Hemolytic Uremic Syndrome

Etiology

Shiga Toxin–Related HUS (Typical HUS)

HUS is typically associated with bacterial infections resulting from consumption of undercooked beef, unpasteurized milk, or other foods or drinks contaminated with cattle manure; cattle are asymptomatic carriers of STEC. Once ingested, STEC penetrates the intestinal mucosal layer and secretes Shiga toxin, which binds to the Gb3 receptor. The Shiga toxin–Gb3 complex binds to ribosomes, inhibiting protein synthesis and causing apoptosis. Inflammatory cytokines are also produced.[4] 

Shiga toxin, causing typical HUS, can be divided into 2 main subtypes: Stx1 and Stx2. Stx2 is associated with more severe disease and a greater need for renal replacement therapy.[4] Traditionally, Escherichia coli 0157:H7 has been linked to typical HUS. However, in recent years, non-0157 serotypes have become dominant. The most common cause of typical HUS in North America and Europe is E coli 026:H11. Shiga toxin from Shigella dysenteriae produces a disease pattern similar to STEC, except that symptoms are much more severe, and the fatality rate of HUS caused by Shigella dysenteriae is estimated at 36%.[10] Salmonella spp can also be associated with STEC-HUS.[8]

In addition to cytotoxic effects, Shiga toxin can activate the complement system by inhibiting complement factor H. Upon entering the bloodstream, Shiga toxin continues to bind to cells via the Gb3 receptor, which is most abundant in the glomerular microvasculature. Endothelial damage is caused by 4 mechanisms: direct cytotoxicity of Shiga toxin, disruption of the hemostatic pathway, increased cytokine release, and activation of the alternative pathway.[4] This endothelial damage then initiates the pathology associated with TMA.[4]  

Atypical HUS

The cause of aHUS is the abnormal activation of the alternative complement pathway. The complement system is part of the innate immune system and comprises 3 activation pathways: classical, alternative, and lectin-binding. The initial steps of each pathway converge at the formation of C3 convertase, leading to the assembly of the membrane attack complex, which then lyses target cells.[8]

About 60% of patients with aHUS have genetic mutations, including loss-of-function or gain-of-function mutations in complement regulators, including the complement factor H gene (CFH), complement factor I gene (CFI), and membrane cofactor protein gene (MCP), or in C3 convertase, including complement C3 gene (C3) and complement factor B gene (CFB). The most common identifiable mutation in aHUS is a pathogenic variant of CFH, which encodes factor H, the main regulatory protein of the alternative complement pathway at the C3b level.[8][9] Of note, genetic analysis of relatives of patients with aHUS who also carry complement system mutations shows that most are asymptomatic, indicating that genetic abnormalities do not necessarily result in aHUS.[6][8] In addition, because of incomplete penetrance, a second inciting agent, such as infection, is often required for aHUS to develop, even when genetic abnormalities are present.[11] 

Secondary HUS

Secondary HUS generally follows the same pathophysiology pattern as aHUS. Multiple insults can cause secondary HUS, with endothelial disruption as a common factor, and complement activation is also implicated. Infection is the most common cause of secondary HUS, and the most significant component of this category is Streptococcus pneumoniae, which accounts for 5% to 15% of all HUS cases in children.[7] S pneumoniae releases neuraminidase, exposing cellular antigens and activating the alternative complement system. Streptococcus pneumoniae infection is the only cause of Coombs-positive HUS, and early antibiotic administration is indicated.[11] Other non-STEC infectious etiologies include enterobacteria, Staphylococcus aureus, Epstein-Barr virus, cytomegalovirus, influenza virus, HIV, and SARS-CoV-2.[6][8][11]

Noninfectious causes of secondary aHUS include the following:

• Inherited vitamin B12 (cobalamin) metabolism disorders
• Diacylglycerol kinase ε (DGKE) mutations
• Autoimmune disease (eg, systemic lupus erythematosus, antiphospholipid antibody syndrome)
• Malignant neoplasms
• Drugs (eg, quinine, calcineurin inhibitors, chemotherapeutic agents)
• Pregnancy
• Malignant hypertension [6][8][9][12][13]

Epidemiology

HUS and aHUS are more common in children younger than 10 years, with most cases in those younger than 5 years.[5] Globally, STEC causes 43 acute illnesses per 100,000 person-years and 3890 cases of HUS.[14] STEC-HUS is one of the most common causes of pediatric renal replacement therapy. Results from a large retrospective study showed that 15% of children (younger than 18 years) who presented to the emergency department with bloody diarrhea developed STEC-HUS.[15] STEC-HUS incidence is estimated at 0.57 cases per 100,000 children, and in the highest risk group, children aged 6 months to 2 years, the incidence is as high as 3 per 100,000 children.[4] Incidence correlates directly with environmental exposure and agricultural practices, such as cattle raising, and most patients are diagnosed between April and September, when cattle are more likely to be colonized with STEC.[4][8] In contrast to HUS, aHUS is notably less frequent; nevertheless, aHUS exhibits substantially elevated morbidity and mortality rates. Like typical HUS, atypical HUS affects young children, predominantly those younger than 5, and prevalence is estimated at 2 to 9 cases per million people aged 20 years or younger.[8] Cases of S pneumoniae usually occur in the winter, during the cold season.

