Acute renal failure after whole body ischemia

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DESCRIPTION (provided by applicant): Acute renal failure (ARF) in the native kidney is associated with a high mortality and morbidity. Despite major advances in the pathogenesis of ARF, there is no specific treatment. Most experimental work on ischemic ARF has used isolated renal injury models. However, when a patient develops ischemic ARF in the native kidney, such as during shock or sepsis, this is almost always a consequence of a whole body event rather than an isolated kidney event. Whole body ischemia reperfusion injury (WBIRI) creates a unique state that affects kidney and many organs simultaneously including lung, heart, intestine, etc. The global changes to the internal milieu are difficult to mimic in isolated organ models and in vitro preparations. In view of the current lack of specific therapy for ARF, as well as the need for the development of more "clinical" models that are closer to the complexity of human disease, we have started to develop a new animal model of whole body IRI in the mouse that leads to ARF. We have performed WBIRI with potassium chloride injection, which results in complete loss of blood pressure due to stoppage of the heart. After cardiac arrest, the mouse undergoes cardiopulmonary resuscitation. The surviving animals uniformly develop ARF. In preliminary studies, we have found that serum creatinine rises, tubular necrosis occurs, and leukocytes infiltrate into the kidney. Based on our preliminary data in this novel murine model of ARF, we propose to better characterize pathophysiologic processes such as inflammation, apoptosis, oxidative stress and adenine nucleotides. In addition, we will examine extra-renal functional changes in heart, lungs, liver and gut that likely interplay with kidney injury during WBIRI. The second aim will be to directly compare the renal pathophysiological processes in the WBIRI model with the classic isolated kidney ischemia model. Our long-term goals are to develop a clinically relevant experimental model which can be used to develop novel therapies for ARF.