Animal models of sepsis and sepsis-induced kidney injury

Abstract

Sepsis and sepsis-induced acute kidney injury: a life-threatening conditionSepsis is a characteristic set of systemic reactions to overwhelming infection. Sepsis, severe sepsis, and septic shock are defined according to established criteria (Table 1) (1). Discovery of antibiotics has dramatically improved the morbidity and mortality of the infectious diseases for the last decades; indeed, antibiotics and volume resuscitation are the first line of sepsis treatment strategy (2). However, overwhelming inflammatory response accompanied by depression in immunological function causes multiple organ injury and determines clinical outcomes. In addition to inflammation and immunological dysregulation, a number of different mechanisms contribute to sepsis at different phases (Figure 1). For instance, systemic hemodynamics evolves from an early hyperdynamic ("warm shock") state to a late hypodynamic ("cold shock") state.Sepsis is the leading cause of death in critically ill patients, and the incidence of sepsis is increasing (3, 4). The mortality rate of severe sepsis is very high (up to 70%), and the calculated costs exceed $15 billion per year in the United States (3). The rate of severe sepsis during hospitalization almost doubled during the last decade and is considerably greater than previously predicted (5). Sepsis causes multiorgan failure, including acute kidney injury (AKI) (6), and patients with both sepsis and AKI have an especially high mortality rate (7). AKI is diagnosed by a sudden decrease in glomerular filtration rate (GFR), the primary measure of kidney function, which is currently detected clinically as a rise in serum creatinine. A multinational prospective observational study including 29,269 critically ill patients revealed that the occurrence of AKI in the intensive care unit (ICU) was approximately 6%, the most frequent contributing factor to AKI being sepsis (50%) (8). Other reports showed that between 45% and 70% of all AKI is associated with sepsis (9-11). Several different pathophysiological mechanisms have been proposed for sepsis-induced AKI: vasodilation-induced glomerular hypoperfusion, dysregulated circulation within the peritubular capillary network, inflammatory reactions by systemic cytokine storm or local cytokine production (12), and tubular dysfunction induced by oxidative stress (13).Continuing concern over the efficacy and safety of the only FDAapproved therapy for severe sepsis (activated protein C) highlights the critical need to improve our understanding of the pathophysiology of sepsis and sepsis-induced AKI and to develop novel treatment strategies for critically ill patients (14). A multitude of potential drug targets have been identified in animal models of sepsis; however, translation from animals to humans has been exceedingly difficult. Several reviews have pointed out that the failure to translate results from animals to humans has been attributed to disease characteristics of sepsis (complexity and heterogeneity), inappropriate clinical trials (study of ineffective drugs...

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

“…Age also determines the severity of SARS in both mouse and macaque experimental models (27,28), and aged mice were more susceptible to exogenous endotoxin (LPS) in an animal model of sepsis-induced kidney injury (29). Although age-related changes may account for some of these findings, there may be other factors as well.…”

Sepsis and Acute Kidney Injury

“…Indeed, recent progress has been very encouraging and has led to several new clinically relevant animal models. 48 Animal models will remain essential in the development of the testing and validation of all new therapies for sepsis and septic shock because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be duplicated by other methods. …”

Median lethal needle caliber in two models of experimental sepsis

“…The aim of these models is to achieve reproducible studies about pathophysiology and the impact of new therapies [9][10][11][12] . Experimental models should replicate the rhythm and severity of human sepsis in the Intensive Care Unit; replicate hemodynamic and immunological stages; replicate histological features of target organs, and show variability between subjects 13 .…”