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Management of Hemolytic-Uremic Syndrome in Children International Journal of Nephrology and Renovascular Disease Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Management of hemolytic-uremic syndrome in children Silviu Grisaru Abstract: Acute renal failure associated with a fulminant, life-threatening systemic disease is University of Calgary, Alberta rare in previously healthy young children; however, when it occurs, the most common cause is Children’s Hospital, Calgary, Alberta, hemolytic-uremic syndrome (HUS). In most cases (90%), this abrupt and devastating illness Canada is a result of ingestion of food or drink contaminated with pathogens that produce very potent toxins. Currently, there are no proven treatment options that can directly inactivate the toxin or effectively interfere with the cascade of destructive events triggered by the toxin once it gains access to the bloodstream and binds its receptor. However, HUS is self-limited, and effective supportive management during the acute phase is proven to be a life saver for children affected by HUS. A minority of childhood HUS cases, approximately 5%, are caused by various genetic For personal use only. mutations causing uncontrolled activation of the complement system. These children, who used to have a poor prognosis leading to end-stage renal disease, now have access to exciting new treatment options that can preserve kidney function and avoid disease recurrences. This review provides a summary of the current knowledge on the epidemiology, pathophysiology, and clinical presentation of childhood HUS, focusing on a practical approach to best manage- ment measures. Keywords: hemolytic, uremic, E.coli O157:H7, thrombotic, microangiopathy, complement system Introduction Hemolytic-uremic syndrome (HUS) is one of the most common etiologies for acute kidney injury and an important cause of acquired chronic kidney disease in children.1 HUS is generally classified into two main types: typical or diarrhea-associated (D+HUS) and atypical (aHUS) or diarrhea-negative HUS. In children, 90% of HUS cases are associated with a prodrome of diarrhea caused by infections with Shiga toxin-producing Escherichia coli that are able to attach to the intestinal wall; these International Journal of Nephrology and Renovascular Disease downloaded from https://www.dovepress.com/ by 54.191.40.80 on 09-Jul-2017 are known as enterohemorrhagic E. coli (EHEC).1 A rare form of HUS caused by streptococcus pneumoniae, usually following invasive pulmonary infection, is occa- sionally classified with +D HUS in the group of infectious HUS, or is included in the aHUS group as it is not preceded by diarrhea.2 The majority of the remaining cases are affected by aHUS, which can be sporadic or familial. Most cases of aHUS are caused by genetic or acquired dysregulations of the complement system.3 Thrombotic microangiopathy (TMA) is the common pathogenetic pathway leading to all forms of HUS as well as thrombotic thrombocytopenic purpura (TTP).4 However, TTP is Correspondence: Silviu Grisaru University of Calgary, Alberta Children’s rare in children and is usually caused by congenital mutation in the ADMTS13 gene, Hospital, 2888 Shaganappi Trail NW, whereas in adults it occurs more frequently due to abnormal autoantibodies against the Calgary, Alberta, Canada T3B 6A8 Email [email protected] ADMTS13 enzyme.4 This paper will review the clinical presentation, epidemiology, submit your manuscript | www.dovepress.com International Journal of Nephrology and Renovascular Disease 2014:7 231–239 231 Dovepress © 2014 Grisaru. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/IJNRD.S41837 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Grisaru Dovepress and pathogenesis of HUS in children, focusing on current Central nervous system complications resolve in most cases; management options. however, these are responsible for the majority of D+HUS- related fatalities, and permanent neurological sequelae have Clinical presentation been reported in more than 20% of cases.17 D+HUS D+HUS is usually preceded by a severe form of infectious aHUS gastroenteritis that typically begins 3 days after exposure to aHUS, by definition, is not preceded by the characteristic food or water contaminated with EHEC. However, follow- bloody diarrhea of EHEC infection; however, since in the ing ingestion of EHEC, incubation periods ranging from majority of cases it involves dysregulation of the comple- 1–12 days have been reported.5,6 Symptoms are nonspecific, ment