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)-producing Escherichia coli. It was shown previously that the baboon, like the human, 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 thrombocytopenia, hemolytic anemia, and renal thrombotic microangiopathy. For further characterization of factors that modulate disease expression, the baboon'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 intervals was compared. Animals that received the Stx-1 as a single dose developed thrombocytopenia, schistocytosis, and acute renal failure. Urinary but not plasma tumor necrosis factor-alpha concentrations rose significantly by 6 h and then declined rapidly. Urinary and plasma interleukin-6 concentrations rose later. Glomeruli showed reduced patency of capillary loops, fragmented red blood cells, fibrin and platelet microthrombi, necrosis and detachment of endothelial cells, and accumulation of flocculent material in subendothelial spaces. Damage to tubular epithelium and peritubular capillary endothelium also was seen. Animals that received four divided doses of Stx-1 developed no clinical or histologic features of hemolytic uremic syndrome. It is concluded that in the primate model, disease expression is modulated by the rate of Stx administration, and it is speculated that in the human, the rate of Stx absorption from the gut is one determinant of disease severity.
Siegler
Richard L
RL
Department of Pediatrics, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah.
Pysher
Theodore J
TJ
Department of Pathology, Primary Children's Medical Center, Salt Lake City, Utah.
Tesh
Vernon L
VL
Department of Medical Microbiology and Immunology, Texas A&M University, Health Science Center, College Station, Texas.
Taylor
Fletcher B
FB
Cardiovascular Biology Research, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
D058186:Acute Kidney Injury / Q000139:chemically induced; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D016207:Cytokines / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000473:pathology; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007275:Injections, Intravenous; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases; D008297:Male; D010215:Papio; D012079:Renal Circulation; D022622:Shiga Toxin 1 / Q000008:administration & dosage*; D013921:Thrombocytopenia / Q000139:chemically induced; D013927:Thrombosis / Q000139:chemically induced; D014556:Urine / Q000737:chemistry
D016207:Cytokines; D022622:Shiga Toxin 1