01.06 Examining Renal Distress in Sepsis-Induced Acute Kidney Injury Using an Agent-Based Model

R. Kambli1, R. C. Cockrell1, G. An1  1University Of Vermont College Of Medicine / Fletcher Allen Health Care, General Surgery, Burlington, VT, USA


Sepsis-induced acute kidney injury (SI-AKI) involves a complex interaction of immune, endothelial, and microvascular cells modulated by inflammatory cytokines and molecular mediators. Understanding the mechanistic pathophysiology of SI-AKI can enhance the prediction and potential treatment of multi system organ failure and subsequent mortality. The dynamics of renal impairment can be better understood using a computational model that integrates the known mechanisms of renal tubular epithelial and endothelial cell injury and the effect of heterogenous hypoperfusion of the kidney. Toward this end we developed an agent-based model (ABM) that simulates the renal immune response leading to SI-AKI.  


The Renal Function ABM (RFABM) represents the proximal tubule as the origin of the SI-AKI immune response. It is informed by current literature regarding the renal response to acute inflammation. Cell types include resident renal macrophages, neutrophils, monocytes, dendritic cells, pericytes, microvascular endothelial cells, and tubular endothelial cells. These cells interact through intracellular receptors and inflammatory cytokines present in extracellular milieu. Simulation experiments include influx of pro inflammatory cytokines and heterogenous hypoperfusion seen in septic shock, with the consequent generation of tubular necrosis and impairment of global renal function. Calibration was performed by generating synthetic populations of immune cells and comparing their behavior to published data on cytokine/mediator trajectories and organ-level damage/dysfunction reflected by creatinine clearance.


The RFABM successfully integrates existing knowledge regarding the molecular and cellular interactions leading to SI-AKI. Simulation experiments reproduced the response to septic insult in terms of the dynamics of cellular/molecular mediators (ex. pro-inflammatory cytokines and reactive oxidative species) as well as clinically accessible lab values of renal damage/dysfunction (creatinine) and were able to demonstrate the additional effect of increased heterogenous hypoperfusion differentiating sepsis from septic shock.


The RFABM is an initial computational model that represents and integrates mechanistic knowledge regarding the generation of SI-AKI. The RFABM replicates the primary dynamics of renal injury in response to circulating inflammatory mediators and differential hypoperfusion and has been designed to be integrated with an existing computational model of systemic inflammation and sepsis. Future work will expand and validate the mechanistic details of the RFABM so it can be used as an in silico experimental proxy system for positing novel drug targets and therapeutic strategies to ameliorate the consequences SI-AKI and general renal inflammation.