ABSTRACT
Objective:A kinetic model of the clearance of protein-bound uremic toxins (PBUTs) in maintenance hemodialysis patients is established to evaluate the effects of adding sorbents with different sorption efficiency to dialysate on the clearance rate of PBUTs, and to predict the sorption efficiency of sorbents using the model.Methods:The kinetic model was established by integrating the parameters of plasma flow rate ( Qp), dialysate flow rate ( Qd), free plasma fraction of PBUTs ( f1), free dialysate fraction of PBUTs ( f2), mass transfer coefficient of dialyzer ( K) and surface area of dialysis membrane ( A), and using the mass balance equation and Fick's first law. The model was also used to evaluate the relationship between the clearance rate of different PBUTs and the parameters of dialyzer and the sorption efficiency of sorbents. Results:The kinetic model of PBUTs clearance (CL): ?CL=Qp1-f1-f2γφf1-f2γ,?γ=QpQd,?φ=eKAf1Qp-f2Qd. The model was used to analyze the dialysis parameters of indoxyl sulfate and p-cresol sulfate dialysis.The clearance rate of PBUTs increased with the decrease of its binding capacity to albumin in plasma and the increase of plasma flow rate in dialyzer, dialysate flow rate, mass transfer coefficient of dialyzer, surface area of dialysis membrane, and sorption capacity of sorbents in dialysate. The increasing trend of PBUTs clearance rate was particularly obvious after applying sorbents. Further analysis of the dialysate flow rate and the sorption efficiency of sorbents in the dialysate showed that the increase of the dialysate flow rate could make up for the difference of the sorption efficiency of sorbents. When the dialysate flow rate tended to be infinite, the sorption efficiency of sorbents in the dialysate had no effect on the clearance rate of PBUTs. Conclusion:Adding sorbents of PBUTs to the dialysate during dialysis can significantly improve the clearance rate of PBUTs, suggesting a promising clinical application value.
ABSTRACT
Background: Testosterone deficiency is reportedly correlated with an elevation of cholesterol in plasma, but the mechanism remains unclear. Our objective was to investigate the effects of testosterone deficiency on cholesterol metabolism and the corresponding molecular changes in vivo and in vitro. Methods: SD rats were randomized into three groups: sham-operated (SHAM), subtotal orchiectomized (SO), and orchiectomized (ORX) and fed for 8 weeks. HepG2 cells were cultured with medium containing testosterone with the final concentrations of 0, 10, 30, and 300 nM. Method of isotope tracing and fluorescence labelling was adopted to investigate cholesterol metabolism. Several key molecules of cholesterol metabolism were also analyzed. Results: SO and ORX rats displayed dysfunctional liver uptake of cholesterol. HepG2 cells incubated with testosterone of lower and excessive level exhibited reduced capacity of cholesterol uptake. Further investigation revealed that lack of testosterone induced increased proprotein convertase subtilisin/kexin type 9 (PCSK9) and decreased low-density lipoprotein receptor (LDLR) both in vivo and in vitro. Moreover, the androgen receptor (AR) antagonist flutamide mimicked the effects of testosterone deficiency on PCSK9 and LDLR indicating the role of AR as a mediator in triggering attenuating liver cholesterol uptake in which testosterone instead of dihydrotestosterone (DHT) is the major functional form of androgen. Conclusion: Testosterone deficiency attenuated cholesterol liver uptake mediated by the PCSK9-LDLR pathway, in which AR and testosterone without transforming to DHT play important roles.
