Hemolytic uremic syndrome (HUS) was first described in 1955. It is one of the most frequent causes of acute renal failure in children and is defined by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The incidence of HUS is 2.7 cases per million people per year in the United States.1 HUS can occur at any age but most often presents between 2 months and 8 years of age, with equal male and female predominance. It has a seasonal peak in the summer and early fall.2 HUS is divided into two main categories, typical diarrhea-associated (D+ HUS) and atypical non-diarrhea associated HUS (aHUS). The most common form is D+ HUS, which is caused by Shiga toxin–producing bacteria and accounts for 90% of cases. Atypical HUS (aHUS), sometimes called D-HUS, accounts for the remaining cases (Table 113-1). Recently, it has become recognized that the two categories of HUS are not mutually exclusive. Some cases of HUS are multifactorial, with as many as 25% of patients with D+ HUS having mutations in complement system gene sequences.3
TABLE 113-1Causes of Atypical Hemolytic Uremic Syndrome (aHUS) ||Download (.pdf) TABLE 113-1 Causes of Atypical Hemolytic Uremic Syndrome (aHUS)
|Drug related |
|Oral contraceptives |
|Post-transplant immunosuppressants (cyclosporine, tacrolimus) |
|Chemotherapy (mitomycin, cisplatin, bleomycin) |
|Streptococcus pneumoniae* |
|Human immunodeficiency virus (HIV) |
|Complement regulatory protein mutations (C3, Factor H, B, I, CD46) |
|Methylmalonic acidemia† |
Shiga toxin-producing Escherichia coli (0157:H7 and other strains) are found in the gastrointestinal (GI) tract of beef cattle and can be isolated from inadequately cooked ground beef. Shiga toxin can also be produced by Shigella dysenteriae and may be present in contaminated water. Other reported vehicles of transmission include deer jerky, salami, unpasteurized milk, unpasteurized apple cider, salmon, and lettuce or radish sprouts.4 After an exposure to contaminated water or food, the average incubation period is 3 days prior to the development of diarrhea. Shiga toxin targets microvascular endothelial cells. This damaging effect on the vascular endothelium triggers multiple cellular and vascular phenomena leading to thrombus formation (a.k.a. thrombotic microangiopathy). Of note, urinary tract infections caused by Shiga toxin producing E. coli have also been reported prior to the development of HUS.5
In contrast to typical D+ HUS, aHUS can be seen in individuals with a genetic predisposition to complement dysregulation. Genetic mutations decrease the activity of complement regulatory proteins, and thus these individuals may have an uncontrolled complement response leading to endothelial damage and thrombosis when they are exposed to an inciting trigger. Environmental triggers such as infection, drugs such as immunosuppressants and oral contraceptives, and pregnancy can all trigger aHUS. Infectious diseases (especially by the influenza virus H1N1) account for the trigger in 50% to 80% of patients, and Shiga toxin induced diarrhea triggers aHUS in 30% of cases.
Five percent of aHUS cases in children are caused by Streptococcus pneumoniae strains. This bacteria produces the enzyme neuraminidase, which exposes cryptoantigen in the T cell surface, producing thrombotic microangiopathy. HUS triggered by S. pneumoniae is usually associated with severe invasive infection such as sepsis, meningitis, or complicated pneumonia.
Classic D+ HUS presents 2 days to 2 weeks after a prodrome of diarrheal illness.4 Typically, the diarrhea is non-bloody for 1 to 3 days before becoming bloody, and is associated with abdominal pain and vomiting.4,6 Just as the child’s symptoms of colitis seem to be resolving, he or she presents with pallor, irritability, and sometimes oligoanuria. Patients commonly have petechiae, edema, dehydration, hypertension, and electrolyte abnormalities. Some patients may appear fluid-overloaded despite intravascular depletion. Third spacing of fluid to extravascular tissues can result from the combined effects of hypoalbuminemia, vascular injury, and hyponatremia. Patients may develop pulmonary edema and effusions due to third spacing.
