Removal of Protein-Bound Uremic Toxins during Hemodialysis Using a Binding Competitor

Abstract

Background and objectives: Current hemodialysis techniques fail to efficiently remove the protein-bound uremic toxins p-cresyl sulfate and indoxyl sulfate due to their high degree of albumin binding. Ibuprofen, which shares the same primary albumin binding site with p-cresyl sulfate and indoxyl sulfate, can be infused during hemodialysis to displace these toxins, thereby augmenting their removal.

Design, setting, participants, & measurements: We infused 800 mg ibuprofen into the arterial bloodline between minutes 21 and 40 of a conventional 4-hour high-flux hemodialysis treatment. We measured arterial, venous, and dialysate outlet concentrations of indoxyl sulfate, p-cresyl sulfate, tryptophan, ibuprofen, urea, and creatinine before, during, and after the ibuprofen infusion. We report clearances of p-cresyl sulfate and indoxyl sulfate before and during ibuprofen infusion and dialysate concentrations of protein-bound uremic toxins normalized to each patient's average preinfusion concentrations.

Results: We studied 18 patients on maintenance hemodialysis: age 36±11 years old, ten women, and mean vintage of 37±37 months. Compared with during the preinfusion period, the median (interquartile range) clearances of indoxyl sulfate and p-cresyl sulfate increased during ibuprofen infusion from 6.0 (6.5) to 20.2 (27.1) ml/min and from 4.4 (6.7) to 14.9 (27.1) ml/min (each P<0.001), respectively. Relative median (interquartile range) protein-bound uremic toxin dialysate outlet levels increased from preinfusion 1.0 (reference) to 2.4 (1.2) for indoxyl sulfate and to 2.4 (1.0) for p-cresyl sulfate (each P<0.001). Although median serum post- and predialyzer levels in the preinfusion period were similar, infusion led to a marked drop in serum postdialyzer levels for both indoxyl sulfate and p-cresyl sulfate (-1.0 and -0.3 mg/dl, respectively; each P<0.001). The removal of the nonprotein-bound solutes creatinine and urea was not increased by the ibuprofen infusion.

Conclusions: Infusion of ibuprofen into the arterial bloodline during hemodialysis significantly increases the dialytic removal of indoxyl sulfate and p-cresyl sulfate and thereby, leads to greater reduction in their serum levels.

Keywords: Albumins; Binding Sites; Biological; Dialysis Solutions; Ibuprofen; Indican; Indoxyl sulfate; Sulfates; Toxins; Tryptophan; albumin binding competitors; creatinine; dialysis; dialytic removal; displacer infusion; hemodialysis; p-Cresyl sulfate; protein bound uremic toxins; toxin displacement; urea.

Graphical abstract

Figure 1.

Schematic of the displacer concept. A displacer substance is infused into the arterial (prefilter) bloodline, where the displacer molecule competes with protein-bound toxins for binding sites. This competition results in higher free toxin levels, facilitating higher toxin removal rates. The use of multiple displacer molecules (“displacer cocktail”) is possible and has been tested ex vivo (19).

Figure 2.

Dialysate solute concentrations before, during, and after the ibuprofen infusion. The concentrations were measured in the dialysate outlet stream, and they are given as relative concentrations normalized to the respective solute concentrations during the preinfusion period. (Left panels) Concentrations of indoxyl sulfate (upper panel) and p-cresyl sulfate (lower panel). (Right panels) Concentrations of tryptophan (top panel), urea (middle panel), and creatinine (bottom panel). *P value <0.01 compared with preceding phase; Wilcoxon signed rank test; **P value <0.001 compared with preceding phase; Wilcoxon signed rank test.

Figure 3.

Time course of prefilter (arterial) ibuprofen concentrations. Ibuprofen was infused between minutes 21 and 40, and the peak concentration was reached at minute 40. The gray symbols indicate average concentrations. The top and bottom edges of boxes indicate the 25th and 75th percentiles, respectively. Thick lines inside boxes indicate medians. Ends of whiskers indicate minimum and maximum values (excluding outliers), and black dots indicate outliers.

Figure 4.

Solute clearances during the three treatment phases. *P value <0.01 compared with preceding phase; Wilcoxon signed rank test; **P value <0.001 compared with preceding phase; Wilcoxon signed rank test.