Improved dialytic removal of protein-bound uraemic toxins with use of albumin binding competitors: an in vitro human whole blood study

Tao, Xia; Thijssen, Stephan; Kotanko, Peter; Ho, Chih-Hu; Henrie, Michael; Stroup, Eric; Handelman, Garry J.

doi:10.1038/srep23389

Cited by 59 publications

(95 citation statements)

References 57 publications

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“…This interference resulted from the combination of competitive displacement and allosteric displacement. With both direct competition for the same binding site and binding-induced allosteric alterations in the protein, we could have unexpected increases in the free concentrations of some PBUTs, just as the finding of the study by Tao et al [17], showing that the use of furosemide and ibuprofen simultaneously and significantly improved the removal of IS and 3-IAA by a 2.9 and a 2.1-fold ratio, respectively, in an in vitro HD model.…”

Section: Discussionsupporting

confidence: 47%

“…For example, Böhringer et al [15] modified HDF with the perfusion of hypertonic NaCl solution to increase the ionic strength (HDF-IPIS) and showed that some PBUTs were removed more efficiently under high ionic strength; however, only the free fraction of IS was significantly increased by this technique in a pilot study including HD patients, in which the mass of PBUTs accumulating in spent dialysate was not significantly different between HD and HDF-IPIS [16]. Tao et al [17] reported that a concentration of 1 mM of ibuprofen could increase the free fraction of IS and PCS by a threefold ratio in uremic plasma.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Ionic Strength, pH and Chemical Displacers on the Percentage Protein Binding of Protein-Bound Uremic Toxins

et al. 2018

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Background and Objectives: While trying to optimize the dialysis clearances of protein-bound uremic toxins (PBUTs), their percentage protein binding (% PB) is an important parameter. We evaluated the effects of ionic strength, pH change and chemical displacers on the dissociation of PBUTs from albumin in vitro. Methods: PBUTs, such as 3-Carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), p-cresylsulfate (PCS), indoxyl sulfate (IS) and indole-3-acetic acid (IAA), were spiked with human serum albumin (HSA) solution prepared with different Nacl concentrations and pH values or in the presence of a series of chemical displacers. Ultrafiltration was performed to separate the free and bound fractions, and the % PB of each PBUT was calculated. Results: For all 4 compounds, their % PB decreased with increasing ionic strength, while only slight changes occurred when the pH of the test solution increased from pH 6.0 to pH 8.5; PCS, IS and 3-IAA were relatively easily dissociated from albumin by drug displacement, while CMPF was released from HSA by all studied drugs with difficulty; the PB % for CMPF, PCS, IS and 3-IAA decreased most remarkably in the presence of free fatty acids, such as oleic acid (41.73% for CMPF, 29.9% for PCS, 23.22% for IS, and 20.34% for 3-IAA) and linoleic acid (43.12% for CMPF, 16.65% for PCS, 29.99% for IS, and 16.29% for 3-IAA). Conclusion: The protein binding of PBUTs can be decreased by higher ionic strength, increased pH and the presence of some chemical displacers, including free fatty acids. Effective dialytic removal of PBUTs may be achieved by applying these methods jointly to blood-purification techniques.

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Section: Discussionsupporting

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Effect of Ionic Strength, pH and Chemical Displacers on the Percentage Protein Binding of Protein-Bound Uremic Toxins

et al. 2018

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“…This discrepancy is still not completely explained, but differences may due to different intestinal generation or due to different metabolism of toxic compounds in these patients. Another recent study to improve dialytic removal of PBUTs has been proposed using albumin competitors IS, indole-3-acetic acid, and hippuric acid [43] . This in vitro study demonstrated that the infusion of albumin binding competitors such as ibuprofen, furosemide, and tryptophan into the plasma circuit was able to improve the removed fraction of IS from 6.4 to 18.3, of indole-3-acetic acid from 16.8 to 34.5, while for hippuric acid the observed effect was modest.…”

Section: Possible Therapeutic Interventionsmentioning

confidence: 99%

The Cardiovascular Burden in End-Stage Renal Disease

Cozzolino

Galassi

Pivari

et al. 2017

Contributions to Nephrology

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It is well documented that chronic kidney disease patients have an extremely high risk of developing cardiovascular (CV) disease (CVD) compared to the general population. Declining renal function itself represents a continuum of CV risk, and in those individuals who survive to reach end-stage renal disease, the risk of suffering a cardiac event is uncomfortably and unacceptably high. Several pathophysiological pathways have been suggested to account for this, including endothelial dysfunction, dyslipidemia, inflammation, left ventricular hypertrophy, troponins, phosphate, vitamin D, fibroblast growth factor-23, and NT-proBNP. All these conditions and biomarkers may have clear associations with current and subsequent CVD.

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“…As an unbound solute diffuses through the membrane, another molecule will dissociate from plasma albumin to maintain the binding equilibrium, replenishing the low free solute concentration and allowing for its continuous diffusion. A recent study using human whole blood in an ex vivo dialysis model showed that infusing albumin-binding competitors upstream of the dialyzer significantly increases the dialytic removal of PBUTs, further demonstrating that binding and displacement occur very rapidly (36). First, it is conceivable to speculate that solute binding to albumin is rapidly reversible and that the time required for the solute to dissociate from the binding site is shorter in comparison to the transit time of blood through the artificial kidney.…”

Section: Discussionmentioning

confidence: 99%

Increasing the removal of protein‐bound uremic toxins by liposome‐supported hemodialysis

Shi

Wang

et al. 2018

Artificial Organs

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Protein‐bound uremic toxins (PBUTs) accumulate at high plasma levels and cause various deleterious effects in end‐stage renal disease patients because their removal by conventional hemodialysis is severely limited by their low free‐fraction levels in plasma. Here, we assessed the extent to which solute removal can be increased by adding liposomes to the dialysate. The uptake of liposomes by direct incubation in vitro showed an obvious dose‐response relationship for p‐cresyl sulfate (PCS) and indoxyl sulfate (IS) but not for hippuric acid (HA). The percent removal of both PCS and IS but not of HA was gradually increased with the increased concentration of liposomes in a rapid equilibrium dialysis setup. In vitro closed circulation showed that adding liposomes to the dialysate markedly increased the dialysances of PBUTs without greatly altering that of urea and creatinine. In vivo experiments in uremic rats demonstrated that adding liposomes to the dialysate resulted in higher reduction ratios (RRs) and more total solute removal (TSR) for several PBUTs compared to the conventional dialysate, which was approximately similar to the addition of bovine serum albumin to the dialysate. These findings highlight that as an adjunct to conventional hemodialysis, addition of liposomes to the dialysate could significantly improve the removal of protein‐bound uremic solutes without greatly altering the removal of small, water‐soluble solutes.

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Improved dialytic removal of protein-bound uraemic toxins with use of albumin binding competitors: an in vitro human whole blood study

Cited by 59 publications

References 57 publications

Effect of Ionic Strength, pH and Chemical Displacers on the Percentage Protein Binding of Protein-Bound Uremic Toxins

Effect of Ionic Strength, pH and Chemical Displacers on the Percentage Protein Binding of Protein-Bound Uremic Toxins

The Cardiovascular Burden in End-Stage Renal Disease

Increasing the removal of protein‐bound uremic toxins by liposome‐supported hemodialysis

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