Hemolytic-uremic syndrome (HUS) is an acute, fulminant disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS usually occurs in children following an infection, typically with Shiga toxin–producing bacteria (eg, Escherichia coli O157:H7
(See also Overview of Platelet Disorders.)
Pathophysiology of HUS
Hemolytic-uremic syndrome, like thrombotic thrombocytopenic purpura (TTP), involves nonimmunologic platelet destruction. Endothelial damage is common. Loose strands of platelets and fibrin are deposited in multiple small vessels and damage passing platelets and red blood cells (RBCs), causing significant thrombocytopenia and anemia (microangiopathic hemolytic anemia). Platelets are also consumed within multiple small thrombi, contributing to the thrombocytopenia.
Multiple organs develop platelet–von Willebrand factor (VWF) thrombi localized primarily to arteriocapillary junctions, described as thrombotic microangiopathy. The brain, heart, and kidneys are particularly likely to be affected. The microthrombi do not include RBCs or fibrin (unlike thrombi in disseminated intravascular coagulation) and do not manifest the vessel wall granulocytic infiltration characteristic of vasculitis. Large-vessel thrombi are uncommon.
Etiology of HUS
Most cases occur in children and follow
Acute infection
Most often (about 90% of cases), the infection is acute hemorrhagic colitis resulting from Shiga toxin–producing bacteria (eg, Escherichia coli O157:H7, or some strains of Shigella dysenteriae). Occasionally, the cause is pneumococcal infection or rarely HIV infection. Activation of the complement system is common in children with HUS caused by acute infection.
A small minority of cases are unrelated to infection and involve
Mutations of the complement system: These mutations involve genes controlling complement proteins or complement factors but sometimes from acquired autoantibodies to certain complement factors. Congenital complement disorders may also increase the risk of HUS after an infection.
Symptoms and Signs of HUS
Children with Shiga toxin–related hemolytic-uremic sydrome (HUS) usually have a prodrome of vomiting, abdominal pain, and diarrhea (frequently bloody) and often a history of exposure to infection. Patients with pneumococcal-related HUS usually have manifestations of pneumonia, meningitis, or sepsis. Fever does not usually occur. About a week after the prodrome, manifestations of hemolytic anemia, thrombocytopenia, and acute kidney injury develop.
HUS due to complement-factor mutations do not usually have an infectious prodrome but may be exacerbated by an infection.
Manifestations of ischemia develop with varying severity in multiple organs. Neurologic manifestations occur in about one quarter of patients and include weakness, confusion, and seizures. Kidney injury may produce hematuria, decreased urination or anuria, and/or hypertension. Despite thrombocytopenia, purpura and overt bleeding are uncommon although gastrointestinal tract ischemia may cause significant hemorrhagic colitis, with abdominal pain, nausea, vomiting, and bloody diarrhea. Cardiac involvement may cause arrhythmias.
Diagnosis of HUS
Complete blood count (CBC) with platelets, peripheral blood smear, direct antiglobulin (Coombs) test, LDH, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen
Exclusion of other thrombocytopenic disorders
Hemolytic-uremic syndrome is suspected in patients with suggestive symptoms, thrombocytopenia, microangiopathic anemia, and signs of acute kidney injury.
If the disorder is suspected, urinalysis, peripheral blood smear, reticulocyte count, serum lactic dehydrogenase (LDH), haptoglobin, renal function tests, serum bilirubin (direct and indirect), PT, PTT, fibrinogen, and direct antiglobulin test are done.
ADAMTS13 enzyme activity levels may be helpful. ADAMTS13 activity is low in TTP but is usually not decreased in HUS. This enzyme is a plasma protease that cleaves von Willebrand factor; deficiency causes thrombotic thrombocytopenic purpura (TTP), and decreased ADAMTS13 activity levels may differentiate atypical cases of TTP from HUS.
ADAMTS13 are always normal, and patients do not respond to plasma exchange, corticosteroids, or complement inhibition.
The diagnosis of HUS is suggested by
Thrombocytopenia and anemia
Fragmented red blood cells on the blood smear indicative of microangiopathic hemolysis (schistocytes: helmet cells, triangular RBCs, distorted-appearing RBCs—see photo Schistocytes)
Evidence of hemolysis (falling hemoglobin level, polychromasia, elevated reticulocyte count, elevated serum LDH and bilirubin, reduced haptoglobin)
Negative direct antiglobulin test
Absence of use of a medication that can cause thrombotic microangiopathy
Normal ADAMTS13 activity
Diagnosis of cause
Stool testing (Shiga toxin enzyme-linked immunosorbent assay or specific culture media for E. coli O157:H7) is done in children with diarrhea and also adults who had a prodrome of bloody diarrhea (1); however, the organism and toxin may have cleared by the time of presentation.
In atypical cases, that is, in patients who have not had preceding infection or who have recurrent disease, testing for complement factor gene mutations is recommended. However, mutations are not always specific for atypical HUS (2), and at least half of patients do not have mutations in complement factor genes (3).
Diagnosis references
1. Gould LH, Bopp C, Strockbine N, et al. Recommendations for diagnosis of shiga toxin--producing Escherichia coli infections by clinical laboratories. MMWR Recomm Rep 2009;58(RR-12):1-14.
2. Timmermans SAMEG, Wérion A, Damoiseaux JGMC, Morelle J, Reutelingsperger CP, van Paassen P. Diagnostic and Risk Factors for Complement Defects in Hypertensive Emergency and Thrombotic Microangiopathy. Hypertension 2020;75(2):422-430. doi:10.1161/HYPERTENSIONAHA.119.13714
3. Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat 2010;31(6):E1445-E1460. doi:10.1002/humu.21256
Treatment of HUS
Supportive care, often including hemodialysis
In patients without a known complement factor deficiency, complement inhibitory medications can usually be stopped when signs of disease activity resolve.
Treatment reference
1. Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 2016;31(1):15-39. doi:10.1007/s00467-015-3076-8
Key Points
Platelets and red blood cells are destroyed nonimmunologically, leading to thrombocytopenia and anemia; renal failure is common in children and adults with hemolytic-uremic syndrome (HUS).
Cause in children is typically hemorrhagic colitis resulting from Shiga toxin–producing bacteria.
Less common causes involve complement dysregulation from a variety of inherited and acquired causes.
Typical diarrhea-associated HUS in children usually spontaneously remits with supportive care, although over half of affected children require renal dialysis and the use of complement inhibition.