system, it is frequently triggered by an infectious event including nausea, cramping, abdominal pain, and diarrhea including gastroenteritis with diarrhea.19 Therefore, initially that is initially watery but becomes bloody in more than 70% it may be difficult to differentiate from D+HUS. More than of cases within 2–3 days from beginning of symptoms.7–9 60% of patients with aHUS present in childhood – the Infections with Shiga toxin-producing E. coli belonging majority at less than 2 years of age, which is also common to the EHEC family can cause extensive colonic injury for D+HUS.19,20 Nevertheless, unlike aHUS, D+HUS rarely with excruciating cramping pain and a severe hemorrhagic affects children younger than 1 year of age and almost colitis; however, milder forms with minimal symptoms and never presents before 6 months of age.21 The presenting non-bloody diarrhea have been described.7,10,11 In 85%–90% symptoms are nonspecific, related to the triggering infec- of cases, the gastroenteritis is self-limited and the symptoms tious event or the developing systemic TMA, resembling subside or disappear 5–8 days from start of symptoms, lead- D+HUS symptoms. ing to full recovery.5,11–14 Complications of the infectious colitis itself, including bowel perforation or massive hemor- Epidemiology rhage, can be fatal; however, the most common and serious HUS is a rare disease with an incidence ranging from For personal use only. complication of EHEC infections is HUS, which develops 0.7–8 cases/100,000 population per year with significant in 10%–15% of affected patients 7–10 days after beginning geographical and seasonal variability. The highest inci- of symptoms.15 dence of D+HUS is reported among children younger than Patients that go on to develop HUS continue to be very 6 years who typically present in the late summer and autumn sick; many are lethargic or irritable. Lab work is character- months.8,14,16,22–25 Prevalence of D+HUS is closely related to ized by thrombocytopenia with platelet counts less than the incidence of EHEC infections and the main reservoir for 150×109/L, hemolytic anemia with schistocytes on blood EHEC pathogens is the gastrointestinal tract of healthy cattle.26 smear, and progressing azotemia. In mild cases of D+HUS Higher incidence of D+HUS in rural areas with a developed in previously healthy children, the azotemia may be missed cattle industry has been reported.8,23 The highest incidence or difficult to document as serum creatinine levels can be of D+HUS in the world was reported in Argentina, while, within normal range despite a more than 50% increase from in Canada, it has been observed in the province of Alberta; baseline.16 D+HUS is a systemic disease that can affect both geographic regions have developed beef production many organs; however, some of the most serious complica- industries.16,27 Large outbreaks originating in contaminated tions relate to involvement of the central nervous system. food have been extensively publicized; one of the most International Journal of Nephrology and Renovascular Disease downloaded from https://www.dovepress.com/ by 54.191.40.80 on 09-Jul-2017 Lethargy, which is observed in many patients on presentation, well-known outbreaks in the US was caused by contami- can progress to development of stupor and coma as well as nated ground beef hamburgers served in a restaurant chain, seizures and strokes.17 Acute kidney injury is characterized hence the popular name for D+HUS: “hamburger disease”.5 by progression to oligoanuria and severe electrolyte imbal- However, contrary to popular belief, most cases of D+HUS are ances that require establishment of acute renal replacement sporadic or occur in small clusters and are not related to poorly therapy in 50%–70% of patients.18 Despite the fulminant cooked contaminated ground beef.8,14,15,22,24,28,29 The majority disease course and multi-organ involvement, D+HUS is of sporadic cases, as well as small and large outbreaks, are self-limited in most cases, with eventual gradual improve- caused by other contaminated foods and beverages, such as ment and full recovery.18 Nevertheless, up to 25% of patients vegetables, cider, or milk,30 and transmission from person are left with ongoing sequelae such as chronic renal failure, to person has also been reported.5,12,31 Moreover, not all out- hypertension, and, rarely, chronic pancreatitis and diabetes.18 breaks of D+HUS are associated with EHEC infections; other 232 submit your manuscript | www.dovepress.com International
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