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Title:
Modeling Toxin-Transporter Dynamics in Chronic Kidney Disease: A Computational and Experimental Framework

Authors:
Leyla Noroozbabaee, Aurélie Carlier, Roos Masereeuw, Silvia Mihaila, Karin Gerritsen, and Jasia King

Abstract:
Chronic kidney disease (CKD) is a significant global health challenge, characterized by progressive loss of kidney function and systemic accumulation of uremic toxins. In healthy conditions, proximal tubule transporters actively secrete protein-bound toxins, maintaining systemic balance. However, in CKD, competition for these transporters leads to elevated toxin retention, further complicating disease progression.

To unravel these complex dynamics, we developed a novel computational-experimental pipeline that integrates structural identifiability analysis, global sensitivity analysis, and Bayesian parameter fitting using in vitro data. This approach enables the development of robust, predictive models to explore toxin-transporter interactions, specifically focusing on indoxyl sulfate (IS) and hippuric acid (HA).

Building on previous models of IS transport, we constructed two models for in vitro IS dynamics and four novel models characterizing HA transport under both healthy and uremic conditions, as well as HA’s competitive interaction with IS. Our findings reveal that uremic concentrations of HA significantly impair OAT1 function, leading to increased retention of HA.