Project Summary
The hemolytic uremic syndrome (HUS) is the most serious complication of high-risk Shiga toxin-producing
Escherichia coli (STEC) infection and the most common cause of acquired acute kidney injury in otherwise
healthy children. HUS develops in up to 20% of children following STEC infection, 60% of whom require
temporary renal replacement therapy (RRT); an additional 50% develop serious extrarenal complications.
Although mortality from acute HUS is low (1-3%), it has remained constant for three decades and
approximately 30% of HUS survivors experience long-term sequelae, chiefly chronic kidney disease,
hypertension, and diabetes. There have been only three relatively small, randomized trials to prevent
progression to HUS and/or to reduce kidney injury once HUS is established; none have demonstrated benefits,
and none have been performed since 1999.
Recent cohort studies suggest that early intravascular volume expansion (hyperhydration) in STEC infected
children could be nephroprotective if and when HUS occurs. However, more evidence is needed before
hyperhydration supplants traditional ‘wait and see’ (i.e., conservative fluid management) reactive care
approaches which focus on outpatient care and minimizing intravenous fluid administration to avoid fluid
overload in children who do develop HUS. Here, we will confirm or refute the hypothesis that aggressive
volume expansion, administered early in STEC infected children, is associated with better renal outcomes and
fewer adverse events than conservative management by accomplishing three Specific Aims: (1) Determine
the effectiveness of hyperhydration in decreasing the prevalence of Major Adverse Kidney Events by 30
days (defined as death, RRT, or sustained loss of kidney function at 30 days) in STEC-infected
children versus conservative fluid management; (2) Determine the effectiveness and safety of
hyperhydration in decreasing HUS and life-threatening, extrarenal complications in STEC-infected
children versus conservative fluid management; (3) Create a biorepository that will be linked to our
clinical data to identify prognostic biomarkers and therapeutic targets in STEC-infected children. To
accomplish these Aims, we will conduct an embedded, open-label, cluster-randomized crossover superiority
trial in 26 emergency departments. Participating sites, located in the United States and Canada, will be
randomly allocated to the order of protocol implementation (hyperhydration or conservative fluid management)
in this two-interval, two-intervention trial, developed with the support of an NIAID R34 grant. The design,
facilitated by rapid molecular enteric diagnostics, overcomes many barriers to studying this challenging disease
and maximizes the potential therapeutic benefits by embedding the intervention into routine clinical care. If we
confirm our hypothesis, this project will provide the first causal evidence of an effective, implementation-ready
intervention for children infected with high-risk STEC.
