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Research recommendations within each topic area are listed in order of priority, stratified by modality type.JE Flythe et al.: BP and volume control in dialysis: a KDIGO conference report

BACKGROUND: Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC-HUS) is a severe acute illness without specific treatment except supportive care; fluid management is concentrated on preventing fluid overload for patients, who are often oligoanuric. Hemoconcentration at onset is associated with more severe disease, but the benefits of volume expansion after hemolytic uremic syndrome (HUS) onset have not been explored.

These observations suggest that the extent of renal damage in children with STEC-associated HUS could depend on the concentration of Stx present on their PMN and presumably delivered by them to the kidney. As previously shown by experimental models from our laboratory, high amounts of Stx could induce a reduced release of cytokines by the renal endothelium, with a consequent lower degree of inflammation. Conversely, low toxin amounts can trigger the cytokine cascade, provoking inflammation, thereby leading to tissue damage.

Hemolytic-uremic syndrome, the main cause of acute renal failure in early childhood, is caused primarily by intestinal infections from some Escherichia coli strains that produce Shiga toxins. The toxins released in the gut are targeted to renal endothelium after binding to polymorphonuclear leukocytes. The presence of Shiga toxins in the feces and the circulating neutrophils of 20 children with hemolytic uremic syndrome was evaluated by the Vero cell cytotoxicity assay and flow cytometric analysis, respectively. The latter showed the presence of Shiga toxins on the polymorphonuclear leukocytes of 13 patients, 5 of whom had no other microbiologic or serologic evidence of infection by Shiga toxin-producing Escherichia coli. A positive relationship was observed between the amounts of Shiga toxins released in the intestinal lumen and those released in the bloodstream. The toxins were detectable on the neutrophils for a median period of 5 days after they were no longer detectable in stools. This investigation confirms that the immunodetection of Shiga toxins on neutrophils is a valuable tool for laboratory diagnosis of Shiga toxin-producing Escherichia coli infection in hemolytic-uremic syndrome and provides clues for further studies on the role of neutrophils in the pathogenesis of this syndrome.Hemolytic-uremic syndrome (HUS) is the most common cause of acute renal failure in children and is characterized by thrombocytopenia and microangiopathic hemolytic anemia (25). Most HUS cases occur as a complication of intestinal infections with Shiga toxin-producing Escherichia coli (STEC) (12,13,24).STEC produce two main types of toxins, Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2), which are composed of A and B subunits. The latter mediates the binding to glycolipid receptors (globotriaosylceramide) present on the surface of target cells (19). After endocytosis, an enzymatically active fragment (9) of the A subunit cleaves the bond connecting adenine to the sugar of 28S rRNA (8) and DNA (3, 4), thus causing the arrest of protein synthesis (8) and the formation of apurinic sites in the nucleus (4, 20). The final result of these intracellular injuries is the triggering of apoptosis (4, 17).The pathogenetic process of STEC infection initially involves colonization of the gut (19). STEC serogroups mainly associated with HUS, like E. coli O157 and E. coli O26 (12, 24), adhere to the intestinal mucosa with a characteristic "attaching-and-effacing" mechanism (18). Afterwards, they release large amounts of Shiga toxins in the intestinal lumen, which damage villus epithelial cells and are absorbed into the circulation and targeted to the renal endothelium (19). The presence of free Shiga toxins in the intestinal lumen can be detected by either cell toxicity or immunological assays, and such a detection represents a useful tool for laboratory diagnosis of STEC infections (13,24).Shiga toxins, during their journey from gut to renal endothelium, bind to circulating polymorphonuclear leukocytes (PMN) through a low-affinity unknown re...