Sepsis or ischemia in experimental acute renal failure: what have we learned?

Acute renal failure (ARF) has been studied in experimental settings for many years and has led to many insights into the cell biology of renal injury. The development of more clinically relevant models of renal injury combining endotoxemia, hypoperfusion, and nephrotoxins has led to a new appreciation of the role of the immune system in the pathogenesis of ARF. Endotoxin produces profound declines in renal blood flow even when systemic pressures are preserved, and this effect appears to be mediated by systemically and locally generated vasoactive factors including cytokines, platelet-activating factor, endothelin, and adenosine. Activated neutrophils (PMN) contribute to injury through the generation of cytokines, production of oxidants, or interactions with renal endothelium. Specific inhibition of immune activation at various steps has been shown to ameliorate the course of experimental endotoxic and ischemic ARF. Inhibition of PMN adhesion to endothelial cells by monoclonal antibodies to binding proteins, and blockade of thromboxane or interleukin action with specific inhibitors have all been shown to improve renal outcome in experimental ARF. These studies demonstrate that immunologically activated mediators are important in the pathogenesis of ARF in sepsis. Strategies to reduce the levels or to block the binding of specific cytokines may hold promise for the treatment of ARF in the critically ill.