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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 μg/100g body wt, with or without lipopolysaccharide at 10 μg/100g 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-α, > interleukin-1β, > interleukin-6. Interferon-γ 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.

Summary In the haemolytic uraemic syndrome (HUS), platelet microthrombi and deposition of fibrin in glomeruli may contribute to the development of renal failure. The balance of procoagulant and fibrinolytic activities in the renal vasculature may therefore have an important role. We measured plasminogen-activator inhibitor (PAI) activity in the plasma of 81 children with diarrhoea-associated (D+) HUS, and found elevated PAI activity in many patients. When we categorized patients by need for dialysis, only the dialysed group had significantly higher levels of activity, compared with a group of normal controls. We also compared PAI activity with patient outcome after one year, and found that those with a poor outcome had significantly higher PAI activity than those with a good outcome. We suggest that plasma PAI activity may be an acute marker for dialysis requirement in HUS, and may have prognostic value for long-term outcome. The possible role of PAI in the pathogenesis of HUS requires further investigation.

Tissue pathway factor inhibitor (TFPI) activity is elevated in pregnant patients at 20 weeks gestation who subsequently develop preeclampsia