Plasma Concentrations of Anionic Uremic Toxins in Hemodialysis Patients and Their Effects on Protein Binding of Pravastatin

Abstract

Uremic toxins (UTs) accumulate in the body of hemodialysis patients. UTs often exert unfavorable eŠects on patients and cause signiˆcant interactions with clinically relevant drugs. In this study, we assayed plasma concentrations of three typical anionic UTs, indoxyl sulfate (IS), 3-indoleacetic acid (IA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), in 20 hemodialysis patients and 5 healthy volunteers. Moreover, the eŠects of these anionic UTs on the binding of pravastatin to human serum albumin (HSA) were also evaluated. CMPF concentrations in the plasma of patients were unchanged before and after dialysis (63.0±6.3 mM and 65.1±6.7 mM, respectively), and these values were about 5-fold greater compared with those in healthy volunteers. Although dialysis decreased the plasma IS concentration from 157.9±19.9 mM to 103.8±13.3 mM, the value after hemodialysis was still ca. 27-fold greater than that in healthy volunteers. IA concentrations before and after hemodialysis were almost identical to those in healthy volunteers. There were no signiˆcant diŠerences in the plasma concentrations of the three anionic UTs between male and female patients. The magnitude of protein binding was in the order CMPF＞IS＞IA, indicating that hemodialysis clearance of these anionic UTs was dependent on their protein binding capacities. The ability of IS to reduce pravastatin binding to HSA was much greater than that of CMPF. The present results suggest that statins bind to site II on HSA, and that their binding is modulated by IS when elevated in hemodialysis patients.

Correlations between Plasma Levels of Anionic Uremic Toxins and Clinical Parameters in Hemodialysis Patients

“…However, the fact that plasma levels of CMPF were almost the same before and immediately after HD (Table 2) and that the HD clearance of these three UTs was well correlated with their protein binding rate 12) could imply the relatively small in‰uence of membrane adsorption on the results in this study.…”

“…Consistent with the previous literature, 8 11) the results obtained from the study demonstrated that the greatest diŠerence in the mean plasma levels between HD patients and healthy subjects was for IS. 12) Our recent study also showed that IS was capable of modulating the binding of pravastatin to albumin, indicating an interaction at albumin binding site II. 12) As dyslipidemia is frequent in HD patients, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors are often prescribed to them.…”

“…12) Our recent study also showed that IS was capable of modulating the binding of pravastatin to albumin, indicating an interaction at albumin binding site II. 12) As dyslipidemia is frequent in HD patients, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors are often prescribed to them. Therefore, an elevation in the plasma IS level in HD patients receiving a HMG-CoA reductase inhibitor may trigger serious adverse eŠects such as rhabdomyolysis.…”

“…IA weakly binds to albumin whereas IS readily binds to the plasma protein. 12) Accordingly, IA but not IS is easily subject to removal from the plasma by HD, leading to a much lower accumulation of IA than IS in HD patients. The fact that the r and p values between IS and IA worsened after HD (Fig.…”

“…In this study, using the previous data obtained from 20 HD patients, 12) we evaluated the correlations among the plasma levels of IS, IA and CMPF and the relationship between the plasma levels of these anionic UTs and three clinical parameters in HD patients, with special focus on the values obtained before and immediately after HD.…”