Characterization of the baboon responses to Shiga-like toxin - Descriptivestudy of a new primate model of toxic responses to Stx-1

The baboon response to intravenous infusion of Shiga toxin 1 (Stx-1) varied from acute renal failure, proteinuria, hyperkalemia, and melena with minim al perturbation of host inflammatory and hemostatic systems thigh-dose grou p, 2.0 mu g/kg; n = 5) to renal failure with hematuria, proteinuria, thromb ocytopenia, schistocytosis, anemia, and melena (low-dose group, 0.05 to 0.2 mu g/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 f actor and interleukin-G although neither of these cytokines was detectable (less than or equal to 5 ng/ml) in the general circulation. Light and elect ron microscopy showed organelle disintegration and necrosis of the renal pr oximal tubular epithelium and of the intestinal mucosal epithelium at the t ips of the microvilli, both of which were previously shown to bear Gb, rece ptors,The renal distal tubular epithelium was spared. The renal proximal tu bular epithelial changes were accompanied by swelling of visceral epithelia l cells (podocytes) and by swelling and detachment of endothelial cells of the glomerular capillaries. In addition, all of the animals receiving low-d ose Stx-l showed microvascular fibrin deposition and thrombosis in renal gl omerular and peritubular capillaries in association with a fall in hematocr it and platelet count and a rise in schistocyte count. The gastrointestinal villous tip lesions were accompanied by varying degrees of mucosal and sub mucosal 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 Gb, re ceptor glycolipid of the renal glomerular and neuronal tissues as determine d using toxin overlay thin-layer chromatography plates was below the limit of detection (<13 pM/g wet tissue). We conclude that, depending on the stat us of the host and amount of toxin infused, Stx-l can produce a variety of responses ranging from damage to cells carrying the Gb, receptor (renal pro ximal tubular epithelial cells and gastrointestinal mucosa) to dam age to r enal glomerular tissues with microvascular thrombosis as a result of the ho st's inflammatory response localized to the kidney. We conclude that this t hrombotic coagulopathy arises from local changes in the kidney because the appearance of host inflammatory mediators was Limited to the urine. This su ggests that the initial host response is localized in the kidney, and that the systemic thrombocytopenia, anemia, and schistocytosis may arise seconda rily.