Pediatric Hemolytic Uremic Syndrome

Updated: Nov 16, 2017
  • Author: Robert S Gillespie, MD, MPH; Chief Editor: Craig B Langman, MD  more...
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Overview

Practice Essentials

Hemolytic-uremic syndrome (HUS) was first described by Gasser in a German publication in 1955. Hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. [1] Since 1955, thousands of cases have been reported, and hemolytic-uremic syndrome is recognized as the most common cause of acute renal failure in the pediatric population.

The clinical course of hemolytic-uremic syndrome can vary from subclinical to life threatening. Studies have revealed distinct subgroups of hemolytic-uremic syndrome and have identified several etiologies for the disease. Nomenclature for the various types of hemolytic-uremic syndrome varies throughout the literature. For consistency, this article uses the following set of terms throughout this review:

  • STEC-HUS is used to describe hemolytic-uremic syndrome mediated by Shiga toxin (Stx)–producing  Escherichia coli. This is also called classic, typical, Stx, diarrhea-positive, or D + hemolytic-uremic syndrome.
  • Atypical HUS (aHUS) is used to describe hemolytic-uremic syndrome not mediated by Shiga toxin. This is also called diarrhea-negative, non–diarrhea-associated, or D - hemolytic-uremic syndrome. This disease is usually mediated by abnormalities of the complement system or other heritable factors.
  • Pneumococcal-associated HUS is a subtype of atypical hemolytic-uremic syndrome, mediated by neuraminidase in the presence of infection with  Streptococcus pneumoniae. This is also called neuraminidase-associated hemolytic-uremic syndrome.

The distinction is important because the clinical courses, treatments, and prognoses differ for each category. The first reported cases were aHUS; however, STEC-HUS is now much more common. Classification based on the presence of diarrhea can be misleading, as a significant percentage of patients with aHUS may have diarrhea.

Hemolytic-uremic syndrome shares many features with thrombotic thrombocytopenic purpura (TTP). For more information, see the Medscape Reference article Thrombotic Thrombocytopenic Purpura. Both diseases include multiorgan dysfunction due to thrombotic microangiopathy, with active hemolysis and thrombocytopenia. The traditional classification describes patients with predominantly renal disease as having hemolytic-uremic syndrome, and patients with predominantly CNS disease as having TTP. However, hemolytic-uremic syndrome can include severe neurologic impairment, and TTP can involve severe renal failure. Involvement of other organ systems also overlaps.

Whether these are, in fact, separate diseases remains controversial; some authors describe "hemolytic-uremic syndrome–TTP" as a single disease entity with a diverse spectrum of presentations. In many cases, both nephrologists and hematologists collaborate on the care of patients with these complex illnesses. Many authors now consider ADAMTS13 activity in distinguishing aHUS from TTP. Patients with very low ADAMTS13 activity, generally less than 10%, are considered to have TTP, while higher levels of activity point to a diagnosis of HUS.

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Pathophysiology

STEC-HUS is usually preceded by a colitis caused by Shiga toxin–producing Escherichia coli (STEC). Subsequent inflammation of the colon facilitates systemic absorption of the Stx and lipopolysaccharide from the GI tract. The major toxins that cause hemolytic-uremic syndrome, Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2), are similar in structure to the classic Stx. These toxins bind to globotriaosylceramide (Gb3), a glycolipid receptor molecule on the surface of endothelial cells in the gut, kidney, and, occasionally, other organs. Differential expression of Gb3 on glomerular capillaries compared with other endothelial cells may explain the predominance of renal injury. Damaged endothelial cells of the glomerular capillaries release vasoactive and platelet-aggregating substances. The endothelial cells swell, and fibrin is deposited on the injured vessel walls.

Swelling and microthrombi formation within the glomerular capillaries produce a localized intravascular coagulopathy. The glomerular filtration rate is reduced, and renal insufficiency ensues. Erythrocytes are damaged and fragmented as they traverse the narrowed glomerular capillaries. This leads to the characteristic microangiopathic hemolytic anemia. Hemolysis may also be a result of lipid peroxidation. See the image below.

Peripheral blood smear in hemolytic-uremic syndrom Peripheral blood smear in hemolytic-uremic syndrome (HUS) showing many schistocytes and RBC fragments due to hemolysis, and relatively few platelets reflective of thrombocytopenia.

Thrombocytopenia is believed to result from a combination of platelet destruction, increased consumption, sequestration in the liver and spleen, and intrarenal aggregation. Platelets are damaged as they pass through the affected glomerular capillaries. Remaining platelets circulate in a degranulated form and show impaired aggregation. Stx also binds to activated platelets.

Abnormalities of anti–platelet-aggregating agents (eg, prostaglandin I2 [PGI2]), platelet-aggregating agents (thromboxane A2 [TXA2]) and von Willebrand factor (vWF) multimers are also important factors that contribute to thrombocytopenia. A decrease in PGI2 during the early stages of hemolytic-uremic syndrome has been noted. Defective PGI2 production is believed to play a role in STEC-HUS; abnormal PGI2 synthesis is believed to play a role in aHUS.