Neurologic findings such as irritability and lethargy often occur and most commonly may be related to dehydration, fatigue, or direct neuronal effects of Shiga toxin. However, practitioners must carefully evaluate patients with neurologic symptoms since thrombotic microangiopathy can also occur in the brain, causing 10% of children to develop seizures, coma, or stroke. Neurologic complications of HUS have been associated with higher rates of morbidity and mortality. Endothelial damage of blood vessels can also occur elsewhere in the body, leading to pancreatitis, hepatitis, GI bleeding, intussusception, and myocarditis.
aHUS predominantly affects the renal vessels, but due to the diffuse thrombotic microangiopathy, other organ systems (brain, heart, intestines, pancreas, and lungs) are more commonly affected than with D+ HUS. The most frequent extra-renal symptoms are neurological (48%), which can include irritability, somnolence, confusion, convulsions, encephalopathy, cerebrovascular accidents, hemiparesia, hemiplexia, and coma. Myocardial infarction has been described in 3% of patients with aHUS and can cause sudden death. Cardiomyopathy, heart failure, and peripheral ischemic heart disease have also been described, in addition to diarrhea (30%), vomiting, and abdominal pain. Variability in presentation makes aHUS more difficult to diagnose, and in some cases difficult to distinguish from D+ HUS.3
The course of HUS can be variable in severity and duration, but there is a general pattern to the illness. Patients are diagnosed following the usual clinical course of resolving colitis and the onset of anemia, thrombocytopenia, and renal dysfunction. Over the next hours to days of illness, the patient’s general clinical picture worsens, with further decreases in hemoglobin, platelets, and urine output and increasing blood urea nitrogen and creatinine. Thirty percent to 50% of patients may progress to renal failure with anuria, requiring dialysis, while others follow a milder course of illness.7 After this period of decline, there is usually a plateau that lasts for several days or even weeks. The child may remain on dialysis and be transfusion dependent during this time. Eventually, most patients recover, heralded by an increase in platelets. Recovery of other systems follows slowly. Most children survive the acute phase; however, there is a mortality rate of 2% to 5%.2,8 The mortality rate has decreased in recent years, and this has been attributed to increased transfer of patients to institutions with pediatric nephrologists and improvement in the use of dialysis in pediatric patients.8
Although the majority of children with D+ HUS are thought to have complete recovery, up to 30% of patients may have long-term sequelae including renal impairment, hypertension, or central nervous system manifestations.5,9 Studies show that mild chronic renal sequelae such as hypertension, proteinuria, or low creatinine clearance may persist in 10% to 50% of patients, depending on the population.2,7,9 End-stage renal disease (ESRD) occurs in 3% to 6% of patients.2,9 In a 20-year longitudinal study in Utah, 11% of patients with D+ HUS had a negative outcome, defined as either death, ESRD, or stroke.2
Predictors of poor prognosis include severe prodromal illness, increased white blood cell count at presentation (>20 K), increasing number of days of anuria, multisystem involvement (especially CNS), and age<2 years.2,10 Severe dehydration at the time of initial diarrheal illness with resultant acute tubular injury may increase the chance of developing oligoanuric HUS and chronic renal sequelae.11
In contrast to typical HUS, aHUS is a chronic condition due to its genetic origins, and has a poorer prognosis. More than 50% of patients with aHUS die from the illness, require dialysis, or develop permanent kidney damage during the year following diagnosis.3 Morbidity and mortality remains high despite the use of monoclonal antibody for treatment. aHUS triggered by S. pneumoniae is also associated with severe illness, with higher long-term morbidity compared to D+ HUS.12
When present, the constellation of findings in HUS is generally easily recognized. Early in the course, however, diagnosis can be more difficult. Other causes of enterocolitis, such as Salmonella, Campylobacter, Yersinia, Clostridium difficile, and amebiasis may cause dehydration and acute kidney injury but usually do not cause thrombocytopenia or hemolytic anemia. Diseases that cause acute renal failure, such as the glomerulonephritides and vasculitides may mimic HUS. Other considerations are early ulcerative colitis, bilateral renal vein thrombosis, systemic lupus erythematosus, and malignant hypertension.
