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

PATHOPHYSIOLOGY

Typical D+ HUS

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

Atypical HUS

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.

Typical D+ HUS

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.

Atypical HUS

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

HOSPITAL COURSE

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

PROGNOSIS

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