A laboratory model of toxin-induced hemolytic uremic syndrome

Background. Verocytotoxin-producing (Shiga-like toxin-producing) Escherichi a 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 betwee n species. We have circumvented this restriction using ricin, which gains e ntry into cells via various galactose receptors. Libe verocytotoxin, ricin specifically cleaves a single adenine from ribosomal RNA. Methods. Rats were given ricin at a dose of 6.7 mu g/100 g body wt, with or without lipopolysaccharide at 10 mu g/100 g body wt. Lipopolysaccharide al one or saline were used as controls. Changes in glomerular filtration rate, hematological parameters, histology, and plasma cytokine concentrations we re measured. Results. Extensive glomerular thrombosis, pyknotic nuclei, and an infiltrat ion of ED1-positive cells into glomeruli were observed eight hours after an injection of ricin. Other vascular beds were unaffected. Histologic change s were preceded by oliguric renal failure, hemolysis, and thrombocytopenia. Ricin produced a rise in plasma concentrations of monocyte chemotactic pro tein-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 r esembling that which occurs in verocytotoxin-producing E. coli-induced HUS. As in HUS, high concentrations of proinflammatory cytokines are present, w hich are probably a result of cytokine superinduction by the toxin.