Overview
Definition:
Hemolytic uremic syndrome (HUS) is a microangiopathic hemolytic anemia characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury
It is a life-threatening condition, primarily affecting children, and can be broadly classified into typical (Shiga toxin-producing Escherichia coli-associated HUS, or STEC-HUS) and atypical forms.
Epidemiology:
Typical HUS is the most common form in developed countries, accounting for about 90% of cases, with an incidence of 2-3 cases per 100,000 children annually
Atypical HUS (aHUS) is rarer but more severe, with a higher mortality and morbidity
It can occur at any age but often presents in infancy or early childhood
Risk factors for STEC-HUS include consumption of contaminated food or water, and contact with infected individuals.
Clinical Significance:
HUS is a medical emergency requiring prompt recognition and management
The microvascular injury can affect multiple organ systems, leading to severe complications including irreversible kidney damage, neurological sequelae, and gastrointestinal complications
Understanding the distinction between typical and atypical forms is crucial as it guides diagnostic workup and therapeutic strategies, particularly concerning the use of plasma exchange and complement inhibition.
Typical Hus
Definition:
Typical HUS, also known as STEC-HUS, is predominantly caused by Shiga toxin-producing *Escherichia coli* (STEC), most commonly O157:H7
The toxin damages the endothelial cells of the microvasculature, leading to platelet aggregation and thrombus formation.
Etiology:
Ingestion of STEC bacteria, typically through undercooked ground beef, contaminated produce, or unpasteurized milk
Person-to-person transmission can also occur
The toxin binds to globotriaosylceramide (Gb3) receptors on endothelial cells, initiating damage.
Clinical Features:
Preceded by a prodromal diarrheal illness, often bloody (hemorrhagic colitis)
Symptoms include abdominal pain, vomiting, and diarrhea, followed by the onset of anemia, thrombocytopenia, and AKI
Other manifestations can include neurological symptoms (lethargy, seizures), hypertension, and less commonly, pancreatitis or myocarditis.
Investigations:
Stool culture for STEC and Shiga toxin detection
Complete blood count (CBC) showing microangiopathic hemolytic anemia (schistocytes on peripheral smear) and thrombocytopenia
Renal function tests (urea, creatinine) showing elevated levels
Urinalysis may show proteinuria and hematuria
Lactate dehydrogenase (LDH) is elevated, and haptoglobin is low
Coagulation profile is typically normal, distinguishing it from DIC.
Atypical Hus
Definition:
Atypical HUS (aHUS) is a rare, genetic or acquired disorder characterized by dysregulation of the alternative complement pathway
Unlike typical HUS, it is not typically preceded by a diarrheal illness and often has a relapsing or progressive course.
Etiology:
Caused by mutations in genes encoding complement regulatory proteins (e.g., complement factor H (CFH), CFHR1-5, complement factor I (CFI), membrane cofactor protein (MCP/CD46), thrombomodulin) or acquired autoantibodies against these proteins (e.g., anti-CFH antibodies)
These defects lead to uncontrolled complement activation on endothelial surfaces, particularly in the kidneys.
Clinical Features:
Onset can be insidious or acute, without a diarrheal prodrome
Recurrent episodes of AKI are common
Other affected organs can include the CNS, heart, lungs, and gastrointestinal tract
Thrombocytopenia and hemolytic anemia are present
Hypertension is frequent
Genetic predisposition is a hallmark, and family history may be positive.
Investigations:
Similar initial investigations as typical HUS: CBC, renal function, LDH, haptoglobin
However, stool studies are negative for STEC
Genetic testing for complement gene mutations is crucial for diagnosis
Screening for anti-CFH antibodies may be indicated
Complement assays can show reduced C3 levels due to alternative pathway activation, but C3 levels may be normal in some cases.
Diagnostic Approach
History Taking:
Key history points include recent gastrointestinal illness (bloody diarrhea), food and water exposures, antibiotic use prior to diarrhea (risk factor for STEC-HUS), family history of kidney disease or HUS, and history of recurrent AKI
Note any neurological symptoms or signs of systemic involvement.
Physical Examination:
Assess for pallor (anemia), petechiae/purpura (thrombocytopenia)
Monitor blood pressure closely for hypertension
Examine for signs of fluid overload (edema, rales)
Neurological assessment for lethargy, confusion, or seizures
Abdominal examination for tenderness
Assess hydration status.
Investigations:
Essential investigations include CBC with peripheral smear for schistocytes, reticulocyte count, LDH, haptoglobin, creatinine, urea, electrolytes, urinalysis (proteinuria, hematuria, casts), coagulation profile (PT, PTT, fibrinogen), and stool studies for STEC
For suspected aHUS, consider complement gene mutation analysis and anti-CFH antibody testing
Blood pressure monitoring is critical.
