Acute renal failure has a high morbidity and mortality. We have finished developing a set of new model of sepsis-induced ARF that employ cecal ligation puncture in elderly mice treated with fluids and antibiotics. We get increases in creatinine and modest changes in renal histology - similar to human ARF - along with clear evidence of injury in other organs (lung, liver, muscle, etc). These models are very exciting because the mice are treated with fluids and antibiotics, as occurs to humans with sepsis. We are now studying the pathophysiology of injury, screening drugs, and studying their mechanisms of action. We have found that renal injury can be dramatically reduced in MyD88 and TLR9 knock out mice, suggeting a significant role for innate immunity. In further experiments, we found that bacterial DNA appears to trigger renal injury through a chloroquine sensitive pathway. We have also performed microarray experiments to search for new drug targets and biomarkers, and additional studies that investigate the mechanism of disease.
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