A laboratory model of toxin-induced hemolytic uremic syndrome.
BACKGROUND
Verocytotoxin-producing (Shiga-like toxin-producing) Escherichia coli infection is the principal cause of hemolytic uremic syndrome (HUS). The pathogenesis is unclear, and there is a need for animal models. These are impeded by the different distribution of verocytotoxin receptors between species. We have circumvented this restriction using ricin, which gains entry into cells via various galactose receptors. Like verocytotoxin, ricin specifically cleaves a single adenine from ribosomal RNA.


METHODS
Rats were given ricin at a dose of 6.7 micrograms/100 g body wt, with or without lipopolysaccharide at 10 micrograms/100 g body wt. Lipopolysaccharide alone or saline were used as controls. Changes in glomerular filtration rate, hematological parameters, histology, and plasma cytokine concentrations were measured.


RESULTS
Extensive glomerular thrombosis, pyknotic nuclei, and an infiltration of ED1-positive cells into glomeruli were observed eight hours after an injection of ricin. Other vascular beds were unaffected. Histologic changes were preceded by oliguric renal failure, hemolysis, and thrombocytopenia. Ricin produced a rise in plasma concentrations of monocyte chemotactic protein-1, > tumor necrosis factor-alpha, > interleukin-1 beta, > interleukin-6. Interferon-gamma showed a small increase at the end of the experiment.


CONCLUSIONS
Ricin induces glomerular thrombotic microangiopathy, closely resembling that which occurs in verocytotoxin-producing E. coli-induced HUS. As in HUS, high concentrations of proinflammatory cytokines are present, which are probably a result of cytokine superinduction by the toxin.
Taylor
C M
CM
Department of Nephrology, Birmingham Children's Hospital, United Kingdom.
Williams
J M
JM
Lote
C J
CJ
Howie
A J
AJ
Thewles
A
A
Wood
J A
JA
Milford
D V
DV
Raafat
F
F
Chant
I
I
Rose
P E
PE
D000818:Animals; D002196:Capillaries / Q000473:pathology / Q000648:ultrastructure; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced* / Q000276:immunology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D007684:Kidney Tubules / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D012276:Ricin / Q000633:toxicity; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology; D013997:Time Factors
D016207:Cytokines; D008070:Lipopolysaccharides; D012276:Ricin