Diseases that cause thrombotic microangiopathy can also be confused with HUS. Disseminated intravascular coagulation (DIC) as seen in sepsis may be confused with HUS due to presence of thrombocytopenia and anemia. However, coagulation profiles will be normal in HUS. Thrombotic thrombocytopenic purpura (TTP) has a similar presentation to HUS. However, TTP is most commonly seen in adults and involves the central nervous system much more often than HUS. Also, patients with TTP have a deficiency of ADAMSTS13, which is a von Willebrand factor–cleaving protease that regulates thrombus formation, while patients with HUS have normal ADAMSTS13 levels.3
The diagnosis of HUS depends on history, physical examination, and laboratory findings. Stool cultures obtained during the acute diarrheal phase may reveal E. coli O157:H7 and therefore heighten the suspicion for HUS. However, stool cultures obtained after the acute diarrheal phase are not as useful since the yield of positive cultures decreases dramatically after the sixth day of illness. Some centers perform both stool culture and Shiga toxin testing simultaneously from a single stool sample.
Laboratory evaluation usually reveals thrombocytopenia as the first sign of HUS followed by the development of anemia with hemoglobin levels in the range of 5 to 9 g/dL.4 Red blood cells have the morphology of schistocytes and helmet-shaped forms due to the microangiopathic hemolysis caused by cell trauma from the renal microvasculature. Fibrin degradation products are elevated, but coagulation studies are normal. White blood cell counts are often increased, and the reticulocyte count may be increased as the marrow attempts to replace hemolyzed red blood cells. Laboratory criteria to diagnosis HUS are hemoglobin level <10 g/dL with signs of fragmented erythrocytes on peripheral smear, thrombocytopenia with a platelet count <150, and acute renal impairment with serum creatinine greater than the age-related range (>97th percentile) or glomerular filtration rate (GFR) <80 mL/min/1.73 m2 by Schwartz formula.5
A broad range of electrolyte abnormalities can be seen related to the renal dysfunction; most often patients have hyperkalemia, hypocalcemia, and either hypo- or hypernatremia. Both blood urea nitrogen and creatinine are variably elevated, based on the degree of renal involvement. Urine samples are usually not considered helpful since they are often contaminated as diarrhea is subsiding, but if obtained may reveal microscopic hematuria, proteinuria, and casts. Amylase, lipase, and liver enzymes may be elevated. Renal ultrasonography is generally not useful as it typically reveals nonspecific findings. Echocardiography should be considered in the face of myocarditis or other cardiac dysfunction. Electrocardiography may be considered to evaluate for the effects of hyperkalemia or if myocardial ischemia is suspected. Computed tomography or magnetic resonance imaging of the brain should be considered when neurologic complications arise. Air or contrast enema can be helpful when GI complications such as intussusception, perforation, stricture, or toxic megacolon are suspected.
The mainstay of therapy is management of renal dysfunction. Urine output and electrolytes should be monitored closely, and fluids adjusted as necessary. Fluid balance is a challenging issue in HUS since renal perfusion must be maintained while avoiding fluid overload. Daily weights and strict intake and output should be recorded during hospitalization to monitor fluid status. Anuric patients should have fluid intake limited to insensible losses (about one-third maintenance) plus output. Diuretics should be avoided in absence of severe fluid overload since they may decrease intravascular volume and perfusion to the kidneys.4 Dialysis is a most effective mode of management for severe fluid overload. Other indications for dialysis include hyperkalemia, severe metabolic acidosis (persistent bicarbonate <10 mmol/L), severe uremia (BUN >36 mmol/L), or signs and symptoms of volume overload.
