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Hemolytic uremic syndrome is a thrombotic microangiopathy, clinically defined by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury.
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Hemolytic uremic syndrome may result from inherited or acquired genetic mutations or can be associated with disease-driven or environmental triggers. Classification systems are based on etiology and pathophysiologic mechanisms.
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Shiga toxin-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome constitute
Typical and Atypical Hemolytic Uremic Syndrome in the Critically Ill
Section snippets
Key points
Classification
The classification of HUS is rapidly evolving based on knowledge of underlying mechanisms and at least 7 classification systems have been proposed to differentiate HUS from other TMAs, and to delineate the differences between the diverse subtypes of HUS.1,2 Current classification systems are based on etiology and primary driving mechanisms involved in each HUS subtype (Fig. 1).1,4, 5, 6, 7, 8 Shiga toxin-associated HUS (STEC-HUS), also known as typical HUS, is caused by Shiga toxin
Epidemiology
HUS is an extremely rare disease that occurs most frequently in children, primarily affecting those younger than 5 years of age (overall annual incidence of 5–6 per 100,000 children), with equal distribution by gender.8 It is one of the leading causes of severe acute kidney injury (AKI) in children.9 HUS in adults is even less common, and most cases are reported during epidemics and outbreaks.10 Although the epidemiology in this group of the population is not well-documented because of the
General pathophysiologic concepts
HUS may result from a variety of etiologies that include genetic mutations, secondary to a systemic disease or as a result of an external environmental trigger. Despite varying in etiology, all forms of HUS along with other types of TMA arise from an initial endothelial injury that leads to the formation of thrombotic and nonthrombotic microvascular lesions characterized by fibrin and platelet-rich thrombi formation, affecting arterioles and capillaries predominantly. Endotheliosis (eg,
Diagnostic approach to the critically ill patient with suspected thrombotic microangiopathy
Patients with TTP and HUS develop organ dysfunction and often require management in the ICU. Therefore, the diagnosis of TMAs is challenging because many syndromes within the scope of critical illness, like sepsis, DIC, and malignant hypertension, mimic the clinical presentation of TMAs. These syndromes share the proinflammatory, endothelialopathy, and complement activation features of TMAs, which also lead to platelet aggregation and thrombus formation.38 Thrombocytopenia with MAHA are common
Pathophysiology
Enterocolitis from Stx-producing E coli (STEC) is the most common cause of HUS in children in the United States and Europe.16 Shiga-toxin producing serotype 0157:H7 is the most frequent causing strain. However, other EHEC serotypes have also been reported to cause HUS, such as O26, O45, O103, O111, O113, O121 and O145.8,14,53, 54, 55 Conversely, in developing countries, Shigella dysenteriae type 1 remains the predominant cause.8,54,56
Infection begins with ingestion of contaminated food or
Pathophysiology
Atypical HUS is primarily caused by a dysregulation of the complement system. Approximately 50% to 70% cases of aHUS have an underlying inherited or acquired complement genetic abnormality. However, no mutations are identified in 30% to 50% of patients,5,26,83 and despite having known related heterozygous gene mutations, some patients never develop aHUS, suggesting that associated at-risk polymorphisms in the various complement genes, disease modifiers, or precipitating events are necessary to
Secondary hemolytic uremic syndrome
The pathophysiologic mechanisms of secondary HUS are incompletely understood and the role of the complement system is not well established. Despite the absence of genetic complement abnormalities, a second-hit theory has been proposed to explain the role of complement in secondary HUS. Endothelial injury and activation lead to an increase in the expression and secretion of proinflammatory and procoagulant mediators that indirectly induce complement activation. Specific mechanisms for some forms
Pathophysiology
Although the pathogenesis of SP-HUS is not fully understood, evidence suggests that Thomsen-Freidenreich antigen (T-antigen) may play an important role in the development of the disease. After exposure to neuraminidase-producing S pneumoniae, N-acetylneuraminic acid is cleaved from glycoproteins on the cell membranes of glomeruli, erythrocytes, and platelets, exposing the underlying T-antigen to the plasma environment.104 T-antigen reacts with circulating anti–T-antigen IgM antibodies present
Pregnancy-associated atypical hemolytic uremic syndrome
During pregnancy, many types of TMA can be triggered including ADAMTS13 deficiency TTP (during the second and third trimesters), aHUS (mostly in postpartum women), and HELLP syndrome, which is a severe variant of pre-eclampsia.6 Pregnancy-associated aHUS occurs in approximately 20% of adult female patients with aHUS, with 80% presenting postpartum, and is associated with severe AKI requiring dialysis.126 Complement abnormalities are identified in the majority of the patients, including
Summary
HUS is characterized by MAHA, thrombocytopenia, and AKI. DIC, TTP, and HUS have similar clinical presentations. The diagnostic approach to a patient with suspect TMA should be implemented promptly to decrease mortality, because identifying the different disorders can help to tailor specific and effective therapies. However, diagnosis is challenging and morbidity and mortality remain high, especially in the critically ill patient population. The development of clinical prediction scores and
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Funding: Supported by NIH (NIGMS) grant 1K08GM117310-01A.