New Concepts in the pathogenesis of acute tubular necrosis associated with sepsis

The kidneys of rhesus monkeys, infused either with a single bolus of endotoxin(10 mg per KG) or continuously at the rate of 10 mg per kg per hour for periods of up to 22 hours, have been examined by light and electron microscopy. Monkeys infused continuously with Ringer's lactate were used as controls. Only minor morphologic changes were observed in those animals receiving a bolus of endotoxin. In the animals continuously infused, sequestration of neutrophils and monocytes was observed in the peritubular capillaries and, to a lesser extent, in the glomeruli. These changes were associated with phagocytosis of endotoxin, occasional fibrinous deposits, and extensive endothelial damage with focal capillary disruption. In the advanced stages, interstitial edema and early necrosis of tubular epithelium were observed. Our data indicate that endothelial damage and associated events relating to the sequestration of phagocytic leukocytes involve the peritubular capillaries primarily and that this process plays a role in the genesis of acute tubular necrosis associated with endotoxemia. In preliminary studies involving the study of kidneys from patients dying with documented Gram negative sepsis and acute renal failure, sequestered nucleated cells have been observed in the peritubular capillaries of the renal cortex and upper medulla. This suggests that similar patterns of endotoxin mediated vascular injury may be occurring in human sepsis.