Management of Shiga toxin-associated Escherichia coli-induced haemolytic uraemic syndrome: randomized clinical trials are needed

The production of Shiga toxin by a bacterial strain is necessary for induction of enteropathogenic haemolytic uraemic syndrome (HUS). Only strains that produce the toxin are associated with HUS. These include enterohaemorrhagic Escherichia coli, Shigella dysenteriae and rarely Citrobacter freundii [1, 2]. All strains associated with haemorrhagic colitis and HUS are Gram-negative, thus producing lipopolysaccharide (LPS), which may also play a role in the pathogenesis of disease. The recent large outbreak of E. coli O104:H4, a strain with combined virulence factors characteristic of enteroaggregative E. coli as well as enterohaemorrhagic E. coli, provides additional evidence that, regardless of the bacterial background, acquirement of the bacteriophage-encoded gene for Shiga toxin 2 enhances the virulence of the strain causing haemorrhagic colitis and HUS. In this issue of NDT, Kielstein et al. [3] present a comprehensive summary of the outcome of this outbreak and the treatment options offered in 491 patients. Appropriate management of Shiga toxin-induced disease is contingent on an understanding of the pathogenesis of the disease as depicted in Figure 1. After ingestion, the bacteria may bind to the terminal ileum and follicle-associated epithelium of Peyer’s patches [4]. Colonization is further enhanced by quorum sensing, a form of communication with other strains in the intestinal microflora, as well as induction by the host hormonal response including epinephrine and norepinephrine, which would presumably be secreted during haemorrhagic colitis [5]. These signals enhance bacterial colonization and the release of virulence factors. There is no evidence of bacteraemia during infection with Shiga toxin-producing E. coli. Following intestinal colonization, the disease is mediated by the systemic spread of bacterial virulence factors, of which Shiga toxin is of major importance. Shiga toxin binds to the globotriaosylceramide Gb3 receptor on Paneth cells [6] and is translocated through the intestinal epithelium [7]. The toxin has been shown to induce dysentery [8] and intestinal apoptosis [9]. The inflammatory host response in the intestine is important for the clearance of bacteria from the gut. A reduced intestinal response increases the bacterial burden and thus enables more circulating bacterial virulence factors, as demonstrated in mice [10]. Bacterial virulence factors gain access to the circulation after passing through the intestinal mucosa and damaging the intestinal endothelium. During HUS, Shiga toxin, as well as LPS, circulate bound to platelets, monocytes and neutrophils as well as aggregates between these blood cells [11–14]. Both Shiga toxin and O157LPS induce the formation of platelet and monocyte microparticles bearing tissue factor and complement [14, 15]. These circulating microparticles were also detected during the recent E. coli O104 outbreak [16]. Thus, blood cell activation may contribute to the thrombotic process. It is unknown whether and how circulatory toxin is transferred from blood cells to Gb3-expressing target organ cells in vivo. It has been suggested that this transfer of toxin may be related to a higher affinity for the glycolipid receptor on endothelial cells in the kidney [17, 18]. Shiga toxin induces glomerular endothelial cell injury and secretion of tissue factor as well as chemokines promoting leukocyte adhesion to endothelial cells [19, 20]. This scenario enables thrombus formation and release of leukocyte proteases and cytokines. In addition, Shiga toxin induces injury and apoptosis of renal cortical tubular cells [21], and the combined effect on glomeruli and tubuli will lead to destruction of the nephron. The brain is also a target organ in Shiga-toxin-induced disease and studies have shown that the toxin injures endothelial cells as well as neurons [22]. To date, there is no specific treatment for Shiga-toxinmediated infection. In light of the known pathogenesis of disease, various management approaches can be selected (Table 1). In the study by Kielstein et al. [3], three treatment strategies were compared, best supportive care, and plasma exchange with, or without, eculizumab. Best supportive care would include volume replacement, parenteral nutrition and dialysis. Volume expansion with isotonic solutions administered during the