Nutritional support is imperative for recovery. Enteral feeding is preferred if permitted by the patient’s clinical status. If this is not possible, parenteral nutrition should be initiated. Diarrhea should be managed with supportive care with the avoidance of antimotility agents and nephrotoxic agents such as NSAIDs. Narcotics should also be avoided since they can cause seizures in children with renal failure.4 Avoidance of antibiotics during the acute phase of diarrheal illness continues to be a controversial topic. A 2002 meta-analysis which concluded that antibiotic therapy may not be harmful has been widely discredited due to the inclusion of one large study that showed beneficial effect of fosfomycin administration. Fosfomycin was compared to other antibiotics in this study and not placebo.4,13 A recent prospective cohort study showed that antibiotic exposure significantly increased the odds of developing oliguric and non-oliguric HUS.14 Currently, antibiotics should be avoided since it seems that risks outweigh any potential benefits.
Hypertension is initially controlled through the careful stabilization of volume status. If hypertension persists, medical management can be initiated. Calcium channel blockers such as nifedipine are frequently used as first-line agents. In cases of long-term renal sequelae, such as hypertension and proteinuria, ongoing surveillance and close follow-up are indicated.
Patients who develop neurologic symptoms, such as irritability, lethargy, confusion, seizures or abnormal neurologic exam require urgent brain imaging to evaluate for stroke. These patients should be transferred to an intensive care unit for closer monitoring. Neurologic complications are known to be important determinants of morbidity and mortality.4,7
Patients can become profoundly and rapidly anemic and may require transfusion if they develop any cardiovascular or respiratory compromise. Eighty percent of patients with HUS need erythrocyte transfusions. Blood products should be volume-reduced and given slowly to prevent the chance of worsening hypertension. Leukocyte depletion of packed red blood cells is recommended to reduce alloimmunization in case renal transplantation is required in the future. Platelets should be given only in the face of active bleeding or the need for an invasive procedure (e.g. dialysis catheter placement, central venous line placement). More liberal use of platelets can actually increase thrombus formation in the renal microvasculature and cause clinical deterioration.7
In aHUS, plasma exchange was traditionally used early in the illness to decrease toxin load. Most recently experts are recommending use of eculixumab, if available, instead of plasma exchange. Eculixumab is an IgG-humanized monoclonal antibody that binds to complement proteins with great affinity and blocks excision of complements that lead to the formation of membrane attack complexes and ensuing damage. Positive clinical responses to eculixumab have been reported.3 If eculixumab is not available, plasma exchange should be done early. Although the evidence is sparse, some practitioners also use eculixumab and plasma exchange for severe D+ HUS accompanied by neurologic complications. This approach makes sense given the severity of illness, poor prognosis, and possibility of multifactorial disease (underlying genetic predisposition). Practitioners should be aware that patients receiving eculixumab have increased susceptibility to encapsulated bacterium, such as meningococcus, pneumococcus, and Haemophilus influenzae type b, due to the suppression of the complement activity. Patients should receive vaccinations as a preventive measure.
Any child with suspected or confirmed HUS should be admitted for close monitoring and evaluation.
Patients with neurologic symptoms, hypertensive emergency, and/or the need for urgent dialysis (severe volume overload, electrolyte derangements, severe acidosis, severe uremia) require admission to an intensive care unit.
Renal function improving and electrolytes stable.
Platelet count rising.
Hemoglobin stable or increasing.
Ability to maintain adequate oral intake for fluid and nutritional needs.
Hypertension resolved or controlled with medication.
Specific consultation services should be based on the severity of illness and the organ systems involved. Examples include the following:
Nephrology evaluation for significant renal dysfunction and management of hypertension.
Cardiology consultation if carditis is present.
Hematology evaluation for management of hemolytic anemia and indications for transfusion.
Gastroenterology or surgical evaluation for complications of colitis.
