Abstract
Protein-bound uraemic toxins (PBUTs) cause various deleterious effects in end-stage kidney disease patients, because their removal by conventional haemodialysis (HD) is severely limited by their low free fraction in plasma. Here we provide an experimental validation of the concept that the HD dialytic removal of PBUTs can be significantly increased by extracorporeal infusion of PBUT binding competitors. The binding properties of indoxyl sulfate (IS), indole-3-acetic acid (IAA) and hippuric acid (HIPA) and their binding competitors, ibuprofen (IBU), furosemide (FUR) and tryptophan (TRP) were studied in uraemic plasma. The effect of binding competitor infusion on fractional removal of PBUT was then quantified in an ex vivo single-pass HD model using uraemic human whole blood. The infusion of a combination of IBU and FUR increased the fractional removal of IS from 6.4 ± 0.1 to 18.3 ± 0.4%. IAA removal rose from 16.8 ± 0.3 to 34.5 ± 0.7%. TRP infusion increased the removal of IS and IAA to 10.5 ± 0.1% and 27.1 ± 0.3%, respectively. Moderate effects were observed on HIPA removal. Pre-dialyzer infusion of PBUT binding competitors into the blood stream can increase the HD removal of PBUTs. This approach can potentially be applied in current HD settings.
Highlights
Protein-bound uraemic toxins (PBUTs) cause various deleterious effects in end-stage kidney disease patients, because their removal by conventional haemodialysis (HD) is severely limited by their low free fraction in plasma
The removal of such solutes in conventional HD primarily relies on diffusion of the free molecules into the dialysate, which is severely limited for protein-bound uraemic toxins (PBUTs) due to their low free fraction and small diffusion gradient
Ibuprofen, which possesses the highest binding affinity among the displacers tested in the study, increased the free fraction of both indoxyl sulfate (IS) and p-cresol sulfate (PCS) approximately 3-fold in uraemic plasma, higher than the free fraction generated by tryptophan and furosemide (Fig. 1)
Summary
Protein-bound uraemic toxins (PBUTs) cause various deleterious effects in end-stage kidney disease patients, because their removal by conventional haemodialysis (HD) is severely limited by their low free fraction in plasma. A broad spectrum of retained solutes in dialysis patients’ blood has been identified and characterized in recent studies[1,2,3,4] This group of solutes is generally defined as uraemic toxins, toxic effects are not established for all of these compounds. Fractionated plasma separation and adsorption (FPSA) was 2 times more efficient in removing IS and p-cresol sulfate (PCS) than regular HD in a clinical study[16], the risk of occlusive thrombosis could be a safety concern for using FPSA for this purpose[17] We propose another innovative method for improving dialytic removal of PBUTs. Our method is based on the observation that albumin-binding ligands can influence the binding properties of albumin to other ligands through direct competition for binding sites, or by allosteric mechanisms[18,19,20]. The binding of a given ligand on www.nature.com/scientificreports/
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