Abstract
Protein-bound uremic toxins (PBUTs) are difficult to remove using conventional dialysis treatment owing to their high protein-binding affinity. As pH changes the conformation of proteins, it may be associated with the binding of uremic toxins. Albumin conformation at pH 2 to 13 was analyzed using circular dichroism. The protein binding behavior between indoxyl sulfate (IS) and albumin was examined using isothermal titration calorimetry. Albumin with IS, and serum with IS, p-cresyl sulfate, indole acetic acid or phenyl sulfate, as well as serum from hemodialysis patients, were adjusted pH of 3 to 11, and the concentration of the free PBUTs was measured using mass spectrometry. Albumin was unfolded at pH < 4 or >12, and weakened interaction with IS occurred at pH < 5 or >10. The concentration of free IS in the albumin solution was increased at pH 4.0 and pH 11.0. Addition of human serum to each toxin resulted in increased free forms at acidic and alkaline pH. The pH values of serums from patients undergoing hemodialysis adjusted to 3.4 and 11.3 resulted in increased concentrations of the free forms of PBUTs. In conclusion, acidic and alkaline pH conditions changed the albumin conformation and weakened the protein binding property of PBUTs in vitro.
Highlights
Patients with chronic kidney disease (CKD) undergoing dialysis treatment have worse clinical outcomes owing to various systemic disorders including cardiovascular disease, mineral and bone disorders, and infectious disease
Basic and clinical studies have demonstrated the strong toxicities of protein-bound uremic toxins (PBUTs) which are associated with systemic disorders [1,2,3,4]; these solutes are difficult to remove with conventional hemodialysis treatment owing to their high protein binding property [6]
Alkaline pH did not change the concentration (Figure S4). These results suggest that acidic and alkaline pH conditions increased the free form of uremic toxins in serum and simultaneously weakened the protein-binding properties of PBUTs
Summary
Patients with chronic kidney disease (CKD) undergoing dialysis treatment have worse clinical outcomes owing to various systemic disorders including cardiovascular disease, mineral and bone disorders, and infectious disease. P-cresyl sulfate (PCS), bind to large proteins including albumin and are called protein-bound uremic toxins (PBUTs) [5]. Basic and clinical studies have demonstrated the strong toxicities of PBUTs which are associated with systemic disorders [1,2,3,4]; these solutes are difficult to remove with conventional hemodialysis treatment owing to their high protein binding property [6]. Conformational transitions of the three recombinant domains of human serum albumin depending on pH. Acta 1997, 260, 27–34, doi:10.1016/s0009‐8981(96)06504‐7.properties of uremic toxins with pH changes in vitro. Ellipticities at 222 nm Impact on drug tolerance, assay sensitivity and post‐validation method assessment of ADA in clinical serum
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