Improved Dialysis Removal of Protein-Bound Uraemic Toxins with a Combined Displacement and Adsorption Technique

Abstract

Introduction: Protein-bound uraemic toxins (PBUTs) are poorly removed by conventional dialytic techniques, given their high plasma protein binding, and thus low, free (dialysable) plasma concentration. Here, we evaluated and compared PBUTs removal among conventional haemodialysis (HD), adsorption-based HD, displacement-based HD, and their 2 combinations both in vitro and in vivo.

Methods: The removal of PBUTs, including 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), p-cresyl sulphate (PCS), indoxyl sulphate (IS), indole-3-acetic acid (3-IAA), and hippuric acid, was first evaluated in an in vitro single-pass HD model. Adsorption consisted of adding 40 g/L bovine serum albumin (Alb) to the dialysate and displacement involved infusing fatty acid (FA) mixtures predialyser. Then, uraemic rats were treated with either conventional HD, Alb-based HD, lipid emulsion infusion-based HD or their combination to calculate the reduction ratio (RR), and the total solute removal (TSR) of solutes after 4 h of therapy.

Results: In vitro dialysis revealed that FAs infusion prefilter increased the removal of PCS, IS, and 3-IAA 3.23-fold, 3.01-fold, and 2.24-fold, respectively, compared with baseline and increased the fractional removal of CMPF from undetectable at baseline to 14.33 ± 0.24%, with a dialysis efficacy markedly superior to Alb dialysis. In vivo dialysis showed that ω-6 soybean oil-based lipid emulsion administration resulted in higher RRs and more TSRs for PCS, IS, and 3-IAA after 4-h HD than the control, and the corresponding TSR values for PCS and IS were also significantly increased compared to that of Alb dialysis. Finally, the highest dialysis efficacy for highly bound solute removal was always observed with their combination both in vitro and in vivo.

Conclusions: The concept of combined displacement- and adsorption-based dialysis may open up new avenues and possibilities in the field of dialysis to further enhance PBUTs removal in end-stage renal disease.

Keywords: Adsorption technology; Displacer augmented dialysis technique; End-stage renal disease; Haemodialysis; Protein-bound uraemic toxins.

Fig. 1

Schematic representations of the experimental setups for in vitro and in vivo dialysis. a A reservoir fluid composed of HSA-uraemic toxin mixtures represented a uraemic patient's plasma on the blood side. The dialysate side consisted of standard bicarbonate dialysate with or without BSA (40 g/L) in the dialysate compartment. In vitro dialysis was conducted at ambient temperature with a volumetrically measured Alb flow of 6.0 mL/min and counter-current dialysate flow of 10.0 mL/min for 30 min. b Setup of the in vivo HD model in uraemic rats. A single-lumen PE50 vascular catheter for removing and returning blood was inserted into the right carotid artery and left jugular vein, respectively. The blood rate and counter-current dialysate flow were set at 1.0 and 5.0 mL/min, respectively. Blood purification therapy was performed for 240 min with single-pass counter-current dialysate flow. HSA, human serum albumin; BSA, bovine serum albumin; HD, haemodialysis; Alb, albumin.

Fig. 2

Time courses of the fractional removal of PBUTs during the in vitro single-pass HD experiments. CMPF (a), PCS (b), IS (c), 3-IAA (d), HA (e). Control group (red): dialysis with standard bicarbonate dialysate; FAs group (blue): dialysis with FAs infusion into the prefilter blood line during minutes 12–30; Alb group (light green): dialysis with BSA added to the dialysate side during minutes 12–30; FAs + Alb group (dark green): FAs were infused into the prefilter blood line and BSA was added to the dialysate side simultaneously during minutes 12–30; Each point represents the mean ± SEM (n = 4). PBUTs, protein-bound uraemic toxins; CMPF, 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid; PCS, p-cresyl sulphate; IS, indoxyl sulphate; 3-IAA, indole-3-acetic acid; HA, hippuric acid; FAs, fatty acids; Alb, albumin; BSA, bovine serum albumin; HD, haemodialysis.

Fig. 3

RRs of small water-soluble solutes and total PBUTs after 4-h HD therapy. BUN (a); Serum creatinine (b); PCS (c); IS (d); 3-IAA (e); HA (f). ***p < 0.001 versus the control group; ^##p < 0.01 versus the Alb group; ^§§p < 0.01 versus ILE group; ^§p < 0.05 versus ILE group. PBUTs, protein-bound uraemic toxins; CMPF, 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid; PCS, p-cresyl sulphate; IS, indoxyl sulphate; 3-IAA, indole-3-acetic acid; HA, hippuric acid; FAs, fatty acids; Alb, albumin; BSA, bovine serum albumin; HD, haemodialysis; BUN, blood urea nitrogen; ILE, intravenous lipid emulsion; RRs, reduction ratios.

Fig. 4

TSR in the collected dialysate for small water-soluble solutes and total PBUTs after 4-h HD therapy. Urea (a); creatinine (b); PCS (c); IS (d); 3-IAA (e); HA (f). ***p < 0.001 versus the control group; *p < 0.05 versus the control group; ^##p < 0.01 versus the Alb group; ^#p < 0.01 versus the Alb group; ^§§p < 0.01 versus ILE group; ^§p < 0.05 versus ILE group. PBUTs, protein-bound uraemic toxins; PCS, p-cresyl sulphate; IS, indoxyl sulphate; 3-IAA, indole-3-acetic acid; HA, hippuric acid; FAs, fatty acids; Alb, albumin; BSA, bovine serum albumin; HD, haemodialysis; ; ILE, intravenous lipid emulsion; TSR, total solute removal.