Introduction and Aims: Protein-bound uremic toxins (PBUT) exert deleterious effects, yet are difficult to remove in hemodialysis (HD) due to their high degree of protein binding (>90%). Displacing these toxins from their albumin binding sites by infusion of binding competitors (“displacers”) can raise their free fraction in the dialyzer and increase their removal (US Patent 8419943B2). Here, we present a mathematical model of PBUT kinetics and simulate the impact of displacer infusion into the arterial line.
Methods: We developed a three-compartment patient model and a dialyzer model that accounts for displacer-protein-toxin interaction (Figure 1). Indoxyl sulfate (IS) was chosen as a prototypical PBUT, and ibuprofen was chosen as a displacer, as both compete for the same site on albumin. We modeled IS removal during a 4-hr HD session with the following parameters: Qp = 250 mL/min, IS and ibuprofen dialyzer clearance K_{D,IS} = K_{D,Ibuprofen} = 150 mL/min, ultrafiltration rate 750 mL/h, initial total IS concentration 100 µmol/L, initial free fraction of IS 8%, dialyzer fiber length 25 cm, fiber radius 100 µm, fiber count 10000, ibuprofen half-life 2 hrs, association constants for protein-toxin and protein-displacer systems 2.3×10^4 M^{-1} and 1.76×10^5 M^{-1}, respectively. We modeled this first without, then with infusion of 800 mg/200 mL ibuprofen (C_{displacer}) into the arterial blood line at a rate of 50 mL/hr (Q_{displacer}). The inner diameter of the blood lines was 6 mm, and the distance between displacer infusion site and dialyzer blood inlet was 50 cm. The protein-toxin-displacer system is assumed to follow law-of-mass-action kinetics.
Results: Total IS removal during a conventional 4-hr HD session was 418 µmoles (plasma reduction ratio 39%), which conforms to literature data (Niwa; Blood Purif 2013;35(S2)). With infusion of ibuprofen, total IS removal increased by 15% to 481 µmoles (plasma reduction ratio 53%). Figure 2 shows the intradialytic time course of total IS concentration in the plasma (blue) and interstitial fluid compartment (red). Dashed lines: concentration profiles without displacer; solid lines: with displacer infusion.
Conclusions: Infusion of binding competitors holds the promise of appreciable increases in the removal of protein-bound uremic toxins during HD. The current iteration of this model appears to provide reasonable results. Additional experiments are warranted to both inform and validate the model further. A future iteration of this mathematical model will serve as a valuable tool in the design of clinical trials aimed at implementing the uremic toxin displacement approach and, ultimately, may be applied to describe the kinetics of other protein-bound solutes such as calcium.
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