the setting of acute tubular necrosis, for example, proximal tubular function is lost. It is therefore desirable to provide not only the small solute clearance conferred by traditional dialytic modalities, but also some supportive cell function.

Within the last decade, human proximal renal tubular cells have been successfully cultured on hollow-fibre scaffolds, and a renal tubule cell assist device (RAD), used in series with a hemofiltration circuit, has been developed. The RAD can replace metabolic and endocrine functions, including improved acid-base balance (via glutamine metabolism) and activation of vitamin D, in acutely uremic dogs [147].

The effectiveness and safety of RAD therapy was evaluated in an open-label, phase-II trial of 58 patients with acute kidney injury (AKI) who were randomly assigned (2:1 ratio) to receive RAD (up to 72 hours) plus continuous venovenous hemofiltration or continuous venovenous hemofiltration alone [148]. There was a nonsignificant trend toward improved survival at 28 days (primary endpoint) with RAD plus continuous venovenous hemofiltration (67 versus 39 percent for continuous venovenous hemofiltration alone). Limitations of the study include low frequency of completion of the planned 72 hours of RAD, as-treated primary analysis, reporting of multiple outcomes, and low statistical power [149].

Despite these limitations, this innovation may eventually represent a significant advance in the management of AKI. The main technological limitations for commercialization of devices providing a cell-based kidney replacement therapies are the lack of consistent source of cells and of cost-effective manufacturing, storage, and distribution processes [150].

Cell sourcing and storage/distribution issues may be addressed through the development of the Bioartificial Renal Epithelial Cell System (BRECS). The BRECS cultures renal epithelial cells onto a cell scaffold made of porous niobium-coated carbon disks until there are approximately 108 cells [151]. Cryopreservation would allow storage for use for acute indications [150]. An implantable assist device would use the RAD technology along with a scaffold composed of ultrathin nanopore membranes using microelectromechanical systems (MEMS) technology [151].

Implantable artificial kidney (IAK) — This experimental technology incorporates nanotechnology and tissue engineering [152]. It contains a "HemoCartridge" and a "BioCartridge." The IAK is connected to an artery and a vein, and drains "urine" into the urinary bladder. The HemoCartridge includes a nanofilter with pores that are highly specialized to retain or allow passage of specific molecules. It operates by arterial pressure, without need for a pump or use of anticoagulants. The BioCartridge contains live tubular cells on a silicon membrane, grown using progenitor cells harvested from cadaveric kidneys. Its main function is to reabsorb water and electrolytes. The system is not immunogenic as blood is not in direct contact with the cells. A creatinine clearance of approximately 30 mL/min is expected. It has been implanted in animals. Main challenges will be thrombosis and the need to periodically replace the BioCartridge.  

Wearable artificial kidney (WAK) — A WAK is a battery-operated device that contains an adsorption cartridge and is worn as a belt [153-156]. It weighs approximately two pounds. Using a hollow fiber dialyzer, dialysate is continuously regenerated by cartridges that contain sorbents. In a pilot study, eight patients with ESKD who wore the WAK for four to eight hours had a mean plasma urea and creatinine clearance rate of 23 and 21 mL/min, respectively [154]. The device was well tolerated, but clotting of the circuit was noted in two patients [156].

Wearable peritoneal dialysis artificial kidney (WAK PD or AWAK) — A wearable device using sorbents to regenerate peritoneal dialysis fluid has been developed. It is a tidal dialysis system with a tidal volume of 500 mL of dialysate. This dialysate is then drained, pumped through a sorbent cartridge, filtered, degassed, and supplemented with electrolytes and glucose before it is returned into the peritoneal cavity. WAK PD performs eight exchanges per hour, delivering a urea clearance of approximately 30 mL/min. Its cartridge needs to be replaced every seven hours [142,143].

SUMMARY AND RECOMMENDATIONS

●Overview – Due largely to the strikingly high mortality rate of patients on conventional intermittent hemodialysis, significant attention has turned to new and innovative forms of kidney replacement therapy. These principally include hemodiafiltration, sorbent hemodialysis, and the use of bioartificial membranes. (See 'Introduction' above.)

●Solute removal – Solute removal during conventional hemodialysis occurs by three different mechanisms: passive diffusion, adsorption of solutes to the dialysis membrane, and convection. Removal of middle- and large-molecular-weight (MW) toxins depends upon certain characteristics, including convection. Convective dialysis regimens have therefore been developed to exploit the ability of convection to remove larger MW solutes. (See 'Toxin removal' above.)

●Convective therapies

•The two principal regimens used to provide convection are intermittent hemofiltration and intermittent hemodiafiltration. Substitution fluid can be infused before (predilution mode) or after the dialyzer (postdilution mode) in both hemofiltration and hemodiafiltration. A generally useful approach is to use predilution in hemofiltration and postdilution in hemodiafiltration, aiming for the maximum volume of fluid exchange in both cases. (See 'Hemofiltration and hemodiafiltration' above.)

•Benefits with convective therapies compared with conventional hemodialysis are better removal of beta-2 microglobulin and improved hemodynamic stability and possibly better cardiovascular outcome and patient survival, especially if the replacement fluid volume exceeds 23 L per session. Convective therapies are rarely used for chronic kidney replacement therapy in the United States. (See 'Mortality' above.)

●Sorbents – Sorbent technologies rely on a physicochemical process where molecules are bound to sorbent particles or porous surfaces either through a chemical or physical process. Sorbents are used in the form of a cartridge connected in series with a dialyzer to adsorb larger-MW toxins. The main function of sorbents is to regenerate spent dialysate. This sorbent application may play a role in the development of a wearable artificial kidney (WAK) and peritoneal dialysis (WAK PD). (See 'Sorbents' above.)

●Other experimental technologies – Experimental technologies include a renal tubule assist device (RAD) used in series with a hemofiltration circuit. The use of cell-based kidney replacement therapy technologies may be part of the development of an implantable artificial kidney (IAK). The latter uses silicon nanotechnology and tissue engineering. (See 'Renal tubule assist device' above and 'Implantable artificial kidney (IAK)' above.)

ACKNOWLEDGMENT — We are saddened by the death of Andreas Pierratos, MD, FRCPC, who passed away in November 2022. UpToDate acknowledges Dr. Pierratos's past work as an author for this topic.