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Animal Model |
From the Cardiovascular Biology Program,*
Oklahoma
Medical Research Foundation, and the Department of
Pathology,
University of Oklahoma Health
Science Center, Oklahoma City, Oklahoma; the Department of Medical
Microbiology and Immunology,
Texas A&M
University Health Science Center, College Station, Texas; and the
Department of Pathology,§
and Division of
Nephrology,¶
Department of Pediatrics,
University of Utah School of Medicine, Salt Lake City, Utah
The baboon response to intravenous infusion of Shiga toxin 1
(Stx-1) varied from acute renal failure, proteinuria,
hyperkalemia, and melena with minimal perturbation of host
inflammatory and hemostatic systems (high-dose group, 2.0
µg/kg; n = 5) to renal failure with
hematuria, proteinuria, thrombocytopenia,
schistocytosis, anemia, and melena (low-dose
group, 0.05 to 0.2 µg/kg; n = 8). Both
groups exhibited renal shutdown and died in 57 hours or less. Both
groups produced urine that was positive for tumor necrosis factor and
interleukin-6 although neither of these cytokines was detectable (
5
ng/ml) in the general circulation. Light and electron microscopy showed
organelle disintegration and necrosis of the renal proximal tubular
epithelium and of the intestinal mucosal epithelium at the tips of the
microvilli, both of which were previously shown to bear
Gb3 receptors. The renal distal tubular epithelium was
spared. The renal proximal tubular epithelial changes were accompanied
by swelling of visceral epithelial cells (podocytes) and by swelling
and detachment of endothelial cells of the glomerular capillaries. In
addition, all of the animals receiving low-dose Stx-1 showed
microvascular fibrin deposition and thrombosis in renal glomerular and
peritubular capillaries in association with a fall in hematocrit and
platelet count and a rise in schistocyte count. The gastrointestinal
villous tip lesions were accompanied by varying degrees of mucosal and
submucosal congestion, hemorrhage, or necrosis.
Electron microscopic images of cerebral cortex and cerebellum showed
diffuse unraveling of myelin sheaths with occasional disintegration of
neuronal cell bodies. In contrast to the gastrointestinal mucosal and
renal proximal tubular epithelium, the Gb3 receptor
glycolipid of the renal glomerular and neuronal tissues as determined
using toxin overlay thin-layer chromatography plates was below the
limit of detection (<13 pM/g wet tissue). We conclude that,
depending on the status of the host and amount of toxin
infused, Stx-1 can produce a variety of
responses ranging from damage to cells carrying the
Gb3 receptor (renal proximal tubular epithelial cells and
gastrointestinal mucosa) to damage to renal glomerular tissues with
microvascular thrombosis as a result of the host's inflammatory
response localized to the kidney. We conclude that this thrombotic
coagulopathy arises from local changes in the kidney because the
appearance of host inflammatory mediators was limited to the urine.
This suggests that the initial host response is localized in the
kidney, and that the systemic thrombocytopenia,
anemia, and schistocytosis may arise
secondarily.
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