Differential Diagnosis:
Differential diagnoses include thrombotic thrombocytopenic purpura (TTP), which typically has more severe neurological involvement and normal renal function initially
disseminated intravascular coagulation (DIC), characterized by abnormal coagulation parameters
and other causes of AKI in children, such as post-infectious glomerulonephritis or acute interstitial nephritis.
Management
Initial Management:
Supportive care is paramount
Fluid management is crucial, balancing hydration with avoiding fluid overload, especially in the presence of AKI and hypertension
Blood pressure control is essential using antihypertensives like calcium channel blockers or ACE inhibitors
Management of anemia and thrombocytopenia is generally supportive
transfusions are indicated for symptomatic anemia or significant bleeding.
Medical Management:
For typical HUS, management is primarily supportive
Antibiotics are generally *not* recommended and may increase the risk of Shiga toxin release
Plasma exchange (PLEX) is controversial and its benefit in typical HUS is debated, usually reserved for severe cases with neurological involvement or persistent AKI
For atypical HUS, treatment with complement inhibitors, such as eculizumab, is the mainstay of therapy
This targets the uncontrolled alternative complement pathway activation.
Dialysis Indications:
Dialysis is indicated for severe acute kidney injury in HUS when there is: oliguria or anuria persisting for >24-48 hours
fluid overload refractory to diuretic therapy
severe electrolyte disturbances (e.g., hyperkalemia > 6.5 mmol/L or rapidly rising K+)
severe metabolic acidosis (pH < 7.1 or bicarbonate < 15 mmol/L) refractory to medical management
uremic symptoms such as encephalopathy or pericarditis.
Supportive Care:
Close monitoring of vital signs, fluid balance, and renal function
Nutritional support should be provided
Management of electrolyte imbalances
Patients require admission to an intensive care unit for close monitoring and management of complications
Education of caregivers regarding the condition and long-term follow-up is important.
Complications
Early Complications:
Neurological sequelae (seizures, stroke, coma) are common, particularly in STEC-HUS
Severe hypertension
Pancreatitis
Myocarditis
Colitis progression leading to perforation or toxic megacolon
Severe anemia and thrombocytopenia.
Late Complications:
End-stage renal disease requiring chronic dialysis or kidney transplantation
Hypertension
Recurrent HUS episodes in aHUS
Neurological deficits
Growth retardation.
Prevention Strategies:
Prevention of STEC-HUS involves safe food handling practices (thorough cooking of meat, washing produce), avoiding unpasteurized products, and good hygiene
For aHUS, genetic counseling and prompt recognition of prodromal symptoms in individuals with known genetic mutations can help initiate early treatment with complement inhibitors to prevent or mitigate kidney damage.
Prognosis
Factors Affecting Prognosis:
For typical HUS, prognosis is generally good with supportive care, with most children recovering renal function within weeks
However, mortality can be up to 5-10%, and some may develop chronic kidney disease
For aHUS, prognosis is poorer without specific treatment
mortality can be as high as 25%, and the risk of end-stage renal disease is significantly higher
Prompt initiation of eculizumab improves outcomes.
Outcomes:
Most children with typical HUS recover renal function completely
Some may have residual proteinuria or hypertension
In aHUS, early treatment with eculizumab can lead to remission and preservation of renal function, but long-term outcomes depend on the severity of initial damage and adherence to treatment.
Follow Up:
Long-term follow-up is essential for all patients, focusing on monitoring renal function, blood pressure, and for signs of recurrent disease or complications
Annual assessment of renal function and urine protein excretion is recommended
Patients with aHUS require lifelong monitoring and management, often in specialized centers.
Key Points
Exam Focus:
Distinguish between typical (STEC) and atypical (complement-mediated) HUS
Recognize the triad of MAHA, thrombocytopenia, and AKI
Know the typical prodrome of hemorrhagic colitis in STEC-HUS
Identify indications for dialysis in HUS
Understand the role of eculizumab in aHUS.
Clinical Pearls:
Always consider HUS in a child with AKI, anemia, and thrombocytopenia, especially after diarrheal illness
Do not give antibiotics to children with bloody diarrhea suspected of STEC infection
A normal coagulation profile helps differentiate HUS from DIC
Early diagnosis and aggressive management, particularly of aHUS, are critical for improved outcomes.
Common Mistakes:
Failing to differentiate between typical and atypical HUS, leading to inappropriate management
Delaying dialysis when indicated, resulting in severe electrolyte imbalances or fluid overload
Inappropriate antibiotic use in STEC-HUS
Underestimating the severity and long-term implications of aHUS.