The role of acute kidney in the pathogenesis of sepsis from pneumonia



 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is common and increases mortality. AKI complicates up to 20% of hospital admissions and 30 to 50% of ICU admissions. Sepsis occurs in 40-45% of patients after AKI diagnosis and doubles mortality. Pneumonia is the most common cause of sepsis and infection-related death in hospitalized patients. Mortality in pneumonia doubles when patients become bacteremic. Since the vast majority of patients with bacteremia are septic, bacteremia may be considered equivalent to sepsis. In this grant, we investigate the mechanisms by which AKI predisposes to bacteremia and sepsis from pneumonia. The mechanism by which pneumonia causes bacteremia is poorly understood and is generally considered to be due to immunosuppression leading to overwhelming of lung bacterial defenses. In preliminary studies, we found that mice with AKI had similar pneumonia severity to controls with pneumonia, yet bacteremia was greater in AKI. Thus, immunosuppression does not explain bacteremia during AKI. In fact, rather than an immunosuppressed response, our preliminary studies demonstrate that the response to endotoxin (the immune activating component of gram negative bacteria) was exuberant and characterized by an increased inflammatory response. Claudin 4, a lung epithelial tight junction protein, was reduced suggesting that increased epithelial permeability was present in AKI with pneumonia. Thus, we suggest that AKI causes immune priming, not immunosuppression, of the lung. Preliminary studies suggest the lung immune priming in AKI coincides with lung neutrophil recruitment. Our overall hypothesis is that AKI primes the lung to exert an exuberant inflammatory response when exposed to endotoxin or pneumonia from gram negative bacteria. We propose that the exuberant inflammatory response mediates lung inflammation, loss of tight junction proteins (e.g., claudin 4), and increased epithelial permeability which facilitates translocation of bacteria into the circulation resulting in bacteremia and sepsis. We have three Specific Aims: 1) Determine if AKI causes lung immune priming, 2) Determine if bacterial translocation is greater in AKI with pneumonia, 3 Determine if loss of claudin 4 mediates bacterial translocation in AKI with pneumonia. In Aim 1, we seek to characterize the immune primed response, determine if this response is specific to alveolar macrophages, and identify factors in AKI which lead to immune priming (i.e., neutrophil recruitment and dialyzable circulating factors (using peritoneal dialysis). In Aim 2, we seek to establish that increased translocation of bacteria explains bacteremia in AKI using intravital confocal microscopy to track and quantify translocation of GFP-labelled bacteria in live mice with pneumonia and AKI. In Aim three, we seek to establish that the inflammatory response of AKI-primed alveolar macrophages mediates bacteremia during pneumonia by down regulating claudin 4 expression and increasing lung epithelial permeability. The experiments in this grant will provide useful leads into the development of interventions to prevent sepsis from pneumonia and improve survival in patients with AKI.