Post-diarrheal uremic syndrome (HUS) is the most common cause of acute renal failure in infants and young children, and is a substantial cause of chronic kidney damage and failure. The diarrhea is caused by enterohemorrhagic E. coli (e.g., E. coli 0157:H7) that produces potent cytotoxins known as Shiga-like toxins (SLTs) or Verotoxins (VTs). There is strong circumstantial evidence that SLT and Lipopolysaccharide (LPS) gain access to the circulation from the gut, damage renal endothelial cells and activate a complex pathogenic cascade that results in oliguric renal failure. Our limited understanding of the pathogenic cascade, however, has hampered efforts to develop effective intervention strategies. A non-human primate model (baboon) will be used to test the hypothesis that acute renal failure in SLT/LPS induced HUS results from increased prothrombotic, vasoconstrictive, and lipid peroxidation activity coupled to decreased antithrombotic, vasodilatory, and antioxidant activity, and that correcting this imbalance favorably influences the natural history of the syndrome. More specifically, purified SLT-I and LPS will be infused into baboons, after which the magnitude and sequence of the appearance of markers of endothelial and renal tubular cell injury, lipid peroxidation, white blood cell, platelet and coagulation cascade activation, and substance that modulate thrombosis and vascular tone will be determined. The importance of LPS in the pathogenic cascade will be measured by determining if LPS causes up-regulation of renal GB3 toxin receptors, and if so, if up-regulation is associated with cytokine production. Once the pathogenic cascade has been characterized, the up-regulated prothrombotic, vasoconstrictive, and lipid peroxidation systems will be selectively and collectively blocked, and the down-regulated antithrombotic, vasodilatory and antioxidant systems will be stimulated. This will provide information concerning the relative importance of each in the pathogenesis of the syndrome, and will identify intervention strategies that can be used to interrupt the pathogenic cascade and thereby prevent full expression of the syndrome.
