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Background and Objective: The SC+ haemodialysis system developed by Quanta Dialysis Technologies is a small, easy-to-use dialysis system designed to improve patient access to self-care and home haemodialysis. A prototype variant of the standard SC+ device with a modified fluidic management system generating a pulsatile push-pull dialysate flow through the dialyser during use has been developed for evaluation. It was hypothesized that, as a consequence of the pulsatile push-pull flow through the dialyser, the boundary layers at the membrane surface would be disrupted, thereby enhancing solute transport across the membrane, modifying protein fouling and maintaining the surface area available for mass and fluid transport throughout the whole treatment, leading to solute transport (clearance) enhancement compared to normal haemodialysis (HD) operation., Methods: The pumping action of the SC+ system was modified by altering the sequence and timings of the valves and pumps associated with the flow balancing chambers that push and pull dialysis fluid to and from the dialyser. Using this unique prototype device, solute clearance performance was assessed across a range of molecular weights in two related series of laboratory bench studies. The first measured dialysis fluid moving across the dialyser membrane using ultrasonic flowmeters to establish the validity of the approach; solute clearance was subsequently measured using fluorescently tagged dextran molecules as surrogates for uraemic toxins. The second study used human blood doped with uraemic toxins collected from the spent dialysate of dialysis patients to quantify solute transport. In both, the performance of the SC+ prototype was assessed alongside reference devices operating in HD and pre-dilution haemodiafiltration (HDF) modes., Results: Initial testing with fluorescein-tagged dextran molecules (0.3 kDa, 4 kDa, 10 kDa and 20 kDa) established the validity of the experimental pulsatile push-pull operation in the SC+ system to enhance clearance and demonstrated a 10 to 15% improvement above the current HD mode used in clinic today. The magnitude of the observed enhancement compared favourably with that achieved using pre-dilution HDF with a substitution fluid flow rate of 60 mL/min (equivalent to a substitution volume of 14.4 L in a 4-hour session) with the same dialyser and marker molecules. Additional testing using human blood indicated a comparable performance to pre-dilution HDF; however, in contrast with HDF, which demonstrated a gradual decrease in solute removal, the clearance values using the pulsatile push-pull method on the SC+ system were maintained over the entire duration of treatment. Overall albumin losses were not different., Conclusions: Results obtained using an experimental pulsatile push-pull dialysis flow configuration with an aqueous blood analogue and human blood ex vivo demonstrate an enhancement of solute transport across the dialyser membrane. The level of enhancement makes this approach comparable with that achieved using pre-dilution HDF with a substitution fluid flow rate of 60 mL/min (equivalent to a substitution volume of 14.4 L in a 4-hour session). The observed enhancement of solute transport is attributed to the disruption of the boundary layers at the fluid-membrane interface which, when used with blood, minimizes protein fouling and maintains the surface area., Competing Interests: Our commercial affiliation does not alter our adherence of any author to all PLOS ONE policies. Please note that this development is not a commercially available machine so there can be no financial gain and is considered by ourselves as precompetitive research to be shared. From the perspective of intellectual property, please note methods of treatment are not patentable under European law so we do not have competing interests in that regard either.

