Response to single and divided doses of shiga toxin-1 in a primate model of hemolytic uremic syndrome

Postdiarrheal hemolytic uremic syndrome is caused by Shiga toxin (Stx)-prod ucing Escherichia coli. It was shown previously that the baboon, like the h uman, has glycolipid receptors for Stx in the gut and the kidney and that a single 50- to 200-ng/kg intravenous dose of purified Stx-1 results in thro mbocytopenia, hemolytic anemia, and renal thrombotic microangiopathy. For f urther characterization of factors that modulate disease expression, the ba boon's response to the intravenous administration of 100 ng/kg Stx-1 given either rapidly as a single bolus or slowly as four 25-ng/kg doses at 12-h i ntervals was compared. Animals that received the Stx-1 as a single dose dev eloped thrombocytopenia, schistocytosis, and acute renal failure. Urinary b ut not plasma tumor necrosis factor-alpha concentrations rose significantly by 6 h and then declined rapidly. Urinary and plasma interleukin-6 concent rations rose later. Glomeruli showed reduced patency of capillary loops, fr agmented red blood cells, fibrin and platelet microthrombi, necrosis and de tachment of endothelial cells, and accumulation of flocculent material in s ubendothelial spaces. Damage to tubular epithelium and peritubular capillar y endothelium also was seen. Animals that received four divided doses of St x-1 developed no clinical or histologic features of hemolytic uremic syndro me. It is concluded that in the primate model, disease expression is modula ted by the rate of Stx administration, and it is speculated that in the hum an, the rate of Stx absorption from the gut is one determinant of disease s everity.