Background: Augmented renal clearance (ARC) commonly occurs in sepsis, potentially resulting in suboptimal drug exposure and ultimately, treatment failure. However, the underlying pathophysiology associated with ARC in sepsis has not yet been fully understood. Methods: From literature search, previously developed QSP models of bacterial infection, host immune response to infection, and cardiorenal system were identified. The QSP models were linked to each other in R 4.2.0 using the RxODE package through inflammatory cytokines induced by bacterial infection. Effects of inflammatory cytokines on the diameters of renal arterioles and systemic vascular resistance were retrieved from previously published studies and quantitatively modeled using Emax models. Model-based simulations were conducted over the period of 1000 hours. Results: Our integrated QSP model suggested substantial vasodilation of both renal arterioles and systemic vascular resistance associated with elevated IL-1b and IL-6 levels. Over the simulation period (up to 1000 hours), ARC occurred with the maximum GFR (147.5 mL/min/1.73 m ) as well as peak plasma concentrations of IL-1b and IL-6 observed in 36 hours following bacterial infection. The elevated GFR was normalized between 100 and 120 mL/min/1.73 m in 200 or more hours after bacterial infection. The mean arterial pressure was maintained within the normal range between 95 to 108.6 mmHg during the simulation period. Conclusion: An integrated QSP model was successfully developed to describe ARC in sepsis patients based on the immune and cardiorenal responses to bacterial infection. Our prototype QSP model of sepsis-induced ARC will accelerate the development of a validated QSP model of sepsis, which might assist in predicting the optimal drug dosages in patients with sepsis over the course of disease.
Hallow KM et al. A quantitative systems physiology model of renal function and blood pressure regulation: Model description. CPT Pharmacometrics Syst Pharmacol.6(6):383-392 (2017)
Diep JK et al. Mechanism-Based Disease Progression Model Describing Host-Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia. CPT Pharmacometrics Syst Pharmacol.7(8):507-516 (2018)
Dai W et al. A Prototype QSP Model of the Immune Response to SARS-CoV-2 for Community Development. CPT Pharmacometrics Syst Pharmacol.10(1):18-29 (2021)