Background: Compared to high-flux dialysis membranes, novel medium cut-off (MCO) membranes show greater permeability for larger middle molecules., Methods: In two prospective, open-label, controlled, randomized, crossover pilot studies, 39 prevalent hemodialysis (HD) patients were studied in four dialysis treatments as follows: study 1, three MCO prototype dialyzers (AA, BB and CC with increasing permeability) and one high-flux dialyzer in HD; and study 2, two MCO prototype dialyzers (AA and BB) in HD and high-flux dialyzers in HD and hemodiafiltration (HDF). Primary outcome was lambda free light chain (λFLC) overall clearance. Secondary outcomes included overall clearances and pre-to-post-reduction ratios of middle and small molecules, and safety of MCO HD treatments., Results: MCO HD provided greater λFLC overall clearance [least square mean (standard error)] as follows: study 1: MCO AA 8.5 (0.54), MCO BB 11.3 (0.51), MCO CC 15.0 (0.53) versus high-flux HD 3.6 (0.51) mL/min; study 2: MCO AA 10.0 (0.58), MCO BB 12.5 (0.57) versus high-flux HD 4.4 (0.57) and HDF 6.2 (0.58) mL/min. Differences between MCO and high-flux dialyzers were consistently significant in mixed model analysis (each P < 0.001). Reduction ratios of λFLC were greater for MCO. Clearances of α1-microglobulin, complement factor D, kappa FLC (κFLC) and myoglobin were generally greater with MCO than with high-flux HD and similar to or greater than clearances with HDF. Albumin loss was moderate with MCO, but greater than with high-flux HD and HDF., Conclusions: MCO HD removes a wide range of middle molecules more effectively than high-flux HD and even exceeds the performance of high-volume HDF for large solutes, particularly λFLC., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: The accumulation of larger and protein-bound toxins is involved in the uraemic syndrome but their elimination by dialysis therapy remains difficult. In the present study, the impact of the albumin permeability of recently introduced advanced high-flux dialysis membranes on the removal of such substances was tested in haemodialysis and online post-dilution haemodiafiltration., Methods: Two types of polyethersulfone membranes only differing in albumin permeability (referred as PU- and PU+) were compared in eight patients on maintenance dialysis in a prospective cross-over manner. Treatment settings were identical for individual patients: time 229 +/- 22 min; blood flow rate 378 +/- 33 mL/min; dialysate flow rate 500 mL/min; substitution flow rate in haemodiafiltration 94 +/- 9 mL/min. Removal of the protein-bound compounds p-cresyl sulfate (pCS) and indoxyl sulfate (IS) was determined by reduction ratios (RRs), dialytic clearances and mass in continuously collected dialysate. In addition, the elimination of the low-molecular weight (LMW) proteins beta(2)-microglobulin, cystatin c, myoglobin (myo), free retinol-binding protein (rbp) and albumin was measured., Results: Plasma levels of the protein-bound toxins were significantly decreased by all treatment forms. However, the decreases were comparable between dialysis membranes and between haemodialysis and haemodiafiltration. The RRs of total pCS ranged between 40.4 +/- 25.3 and 47.8 +/- 10.3% and of total IS between 50.4 +/- 2.6 and 54.6 +/- 8.7%. Elimination of free protein-bound toxins as assessed by their mass in dialysate closely correlated positively with the pre-treatment plasma concentrations being r = 0.920 (P < 0.001) for total pCS and r = 0.906 (P < 0.001) for total IS, respectively. Compared to haemodialysis, much higher removal of all LMW proteins was found in haemodiafiltration. Dialysis membrane differences were only obvious in haemodialysis for the larger LMW proteins myo and rbp yielding significantly higher RRs for PU+ (myo 46 +/- 9 versus 37 +/- 9%; rbp 18 +/- 5 versus 15 +/- 5%; P < 0.05). Additionally, the albumin loss varied between membranes and treatment modes being undetectable with PU- in haemodialysis and highest with PU+ in haemodiafiltration (1430 +/- 566 mg)., Conclusions: The elimination of protein-bound compounds into dialysate is predicted by the level of pre-treatment plasma concentrations and depends particularly on diffusion. Lacking enhanced removal in online post-dilution haemodiafiltration emphasizes the minor significance of convection for the clearance of these solutes. Compared to LMW proteins, the highly protein-bound toxins pCS and IS are less effectively eliminated with all treatment forms. For a sustained decrease of pCS and IS plasma levels, alternative strategies promise to be more efficient therapy forms.

PUREMA H (referred to as PES) is an innovative dialysis membrane for enhanced low-molecular-weight (LMW) protein removal. The purpose of the study was to prove whether its efficacy in hemodialysis (HD) matches that of online hemodiafiltration (HDF) with conventional high-flux membranes. In a prospective, randomized, cross-over study on eight maintenance dialysis patients, treatment efficacy of HD with PES was compared with online postdilution HDF with the two synthetic high-flux membranes polysulfone (referred to as PSU) and Polyamix (referred to as POX). Apart from the infusion of replacement fluid, which was set at 20% of the blood flow rate of 300 mL/min, operating conditions in HD and HDF were kept identical. Small solute and LMW protein plasma clearances as well as the reduction ratio (RR) of cystatin C and retinol-binding protein were not different between the therapies. HDF with POX resulted in a significantly lower myoglobin RR as compared with HD with PES, and HDF with PSU. A 4% higher beta(2)-microglobulin RR was determined in HDF with PSU (73 +/- 5%) as compared with PES in HD (69 +/- 5%). The albumin loss was below 1 g for all treatments. Despite the fact that simple HD did not fully exploit the characteristics of PES, it achieved essentially similar LMW protein removal and albumin loss as compared with online postdilution HDF with the conventional synthetic high-flux membranes PSU and POX. Therefore, HD with PES may have beneficial effects on the outcome of maintenance dialysis patients similar to high-efficiency HDF.

