Hemolytic Uremic Syndrome

Excerpt

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS is most commonly caused by Shiga toxin (typical HUS) or, less commonly, infections or genetic abnormalities activating the alternative complement pathway (atypical HUS). Additional causes can be secondary to malignancy, autoimmune disorders, genetic mutations, and medication use. Extrarenal manifestations are common in HUS, particularly neurological symptoms. Prompt recognition of HUS's varied etiologies and manifestations is essential for timely diagnosis and intervention, optimizing patient outcomes.

Thrombotic microangiopathy encompasses various systemic diseases in which endothelial damage causes thrombosis in the microvasculature, including capillaries, arterioles, and venules, resulting in consumptive platelet aggregations. This leads to mechanical shearing of the red blood cells (RBCs), Coombs-negative hemolytic anemia, and end-organ damage. The triad of thrombocytopenia, hemolytic anemia, and ischemic end-organ damage defines thrombotic microangiopathy. Some of the more common TMAs from which HUS must be differentiated are thrombotic thrombocytopenic purpura (TTP); syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP); and disseminated intravascular coagulation (DIC). Despite similar pathogeneses, the treatments of these entities differ significantly.

Prior classifications of HUS often depended on the presence or absence of bloody diarrhea, with its presence used to diagnose typical HUS associated with Shiga toxin. However, atypical HUS can also present with bloody diarrhea in up to 30% of cases, so an etiology-based classification system is preferred.

Typical HUS

Shiga toxin–producing Escherichia coli (STEC), called typical HUS, is the most common cause of HUS. Typical HUS comprises 90% to 95% of HUS cases and commonly arises from consuming contaminated food or drink and through person-to-person contact. The incidence of HUS among individuals infected with STEC ranges from 5% to 15%, predominantly affecting children younger than 5. Typically, a presentation of bloody diarrhea occurs around day 2 or 3 following exposure, with HUS onset developing 3 to 10 days after the start of diarrhea. Other common symptoms are vomiting (67%), fever (37%), and abdominal pain (29%).

Atypical HUS

Atypical HUS (aHUS) constitutes 5% to 10% of HUS cases and is linked to genetic mutations affecting the alternative complement pathway. Under physiological conditions, the alternative complement system is continuously active at low levels. However, inflammatory conditions such as infections can induce endothelial damage, triggering the activation of the coagulation cascade and causing a TMA presentation.

The initial clinical manifestation of aHUS typically involves nonspecific symptoms like fatigue, pallor, or somnolence. These symptoms can progress to signs of acute kidney injury (AKI), including oliguria, uremia, and fluid overload. The risk of progression to stage 3 or 4 chronic kidney disease (CKD) and end-stage renal disease (ESRD) in aHUS is high. In contrast to typical HUS, patients with aHUS often fail to regain kidney function without treatment. Untreated, approximately 50% of aHUS cases progress to dialysis dependency, with a mortality rate of 25%.

Similar to typical HUS, aHUS may exhibit extrarenal manifestations, notably cardiac and neurological, including heart failure, pulmonary hypertension, seizures, coma, and blindness. These manifestations significantly contribute to the morbidity and mortality associated with aHUS. In contrast to typical HUS, patients with aHUS commonly relapse; patients must be monitored closely for relapse after treatment is discontinued.

Secondary HUS

The last category of HUS involves patients with HUS secondary to underlying conditions or infections, commonly presenting as aHUS with abnormal complement system activation. The most significant component of this category is HUS caused by Streptococcus pneumoniae, accounting for 5% to 15% of all cases of HUS in children. S pneumoniae releases neuraminidase, exposing cellular antigens and activating the alternative complement system. This is the only cause of Coombs-positive HUS, and early antibiotic administration is indicated.

Other causes of secondary aHUS are as follows:

1. inherited vitamin B12 (cobalamin) metabolism disorders;

2. diacydiacylglycerol kinase ε (DGKE) mutations;

3. HIV;

4. influenza virus;

5. autoimmune disease, eg, systemic lupus erythematosus, antiphospholipid antibody syndrome;

6. drugs, eg, quinine, calcineurin inhibitors, chemotherapeutic agents; and

7. malignant hypertension.

Recent studies have shown that COVID-19 can trigger aHUS in adults and children. Pregnancy triggers aHUS activation, leading to increased pregnancy complications in women with established aHUS compared to those without the condition.