Hemolytic uremic syndrome (HUS) is a disease characterized by the sudden occurrence of acute hemolytic anemia (fragmentation of red blood cells), kidney failure (uremia) and low levels of platelets in the blood (thrombocytopenia). Except kidney, other organs (such as brain or heart) may also be affected by damage to very small blood vessels. HUS is predominantly found in children under the age of 5, which is the most common cause of acute kidney failure in children, while it is increasingly recognized in adults.
Symptoms of Hemolytic Uremic Syndrome
Fig. 1 Schizocytes in hemolytic-uremic syndrome.1
Causes of Hemolytic Uremic Syndrome
HUS can be classified as typical and atypical. Typical HUS is often caused by infections of the gastrointestinal tract, associated with gastrointestinal symptoms, including vomiting and diarrhea. Atypical HUS is not associated with an infection of the digestive tract but has close relationship with several genetic mutations that cause chronic, uncontrolled, and excessive activation of complement.
The most common cause of typical HUS is infection with E. coli bacteria that produce certain toxins (shiga toxin-producing E. coli or STEC). The widely accepted E. coli serotypes include O157:H7 and O104:H4. Other E. coli serotypes implicated include O111:H8, O103:H2, O121, O145, O26, and O113. When the organism is infected, the immune reaction can cause direct damage to kidney cells resulting in kidney injury. Alternatively, the destroyed red blood cells or platelets may clog up the filtering system of kidney, causing metabolic waste accumulation and kidney injury. Recent studies showed that a variety of viruses have also been implicated as a causative agent.
Atypical HUS can occur in sporadic cases or in families, the latter is associated with genetic abnormalities of the complement regulatory proteins, including C3, factor B, factor H, factor I, and CD46 (membrane cofactor protein, MCP). Shiga-toxin can not only direct activate the alternative pathway of complement but also interferes with complement regulation by binding to complement factor H, an inhibitor of the complement cascade. So factor H appears to be particularly important.
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A: The complement system plays a crucial role in the pathogenesis of HUS. HUS is often associated with dysregulation of the alternative complement pathway, which can result in uncontrolled activation of the complement system. This activation can lead to the formation of membrane attack complexes (MAC) on the surface of endothelial cells, causing damage to blood vessels and triggering a cascade of events that ultimately result in thrombotic microangiopathy, hemolysis, and kidney injury.
A: Future research should focus on elucidating the mechanisms underlying complement dysregulation in HUS subtypes, developing more cost-effective therapies, and exploring alternative targets beyond complement C5.
A: Yes, the field of complement therapeutics is continually evolving. Emerging therapies include those targeting specific complement components, such as C3 and C1s, as well as novel approaches like gene therapy and small molecule inhibitors. These developments hold promise for more precise and effective treatments for HUS.