Abstract
Research has shown that traditional dialysis is an insufficient long-term therapy for patients suffering from end-stage kidney disease due to the high retention of uremic toxins in the blood as a result of the absence of the active transport functionality of the proximal tubule (PT). The PT’s function is defined by the epithelial membrane transporters, which have an integral role in toxin clearance. However, the intricate PT transporter–toxin interactions are not fully explored, and it is challenging to decouple their effects in toxin removal in vitro. Computational models are necessary to unravel and quantify the toxin–transporter interactions and develop an alternative therapy to dialysis. This includes the bioartificial kidney, where the hollow dialysis fibers are covered with kidney epithelial cells. In this integrated experimental–computational study, we developed a PT computational model that focuses on indoxyl sulfate (IS) transport by organic anionic transporter 1 (OAT1), capturing the transporter density in detail along the basolateral cell membrane as well as the activity of the transporter and the inward boundary flux. The unknown parameter values of the OAT1 density , IS uptake (, and dissociation ( were fitted and validated with experimental LC-MS/MS time-series data of the IS concentration. The computational model was expanded to incorporate albumin conformational changes present in uremic patients. The results suggest that IS removal in the physiological model was influenced mainly by transporter density and IS dissociation rate from OAT1 and not by the initial albumin concentration. While in uremic conditions considering albumin conformational changes, the rate-limiting factors were the transporter density and IS uptake rate, which were followed closely by the albumin-binding rate and IS dissociation rate. In summary, the results of this study provide an exciting avenue to help understand the toxin–transporter complexities in the PT and make better-informed decisions on bioartificial kidney designs and the underlining transporter-related issues in uremic patients.
Highlights
10% of the global population is affected by end-stage kidney disease (ESKD)
Building on these modeling works, in this integrated experimental–computational study, we developed a proximal tubule computational model focusing on the organic anionic transporter 1 (OAT1) transporting indoxyl sulfate (IS, an anionic protein-bound uremic toxin), capturing in detail the transporter density along the basolateral cell membrane as well as the activity of the transporter
We found that the computational model can accurately replicate the OAT1 function and IS transport by modeling the IS uptake boundary condition as mass action kinetics using k f U ptake as a constant, where case 1 was the most reliable function of the uptake boundary condition, which was followed closely by modeling k f U ptake as the Michalis–Menten function
Summary
10% of the global population is affected by end-stage kidney disease (ESKD). According to the European Union Toxin (EUTox) database, a uremic toxin is a food and drug organic metabolite in the bloodstream that needs to be removed from the blood circulation If these uremic toxins remain in the bloodstream, the patient will suffer from a number of complications, including, but not limited to, cardiovascular disease, anemia, and progressive kidney failure [3,4,5]. Hemodialysis falls short as a treatment since it only reproduces the glomerulus’ filtration function in removing water-soluble, some middle molecules, and not yet bound uremic toxins The latter are not effectively cleared since they are too big to be removed via ultrafiltration once bound to albumin (MW > 65 kDa). To improve the effectiveness of hemodialysis, the functionality of the proximal tubule needs to be mimicked
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