What is the pathophysiology and management of Hemolytic Uremic Syndrome (HUS)?

From the Guidelines

Hemolytic Uremic Syndrome (HUS) damages kidneys by causing microvascular thrombosis, particularly in the kidneys, due to the activation of platelets and the coagulation cascade by Shiga toxin, leading to renal impairment and acute kidney injury. This condition is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, with the most common form being caused by Shiga toxin-producing Escherichia coli (STEC), particularly serotype O157:H7 1. The pathophysiology of HUS involves the damage of endothelial cells in small vessels by the Shiga toxin, which activates platelets and the coagulation cascade, resulting in microvascular thrombosis, hemolysis of red blood cells, consumption of platelets in microthrombi, and renal impairment due to reduced blood flow.

Key Points in HUS Pathophysiology and Management

• The Shiga toxin damages endothelial cells in small vessels, leading to microvascular thrombosis, particularly in the kidneys 1.
• Management of HUS is largely supportive, focusing on fluid and electrolyte management, blood pressure control, and renal support 1.
• Patients often require hospitalization with careful monitoring of fluid status, electrolytes, and renal function, and severe cases may need dialysis for acute kidney injury, and blood transfusions for significant anemia.
• Platelet transfusions are generally avoided unless there is life-threatening bleeding, as they may worsen microvascular thrombosis, and antibiotics are controversial in STEC infections as they may increase toxin release, so they're typically avoided in the early stages 1.
• Early diagnosis and prompt supportive care are crucial for improving outcomes, as most children with typical HUS recover with appropriate management, though some may develop chronic kidney disease requiring long-term follow-up 1.

Importance of Early Identification and Supportive Care

• Early identification of STEC infections is important to reduce the risk of complications and the risk of person-to-person transmission 1.
• Frequent monitoring of hemoglobin and platelet counts, electrolytes, and blood urea nitrogen and creatinine is recommended to detect hematologic and renal function abnormalities that are early manifestations of HUS and precede renal injury 1.
• Examining a peripheral blood smear for the presence of red blood cell fragmentation is necessary when HUS is suspected 1.

From the Research

Pathophysiology of Hemolytic Uremic Syndrome (HUS)

• HUS is defined by the simultaneous occurrence of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, leading to the pathological lesion termed thrombotic microangiopathy, which mainly affects the kidney, as well as other organs 2.
• The underlying cause of HUS may differ, but it is associated with endothelial cell injury and platelet activation 2.
• Most cases of HUS are associated with gastrointestinal infection with Shiga toxin-producing enterohaemorrhagic Escherichia coli (EHEC) strains, while atypical HUS (aHUS) is associated with complement dysregulation due to mutations or autoantibodies 2, 3.

Management of HUS

• There is no specific treatment for EHEC-associated HUS, but patients benefit from supportive care, whereas patients with aHUS are effectively treated with anti-C5 antibody to prevent recurrences, both before and after renal transplantation 2.
• Clinical signs and symptoms may overlap among the different forms of HUS; however, pneumococcal-HUS and aHUS have a worse prognosis compared with STEC-HUS 3.
• Early diagnosis and identification of underlying pathogenetic mechanism allows instating specific support measures and therapies, including complement inhibition by eculizumab administration, which leads to a rapid and sustained normalization of hematological parameters with improvement in long-term renal function 3, 4.
• General management of acute renal failure includes appropriate fluid and electrolyte management, antihypertensive therapy, and the initiation of renal replacement therapy when appropriate 4.
• Specific management issues in HUS include management of the haematological complications of HUS, monitoring for extra-renal involvement, avoiding antidiarrhoeal drugs, and possibly avoiding of antibiotic therapy 4.

Kidney Damage in HUS

• The kidney damage in HUS is caused by the thrombotic microangiopathy, which leads to fibrin and platelet deposition on the endothelial cell surface, resulting in a prothrombotic and proinflammatory state 5.
• The alternative complement pathway plays a crucial role in the pathogenesis of aHUS, and genetic mutations in this pathway can lead to uncontrolled complement activation, resulting in endothelial damage and thrombotic microangiopathy 3, 6.
• The kidney damage in HUS can be severe, with approximately two thirds of children with HUS requiring dialysis therapy, while about one third will have milder renal involvement without the need for dialysis therapy 4.