AUTHOR: C. John Sperati, MD, MHS
Hemolytic uremic syndrome (HUS) is a life-threatening disorder characterized by microangiopathic hemolytic anemia and severe acute kidney injury. HUS is a manifestation of the broader syndrome known as thrombotic microangiopathy (TMA).1 HUS, as opposed to some other forms of TMA, is notable for the severity of kidney injury. Although lacking a precise definition, HUS is commonly defined by the presence of acute kidney injury, anemia (hemoglobin <lower limit of normal), hemolysis (lactate dehydrogenase >upper limit of normal), and thrombocytopenia (platelets <lower limit of normal). Shiga toxin-producing E. coli infection (STEC-HUS) and hereditary or acquired complement dysregulation (atypical HUS, aHUS) are two important causes of HUS and are the focus of this chapter.
STEC-HUS (Shiga toxin-producing E. coli-hemolytic uremic syndrome)
aHUS (atypical hemolytic uremic syndrome)
TMA (thrombotic microangiopathy)
| ||||||||||||
Diarrhea-associated HUS, most commonly a result of infection with STEC-HUS, is largely a disease of children and the most common form of HUS in children <5 yr of age. The incidence is estimated at 2 to 3/100,000 persons. It is more common in summer and fall months and in rural areas.1,2
The incidence of atypical HUS (aHUS) is far less common, estimated at ∼0.1 per million children <17 yr old and <0.5 per million adults. The disease may be more common in adult women than men, without an apparent sex difference in pediatric patients. Although germline mutations that affect the complement cascade are common, a positive family history is present in <30%.3
In children with STEC-HUS, fever, abdominal pain, vomiting, and nonbloody diarrhea begin a median of 3 days after ingestion of contaminated material. Bloody diarrhea ensues 1 to 3 days later, and STEC-HUS typically develops within a week of the onset of diarrhea. Fever is often absent at clinical presentation, and fatigue, dehydration, oliguria, and pallor are common presenting signs. Seizures can develop with severe disease. Leukocytosis is associated with a worse prognosis.
The onset of aHUS may be preceded by an identifiable “second hit” event such as infection or pregnancy in 50% of patients or fewer. Acute kidney injury is particularly severe in aHUS, with 70% to 80% of patients requiring kidney replacement therapy (e.g., hemodialysis) shortly after presentation. The absence of severe acute kidney injury should prompt consideration of an alternative diagnosis. Thrombocytopenia is modest and often >60,000 cells/mm.3 Schistocytes may be present on peripheral blood smear but are often fewer than expected. Notably, GI symptoms may be present in 30% of patients, potentially mimicking STEC-HUS. Multi-organ system involvement with cardiovascular and neurologic complications is common. C3 levels are low in ∼50% of cases. Therefore, normal C3 concentration does not exclude aHUS. Proteinuria, potentially in the nephrotic range, and microscopic hematuria are frequently found.
Endothelial activation and injury with subsequent microvascular thrombosis underlie the pathophysiology of HUS.
STEC-HUS is commonly attributed to ingestion of beef contaminated with the enterohemorrhagic O157:H7 strain of E. coli. However, non-O157 strains now account for approximately 50% of cases, and sources include contaminated water, milk, cider, fish, and vegetables. Endothelial injury is initiated by binding of Shiga toxin, followed by leukocyte recruitment, increased thrombin generation, impaired fibrinolysis, and small vessel thrombosis. Secondary activation of complement may contribute to endothelial injury early in the disease.
In aHUS, a germline sequence variant affecting the alternative pathway of complement or an acquired autoantibody directed against complement factor H is identified in 60% to 80% of patients. A second-hit or “complement amplifying condition” (e.g., infection, pregnancy, inflammation) may be present. Endothelial injury results from the terminal membrane attack complex (C5b-9) and leukocyte recruitment, leading to activation of the coagulation system and small vessel thrombosis. The genes most commonly implicated in aHUS are complement factors H (CFH), I (CFI), and B (CFB); membrane cofactor protein (MCP); complement component 3 (C3); thrombomodulin (THBD); and complement factor H-related protein 5 (CFHR5). Homozygous deletion of the gene region encompassing complement factor H-related protein 1 (CFHR1) is associated with the development of autoantibodies against factor H (FH). Mutations of the diacylglycerol kinase Ε (DGKE) and metabolism of cobalamin associated C (MMACHC) genes are associated with aHUS, although the mechanism of TMA remains unclear and may not involve complement dysregulation.4,5