Background: Mid-dilution haemodiafiltration (HDF) results in an improved middle molecule removal compared with standard HDF. The OLpur MD 190 haemodiafilter represents a new dialyser design exclusively for mid-dilution on-line HDF. Compared with standard haemodialysers, structural changes in the headers allow the infusion of high replacement fluid volumes after a first post-dilution and before a second pre-dilution stage., Methods: We compared in vitro the new device [blood flow (QB) 400 ml/min, substitution flow (QS) 100 and 200 ml/min, dialysate flow (QD) 800 ml/min] with a conventional high-flux dialyser of the same surface area in haemodialysis (HD) (QD 500 ml/min) and post-dilution HDF (at QS 60, QD = 500 ml/min and at QS 100, QD = 800 ml/min) modes. Subsequently, we performed an initial clinical application of the new device in six mid-dilution HDF treatments of five end-stage renal disease patients (QB 400 ml/min, QS 200 ml/min, QD 800 ml/min, treatment duration 205+/-23 min)., Results: In vitro urea and beta2-microglobulin clearances in mid-dilution HDF were, respectively, 309.2+/-5.5 and 144.4+/-15.2 ml/min (QS 100) and 321.6+/-4.1 and 204.9+/-4.1 ml/min (QS 200), compared with 278.6+/- 17.2 and 94.0+/-7.6 ml/min in HD, and 310.8+/-10.2 and 123.0+/-6.5 ml/min (QS 60) and 323.6+/-11.2 and 158.0+/-10.3 ml/min (QS 100) in post-dilution HDF. The in vivo trials showed the clinical utility of the device and confirmed the in vitro data: urea and beta2-microglobulin clearances were, respectively, 324.6+/- 10.9 and 207.9+/-29.3 ml/min, while reduction ratios were 75.0+/-5.5 and 83.6+/-4.7%., Conclusion: Our preliminary results need confirmation in a prospective cross-over study. However, the Nephros MD 190 haemodiafilter promises to be a true technological step ahead in terms of improved beta2-microglobulin removal.

Background: Several studies have indicated that the improved elimination of middle molecules by convective renal replacement procedures might be associated with a better outcome in end-stage renal disease (ESRD). On-line mid-dilution hemodiafiltration (HDF) with the Nephros OLpur MD 190 hemodiafilter represents a novel extracorporeal renal replacement therapy concept to increase the removal of middle molecules., Methods: In a prospective cross-over study in 10 ESRD patients, this technique was compared to on-line post-dilution HDF with a conventional synthetic high-flux dialyzer, operated at its technical limit, concerning small and middle molecular solute removal. Each patient was treated 3 times for 4.0 +/- 0.4 hours with both filters. Blood flow was 400 mL/min, substitution flow (Q(S)) during mid-dilution HDF 200 mL/min, and during post-dilution HDF 100 mL/min, and effective dialysate flow of 700 - Q(S) mL/min. Instantaneous clearances, reduction ratios (RR), and middle molecule mass transfer in continuously collected dialysate were determined., Results: While urea and creatinine clearances were significantly lower (6.4% and 3.9%, respectively), middle molecule removal was much more efficient in mid-dilution HDF over the whole range of investigated proteins: compared to post-dilution HDF, beta(2)-microglobulin (11.8 kD) clearance (165.8 +/- 26.59 vs. 201.9 +/- 20.63 mL/min; P < 0.001), RR (80.0 +/- 5.4% vs. 82.2 +/- 5.7%; P < 0.001), and dialysate mass transfer (53% higher; P < 0.001) were significantly higher. For the larger middle molecules, cystatin C (13.4 kD) and retinol-binding protein (21.2 kD), mid-dilution HDF resulted in an even more superior performance, indicated by significantly higher values of all investigated parameters., Conclusion: On-line mid-dilution HDF with the Nephros OLpur MD 190 hemodiafilter appears to be a true technologic step ahead in terms of improved middle molecule removal. This efficient procedure gives hope to play a role in preventing or at least retarding dialysis-related long-term complications, such as beta(2)m amyloidosis, in ESRD patients, and may contribute to a more adequate dialysis therapy.