Since HUS is a rare but serious complication of a common presenting condition, it may be helpful to identify clinical or laboratory predictors for children at risk for development of HUS. Many children with severe diarrhea may be briefly hospitalized due to dehydration and then discharged prior to development of HUS symptoms, and stool culture results may not be available at the time of discharge. Anticipatory guidance and follow-up can be tailored for a high-risk group. Several recent prospective studies have sought to identify predictors for development of HUS in children with Shiga toxin–associated diarrhea. One prospective cohort study reported that higher leukocyte count, vomiting, and exposure to antibiotics during the acute phase of illness among children with E. coli 0157:H7 may predict the development of HUS.14 Higher white blood cell count with neutrophilic predominance on admission was also associated with development of HUS in children in a prospective epidemiologic surveillance study in Argentina.5 Further studies are needed to assess cost–benefit and patient outcomes with the use of screening white blood cell counts in patients hospitalized with bloody diarrhea. Interestingly, the study in Argentina also identified high serum Shiga toxin levels at the beginning of a diarrheal illness in patients who later developed HUS.5 A screening strategy using serum Shiga toxin levels at the time of hospital admission for patients with suspected bacterial gastroenteritis also warrants further study.
Early identification may also be useful because early management decisions during the diarrheal phase may modify HUS outcomes. Generous administration of intravenous fluids during the first 4 days of gastroenteritis and use of isotonic fluids may reduce the risk for development of oligoanuric HUS, which is usually associated with a more complicated hospital course and long-term renal sequelae.11 No studies have identified methods to prevent the development of HUS at this time.
Because many cases of HUS follow a GI illness, prevention of the inciting illness may lead to the prevention of HUS. This is relevant in the case of infection with E. coli 0157:H7, because about 13% of infected pediatric patients develop HUS. Reduction in E. coli infection can be accomplished by avoiding raw or undercooked ground beef and unpasteurized milk, cheese, or cider. Decreasing levels of 0157:H7 in cattle, thereby reducing the risk of humans acquiring the disease, can be accomplished by modification of the animals’ diet before slaughter, and by irradiation of meat.
Infection can be associated with exposure to farm and zoologic animals (e.g. petting zoos, farm tours), because many animals shed this organism.15 Person-to-person transmission is also a concern, especially in places such as daycare centers, where outbreaks might occur. Hand hygiene is an effective tool to reduce transmission, although compliance can be a challenge. In the hospital setting, contact precautions are indicated to limit the risk of transmission.
Routine antibiotic treatment of E. coli 0157:H7 is not recommended, because antimicrobial therapy of the diarrheal illness may increase and certainly does not decrease the risk of developing HUS.13
HUS is defined by a clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and varying degrees of acute kidney injury.
Ninety percent of cases are preceded by Shiga toxin–induced enteritis.
A small percentage of atypical cases follow an invasive S. pneumoniae infection or occur in genetically predisposed hosts.
Multisystem extrarenal involvement can occur in severe cases, with involvement of the brain, heart, lungs, pancreas, liver, and intestines.
Diagnosis is made clinically and by laboratory findings.
Management for typical D+ HUS involves meticulous fluid balance, judicious red cell transfusions, nutritional support, antihypertensive medication, and dialysis when indicated.
Patients with aHUS and/or neurologic symptoms may benefit from eculixumab and plasma exchange therapy.
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MK. A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in Utah. Pediatrics
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et al. An epidemiologic surveillance of Shiga-like toxin-producing Escherichia coli infection in Argentinean children. Risk factors and serum Shiga-like toxin 2 values. Pediatr Infect Dis J
K. Management of diarrhea-associated hemolytic uremic syndrome in children. Clin Exp Nephrol
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National Association of State Public Health Veterinarians, Inc. Compendium of measures to prevent disease associated with animals in public settings, 2005. MMWR Recomm Rep. 2005;54:1–12.