Effect of an Oral Shiga Toxin–Binding Agent on Diarrhea-Associated Hemolytic Uremic Syndrome in Children<SUBTITLE>A Randomized Controlled Trial</SUBTITLE>

Abstract

Context Diarrhea-associated hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children. Most cases are caused by an intestinal infection with Shiga toxin-producing strains of Escherichia coli.Objective To determine if administration of an oral agent that binds Shiga toxin could diminish the severity of diarrhea-associated HUS in pediatric patients. Design, Setting, and Patients Multicenter, randomized, double-blind, placebocontrolled clinical trial of 145 children (96 experimental and 49 placebo) aged 6 months to 18 years with diarrhea-associated HUS conducted between July 27, 1997, and April 14, 2001, at 26 tertiary care pediatric nephrology centers in the United States and Canada. Trial included 2 phases, the hospital course for treatment of the acute illness and a 60-day outpatient follow-up period after discharge from the hospital.Intervention Patients were assigned to receive the binding agent, 500 mg/kg daily, or cornmeal placebo orally for 7 days in a 2:1 randomization scheme. Main Outcome MeasuresCombined frequency of death or serious extrarenal events and need for dialysis in the experimental vs placebo group.Results A total of 62 patients (43%) were male and 123 (85%) were white. The median age of the patients was 4.2 years. Most patients (59%) were transferred from other hospitals to participating sites. The severity of disease at the time of randomization was comparable in the 2 groups. The prevalence of death or serious extrarenal events was 18% and 20% in the experimental and placebo groups, respectively (P=.82). Dialysis was required in 42% of experimental and 39% of placebo groups (P=.86).Conclusions Oral therapy with a Shiga toxin-binding agent failed to diminish the severity of disease in pediatric patients with diarrhea-associated HUS.

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

“…Research in this field is still ongoing, but to date, the results have been disappointing [111] . Another option for the future is to treat patients during the diarrheal phase with monoclonal antibodies against Shiga toxin [112] .…”

Management of hemolytic-uremic syndrome in children

“…SYNSORB Pk (Synsorb Biotech Inc., Calgary, AB, Canada) was a synthetic potent STX binder that was designed to bind STX in the gut, thus blocking absorption of STX; unfortunately, a large Phase III trial with this agent failed to demonstrate any benefit. 59 Blocking the effect of blood-borne STX with inactivating antibodies has also been attempted, and, currently, a trial with monoclonal anti-STX1 and anti-STX2 antibodies is taking place in South America. 64,65 Nevertheless, the main challenge with STX binding and blocking agents has been timing of administration, which needs to occur before the STX effect is further amplified by a cascade of events involving the thrombotic, inflammatory, and complement systems.…”

“…54 However, a toxin binder designed to diminish toxin absorption was not proven effective in a prospective randomized controlled trial. 59 Antibiotics have not been shown to directly influence interaction between toxins and their Gb3 receptor, suggesting that the antibiotic influence on risk and outcome of HUS is mediated by modulation of toxin bioavailability. [60][61][62] Recently, further evidence for a possibly beneficial role of early use of antibiotics in patients with D+HUS was provided by the retrospective analysis of antibiotic use during the 2011 German mega-outbreak.…”

Strategies to avoid shiga toxin effects

“…However, the effects of the Synsorb Pk Ò were not beneficial in preventing extrarenal complications. 13 Another attempt was investigated by Paton et al 14 who designed a recombinant bacterium displaying on its surface a Stx receptor mimic, which show a high affinity for Stx and can neutralize significant amounts of Stx in the intestine.…”