A novel mathematical model of protein-bound uremic toxin kinetics during hemodialysis

Abstract

Protein-bound uremic toxins (PBUTs) are difficult to remove by conventional hemodialysis; a high degree of protein binding reduces the free fraction of toxins and decreases their diffusion across dialyzer membranes. Mechanistic understanding of PBUT kinetics can open new avenues to improve their dialytic removal. We developed a comprehensive model of PBUT kinetics that comprises: (1) a three-compartment patient model, (2) a dialyzer model. The model accounts for dynamic equilibrium between protein, toxin, and the protein-toxin complex. Calibrated and validated using clinical and experimental data from the literature, the model predicts key aspects of PBUT kinetics, including the free and bound concentration profiles for PBUTs and the effects of dialysate flow rate and dialyzer size on PBUT removal. Model simulations suggest that an increase in dialysate flow rate improves the reduction ratio (and removal) of strongly protein-bound toxins, namely, indoxyl sulfate and p-cresyl sulfate, while for weakly bound toxins, namely, indole-3-acetic acid and p-cresyl glucuronide, an increase in blood flow rate is advantageous. With improved dialyzer performance, removal of strongly bound PBUTs improves gradually, but marginally. The proposed model can be used for optimizing the dialysis regimen and for in silico testing of novel approaches to enhance removal of PBUTs.

Removal of Protein-Bound Uremic Toxins during Hemodialysis Using a Binding Competitor

“…Overall, kidney replacement therapies have come a long way, leading to improved outcomes in patients on hemodialysis. However, these advancements have done little to augment the removal of protein-bound uremic toxins, a notion supported by mathematical models (21,22). Researchers have attempted to improve protein-bound uremic toxin removal using many different strategies.…”

A model-based analysis of phenytoin and carbamazepine toxicity treatment using binding-competition during hemodialysis

“…In both cases, the competitor drug reduced the required treatment time well below conventional HD time, with even a greater reduction in cases in which the drug protein-binding is stronger. The model was previously applied to protein-bound uremic toxins in which competitive binding outperformed both pre- and post-dilution hemodiafiltration and membrane adsorption 6 , 9 . It is important to note that HD results in a rapid decline in toxic drug concentration, which only refers to the plasma compartment.…”

“… Here, is the free drug diffusive mass-transfer coefficient between intracellular and interstitial pool; and , respectively, are interstitial and intracellular fluid volume; is solute reaction rate term in interstitial pool. We assumed a of 1,200 mL/min and of 100 mL/min for the simulations for both T and D —values were adapted from 9 . A higher value of than indicate a more permeable structure of the capillary endothelium compared to the cellular walls.…”

Iron oxide nanoparticles improved biocompatibility and removal of middle molecule uremic toxin of polysulfone hollow fiber membranes

“…Middle molecular weight toxin like β 2 ‐microglobulin may form large molecules which later deposit and harm nearby tissues, causing anxiety or amyloidosis to patients . Generally, uremic toxin removal by membrane is based on the concentration differences and convective separation . However, the removal of larger uremic toxins is difficult as the clearance by diffusion decreases with the increasing molecular weight of molecules .…”