Gram negative sepsis is a common cause of acute renal failure (ARF) in humans but the underlying mechanisms are poorly understood. Recent observations from this laboratory indicate that sepsis sensitizes the kidney to superimposed nephrotoxic and ischemic insults. Gram negative bacteria (GNB) injected into rats in a dose which causes no hemodynamic instability or direct renal injury produce severe AR in concert with non-toxic amounts of gentamicin or with modest renal ischemia. This effect is induced by endotoxin (lipopolysaccharide, or LPS). However, the tubular cell pathways by which LPS potentiates toxic/ischemic injury and possible, systemic mediators of this reaction remain to be defined. It is proposed to study these issues, using the GNB-gentamicin interaction as a model. This has clinical relevance since aminoglycosides are a mainstay in the treatment of Gram negative, sepsis. The following are specific goals: A) Define whether gentamicin and endotoxin, both of which can cause renal glutathione loss, combine to induce ARF by producing severe oxidant tissue damage. B) Determine whether gentamicin and endotoxin, both of which can interfere with mitochondrial ATP production, together induce severe renal cortical ATP depletion, thereby precipitating ARF. C) Determine whether systemic mediators play a role in the endotoxin-gentamicin interaction. Specific mediators to be tested are complement, neutrophils platelets, and macrophage derived tumor necrosis factor. D) Determine whether the ability of endotoxin to enhance renal cortical gentamicin uptake is mediated either directly or indirectly, by an endotoxin triggered increase in the affinity of the drug's proximal tubular brush border membrane binding site. The ultimate goals of these investigations are to 1) further our understanding of the pathogenesis of sepsis-induced ARF so that it might be prevented; and 2) begin to define the role of systemic mediators of acute tubular injury, an are almost totally ignored in previous investigations of the pathogenesis of ARF.
Showing the most recent 10 out of 101 publications