TXA2 levels are increased during the acute stage of hemolytic-uremic syndrome, leading to increased platelet aggregation. Another possible cause for increased platelet aggregation is large vWF multimers. In vitro, these large multimers have a greater ability to aggregate platelets than the normal, smaller multimers. Normal plasma contains a vWF-cleaving metalloproteinase (ADAMTS13) that rapidly degrades large vWF multimers. Many cases of TTP are associated with deficient function of ADAMTS13.

Abnormalities of ADAMTS13 may take the form of decreased quantity or absence of the enzyme, a mutation resulting in normal quantity of a defective enzyme, or an antibody inhibitor of the enzyme. Genetic or acquired defects in this protease have also been reported in patients with aHUS, but less frequently than in patients with TTP. Alterations in ADAMTS13 are not involved in the pathogenesis of STEC-HUS. The role of ADAMTS13 in both TTP and, less commonly, aHUS, remains incompletely understood.

WBCs are usually elevated in the blood of patients with hemolytic-uremic syndrome. Activated neutrophils are believed to damage endothelial cells by releasing elastase (a catabolic enzyme that promotes endothelial cell detachment) and by producing free radicals. Monocytes may be stimulated to release cytokines (ie, interleukin 1 and tumor necrosis factor [TNF]) that also damage endothelial cells.

aHUS has several genetic forms. Genetically induced cases are usually not preceded by diarrheal illness, often manifest a recurrent course, and are associated with a more guarded long-term prognosis regarding maintenance of normal kidney function. The best-studied genetic variant of hemolytic-uremic syndrome involves mutations in one of the short consensus repeat segments of the gene for factor H, a protein that regulates complement. Hemolytic-uremic syndrome with factor H mutations usually progresses to end-stage renal disease (ESRD) and has a nearly 100% recurrence rate in renal allografts. [2]

Mutations in factor I and membrane cofactor protein (MCP), also complement regulatory proteins, are also associated with aHUS. Factor I mutations are associated with a very high rate of recurrence, but patients with MCP mutations may have a more favorable long-term prognosis. Mutations of thrombomodulin, another complement regulatory protein, were identified in 5% of a group of patients with aHUS. [3] Autosomal dominant and autosomal recessive forms of aHUS due to a yet unidentified mutation have also been described.

Pneumococcal-associated hemolytic-uremic syndrome constitutes a distinct subgroup of aHUS. This variant occurs with infections caused by S pneumoniae, usually pneumonia. [4] It is actually a distinct entity that has little relation to the aHUS associated with complement factor mutations. The bacterial toxin neuraminidase damages endothelial cells and initiates hemolytic-uremic syndrome in this setting.

As a toxin-mediated disease, pneumococcal-associated hemolytic-uremic syndrome has much in common with STEC-HUS mediated by Stx. Bacteria with neuraminidase remove N- acetylneuraminic acid from cell-surface glycoproteins and expose the normally hidden T antigen (Thomsen-Friedenreich antigen) on erythrocytes, platelets, and glomeruli. Serum contains anti-T immunoglobulin M (IgM), which can react with the antigen and cause damage to RBCs and the kidneys.

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Epidemiology

Frequency

United States

Between 1982 and 2002, 354 E coli O157:H7–associated hemolytic-uremic syndrome cases were reported. Transmission route was highest among swimming outbreaks, followed by person-to-person, unknown, animal contact, foodborne, and drinking water–related outbreaks. Daycare centers were the most common person-to-person outbreak setting. Although contaminated ground beef was the most common cause of foodborne outbreaks, produce-associated outbreaks are also common (ie, lettuce, sprouts, cabbage, apple cider, apple juice). These have been attributed to fecal contamination of produce in the fields, from wild animals or from fertilization containing human or animal fecal matter.

Incidence is increased during the summer and early fall. Outbreaks of diarrhea followed by hemolytic-uremic syndrome have been reported in institutions, boarding schools, and daycare centers. Seasonal variation is not observed in aHUS. STEC-HUS is much more common than aHUS.

International

Hemolytic-uremic syndrome occurs worldwide but has a higher incidence in South Africa, Holland, and Argentina. The largest outbreak to date occurred in Germany in 2011.

Mortality/Morbidity

Mortality rates have decreased progressively from near universal fatality in 1955 to only 3-5% during the 1990s. This improvement is attributed to better management during the acute stage of the disease, with aggressive management of hypertension, fluid overload, electrolyte disturbances, and nutrition, often requiring dialysis. The mortality rate in underdeveloped countries remains as high as 72%. Patients with hereditary hemolytic-uremic syndrome have a worse prognosis. The vast majority of patients with autosomal dominant or recessive forms of the disease progress to ESRD.

Race

Hemolytic-uremic syndrome occurs in all races; however, it is very rare in blacks. This observation has no explanation.

Sex

Males and females are affected in equal numbers; however, the disease may affect female patients more severely.

Age

A large majority of cases of STEC-HUS occur in children aged 7 months to 6 years. STEC-HUS is much less common in adults, although the disease may occur at any age. A large outbreak in Germany due to a novel strain of E. coli 0104:H4 forms a notable exception, in which 88% of patients were adults. [5] No age predilection is noted for aHUS. Genetically mediated forms may present as early as birth or the neonatal period.

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