Hemodiafiltration (HDF) is a well-recognized treatment modality that offers a way of optimizing renal replacement therapy efficacy of end-stage renal disease (ESRD) patients. On-line production of substitution fluid by the 'cold sterilization' process (ultrafiltration) gives access to an unlimited amount of sterile and non-pyrogenic IV grade solution. This advantageous low-cost solution may therefore be employed to develop various forms of high-flux HDF modalities (ol-HDF). High-flux post-dilutional HDF (post-HDF) has mainly been used in clinical practice since it offers the most efficient and best compromise between diffusive and convective clearances. Nowadays, the new targets in anemia correction have created hemorheological conditions that render high filtration rate more difficult to achieve and/or at the expense of higher transmembrane pressure. To overcome this new challenging condition and keeping the same concept, it has been proposed to develop alternative modalities with various sites of fluid substitution (predilution, mixed pre-post with various percentages) in HDF. In this presentation we discuss the benefits of using pre-HDF and show how to match performances with post-HDF. Potential advantages of new ol-HDF options (pre-, mixed and mid-dilution) that are advocated have to be demonstrated in clinical trials. On-line HDF is a multipurpose treatment method that is employed to improve care and outcomes of ESRD patients. Due to its versatility, ol-HDF should be considered as a technical platform permitting to personalize and tailor treatment to patients' needs. The mode of substitution (post-, pre-, mixed or mid-dilution) should be established according to hemorheological conditions of the individual patient., (Copyright (c) 2004 S. Karger AG, Basel.)

Background The kinetics of β2-microglobulin during hemodialysis and hemodiafiltration is well described by a two-compartment model where clearance by the dialyzer is from a central compartment volume that approximates plasma volume and a total distribution volume that approximates extracellular fluid volume. The kinetics of middle molecules with molecular weights larger than β2-microglobulin have not been extensively studied. Methods Intradialytic plasma concentrations and overall dialyzer clearances of β2-microglobulin (11.8 kD), myoglobin (16.7 kD) and complement factor D (24.4 kD) were used to estimate three kinetic parameters from a two-compartment model, namely intercompartmental clearance, central compartment volume and total distribution volume, in hemodialysis patients; these data were collected during two clinical trials of medium cut-off dialyzers (with extended middle molecule removal) during hemodialysis and high-flux dialyzers during hemodialysis and hemodiafiltration. In the current exploratory analyses, the kinetic parameters from all dialyzers were combined. Overall dialyzer clearance was evaluated by total mass removed in the dialysate. Results In total, 345 sets of kinetic parameters from 35 patients were determined. Intercompartmental clearance and central compartment volume for myoglobin and complement factor D were smaller (P < 0.001) than those for β2-microglobulin. Independent of middle molecule, intercompartmental clearance and central compartment volume were associated with overall dialyzer clearance (P < 0.001), but total distribution volume was not (P = 0.083). Conclusions A two-compartment kinetic model can only describe intradialytic kinetics of middle molecules with molecular weights larger than β2-microglobulin if the central compartment is small and dependent on overall dialyzer clearance. [ABSTRACT FROM AUTHOR]

The protein-bound uremic toxins para-cresyl sulfate (pCS) and indoxyl sulfate (IS) are associated with cardiovascular disease in chronic renal failure, but the effect of different dialysis procedures on their plasma levels over time is poorly studied. The present prospective, randomized, cross-over trial tested dialysis efficacy and monitored pre-treatment pCS and IS concentrations in 15 patients on low-flux and high-flux hemodialysis and high-convective volume postdilution hemodiafiltration over six weeks each. Although hemodiafiltration achieved by far the highest toxin removal, only the mean total IS level was decreased at week three (16.6 ± 12.1 mg/L) compared to baseline (18.9 ± 13.0 mg/L, p = 0.027) and to low-flux dialysis (20.0 ± 12.7 mg/L, p = 0.021). At week six, the total IS concentration in hemodiafiltration reached the initial values again. Concentrations of free IS and free and total pCS remained unaltered. Highest beta2-microglobulin elimination in hemodiafiltration (p < 0.001) led to a persistent decrease of the plasma levels at week three and six (each p < 0.001). In contrast, absent removal in low-flux dialysis resulted in rising beta2-microglobulin concentrations (p < 0.001). In conclusion, this trial demonstrated that even large differences in instantaneous protein-bound toxin removal by current extracorporeal dialysis techniques may have only limited impact on IS and pCS plasma levels in the longer term. [ABSTRACT FROM AUTHOR]