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Multicenter Study
. 2020 Feb 23;21(4):1522.
doi: 10.3390/ijms21041522.

Serum Levels and Removal by Haemodialysis and Haemodiafiltration of Tryptophan-Derived Uremic Toxins in ESKD Patients

Joosep Paats  1 , Annika Adoberg  2 , Jürgen Arund  1 , Annemieke Dhondt  3 , Anders Fernström  4 , Ivo Fridolin  1 , Griet Glorieux  3 , Liisi Leis  2 , Merike Luman  1   2 , Emilio Gonzalez-Parra  5 , Vanessa Maria Perez-Gomez  5 , Kristjan Pilt  1 , Didier Sanchez-Ospina  5 , Mårten Segelmark  4 , Fredrik Uhlin  1   4 , Alberto Arduan Ortiz  5
Affiliations
Multicenter Study

Serum Levels and Removal by Haemodialysis and Haemodiafiltration of Tryptophan-Derived Uremic Toxins in ESKD Patients

Joosep Paats et al. Int J Mol Sci. .

Abstract

Tryptophan is an essential dietary amino acid that originates uremic toxins that contribute to end-stage kidney disease (ESKD) patient outcomes. We evaluated serum levels and removal during haemodialysis and haemodiafiltration of tryptophan and tryptophan-derived uremic toxins, indoxyl sulfate (IS) and indole acetic acid (IAA), in ESKD patients in different dialysis treatment settings. This prospective multicentre study in four European dialysis centres enrolled 78 patients with ESKD. Blood and spent dialysate samples obtained during dialysis were analysed with high-performance liquid chromatography to assess uremic solutes, their reduction ratio (RR) and total removed solute (TRS). Mean free serum tryptophan and IS concentrations increased, and concentration of IAA decreased over pre-dialysis levels (67%, 49%, -0.8%, respectively) during the first hour of dialysis. While mean serum total urea, IS and IAA concentrations decreased during dialysis (-72%, -39%, -43%, respectively), serum tryptophan levels increased, resulting in negative RR (-8%) towards the end of the dialysis session (p < 0.001), despite remarkable Trp losses in dialysate. RR and TRS values based on serum (total, free) and dialysate solute concentrations were lower for conventional low-flux dialysis (p < 0.001). High-efficiency haemodiafiltration resulted in 80% higher Trp losses than conventional low-flux dialysis, despite similar neutral Trp RR values. In conclusion, serum Trp concentrations and RR behave differently from uremic solutes IS, IAA and urea and Trp RR did not reflect dialysis Trp losses. Conventional low-flux dialysis may not adequately clear Trp-related uremic toxins while high efficiency haemodiafiltration increased Trp losses.

Keywords: chronic kidney disease; end-stage kidney disease; haemodiafiltration; haemodialysis; indole-3 acetic acid; indoxyl sulfate; tryptophan; tryptophan-derived uremic toxins; uremic toxins.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure A1
Figure A1
Mean concentrations normalized for the baseline pre-dialysis value, at different time points during the dialysis sessions for Trp, IS, IAA and urea for (a) total serum values; (b) free serum values; and (c) dialysate values. P values are shown on Figure 1.
Figure A1
Figure A1
Mean concentrations normalized for the baseline pre-dialysis value, at different time points during the dialysis sessions for Trp, IS, IAA and urea for (a) total serum values; (b) free serum values; and (c) dialysate values. P values are shown on Figure 1.
Figure 1
Figure 1
Mean ± SD concentrations at different time points during the dialysis sessions for Trp, IS, IAA (µmol/L) and urea (mmol/L) for (a) total serum values (n = 310); (b) free serum values (n = 310); and (c) dialysate values (n = 257). *** p < 0.001; ** p < 0.01; * p < 0.05 vs. previous timepoint value.
Figure 1
Figure 1
Mean ± SD concentrations at different time points during the dialysis sessions for Trp, IS, IAA (µmol/L) and urea (mmol/L) for (a) total serum values (n = 310); (b) free serum values (n = 310); and (c) dialysate values (n = 257). *** p < 0.001; ** p < 0.01; * p < 0.05 vs. previous timepoint value.
Figure 2
Figure 2
Reduction ratios (RR) at different time points during the dialysis sessions for Trp, IS, IAA and urea calculated from (a) total serum values (n = 309) and (b) free serum values (n = 309). *** p < 0.001; ** p < 0.01; * p < 0.05 vs. previous timepoint value.
Figure 2
Figure 2
Reduction ratios (RR) at different time points during the dialysis sessions for Trp, IS, IAA and urea calculated from (a) total serum values (n = 309) and (b) free serum values (n = 309). *** p < 0.001; ** p < 0.01; * p < 0.05 vs. previous timepoint value.
Figure 3
Figure 3
Reduction ratios (RR) at different time points during the dialysis sessions for Trp, IS, IAA and urea calculated from the dialysate values (n = 244). *** p < 0.001; ** p < 0.01; * p < 0.05 vs. previous timepoint value.
Figure 4
Figure 4
Reduction ratios (RR) and total removal of solute (TRS) calculated for urea, Trp, IS and IAA from the start and end (240 min) of the dialysis session for different dialysis modalities and settings: (a) RRs assessed from total serum concentrations (n = 77); (b) RRs assessed from free serum concentrations (n = 77); (c) RRs assessed from spent dialysate concentrations (n = 53); and (d) TRS of urea (in mmol), Trp, IS and IAA (in µmol) (n = 74). *** p < 0.001; ** p < 0.01; * p < 0.05 vs. previous modality value.
Figure 4
Figure 4
Reduction ratios (RR) and total removal of solute (TRS) calculated for urea, Trp, IS and IAA from the start and end (240 min) of the dialysis session for different dialysis modalities and settings: (a) RRs assessed from total serum concentrations (n = 77); (b) RRs assessed from free serum concentrations (n = 77); (c) RRs assessed from spent dialysate concentrations (n = 53); and (d) TRS of urea (in mmol), Trp, IS and IAA (in µmol) (n = 74). *** p < 0.001; ** p < 0.01; * p < 0.05 vs. previous modality value.
Figure 5
Figure 5
Location of centres and country life expectancy (GBD 2017 study) [57], renal replacement therapy (RRT) incidence and transplant rate (data from ERA-EDTA Registry, Belgium data correspond to Dutch-speaking Belgium) [58].
Figure 6
Figure 6
The schematic clinical set-up, sample collection, and analysis during the clinical studies.
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