Pathophysiology

Although renal damage is a hallmark of HUS, all forms of HUS cause damage in nearly every organ system. About 20% of patients demonstrate extrarenal manifestations, with neurologic, gastrointestinal, and cardiac manifestations being the most common. Cardiac and neurologic conditions can especially contribute to morbidity and mortality.[8] Extrarenal symptoms can be seen in both the acute and postrecovery phases of HUS.[16]

Renal

Renal insufficiency and failure are part of the diagnostic criteria for this disease. Oliguria, anuria, and proteinuria are common. Up to 50% of children and adults require dialysis at some point in their illness. Untreated, approximately 50% of aHUS cases progress to dialysis dependency, with a mortality rate of 25%.[8][16][17]

Neurologic

Manifestations can include stroke, seizures, coma, blindness, and confusion, which are poor prognostic indicators.[8][11] 

Cardiac

Cardiac injury can also cause significant morbidity. Complications can include myocardial infarction, pulmonary hypertension, heart failure, hypertension, and peripheral vascular disease.[8][11]

Gastrointestinal 

Bloody diarrhea is a common symptom of all forms of HUS. Pancreatitis, liver dysfunction, bowel ischemia, and bowel perforation can also occur.[8][16][18] Severe gastrointestinal tract manifestations may be more common with STEC than with aHUS, although all forms of HUS can present with bloody diarrhea.[19]

Pulmonary 

Although uncommon, pulmonary hypertension and pulmonary hemorrhage have been reported and can both result from and contribute to cardiac dysfunction.[8]

Musculoskeletal and Dermatologic

Although these symptoms are less frequent, rhabdomyolysis, ulcerative skin lesions, and gangrene have been reported.[8][16][20]

Histopathology

Most biopsies in patients with HUS were performed before 1990 because individuals with suspected HUS are no longer routinely biopsied due to thrombocytopenia and general instability. When biopsies are performed, light microscopy reveals fragmented red blood cells in glomerular capillary loops and variable fibrin staining in glomerular capillaries and renal arterioles. Electron microscopy shows endothelial and mesangial cell deposits of fibrin and proteinaceous material extending into the capillary lumen, giving the appearance of a double-contoured glomerular basement membrane. In typical STEC-associated HUS, staining for C1q, C3, or C4 is not observed. Despite extrarenal manifestations, other organs are generally not biopsied, with the exception of the gastrointestinal tract, which can show extensive vascular thrombosis histologically.[Pediatric Kidney Disease. Postinfectious Hemolytic Uremic Syndrome]

History and Physical

The typical patient is a child younger than 5 years with painful diarrhea and abdominal cramping 1 to 10 days (median, 4 days) after exposure to Escherichia coli that produces Shiga toxin; fever and vomiting may also occur. HUS generally begins 5 to 13 days after diarrhea starts (median, 6.5 to 7 days).[4] HUS symptoms include renal findings, such as anuria, oliguria, and fluid overload, and symptoms related to anemia, such as syncope, fatigue, and pallor. Petechiae and easy bleeding may be notable due to thrombocytopenia.

Although less common in adults, HUS, particularly during food-related outbreaks, shows greater variability and a more unfavorable prognosis. In adult patients, neurologic symptoms such as confusion, seizures, and coma are markedly more prevalent than in children. Older adults may also experience neuropsychiatric symptoms.[14]

The initial clinical manifestations of aHUS typically include nonspecific signs and symptoms such as fatigue, pallor, or somnolence. These symptoms can progress to signs of acute kidney injury, including oliguria, uremia, and fluid overload. The risk of progression to stage 3 or 4 chronic kidney disease in aHUS is high.[8][9][11] If the inciting factor is S pneumoniae, patients may have underlying pneumonia, empyema, or meningitis. Diarrhea, including bloody diarrhea, can also be prominent in atypical HUS.[4] 

Evaluation

The diagnosis of HUS requires a high index of suspicion based on symptoms, travel history, laboratory data, and dietary history.[21][22][23] Initial tests should include a complete blood count with differential and a comprehensive metabolic panel. Elevated lactate dehydrogenase and indirect bilirubin levels, as well as low haptoglobin and elevated plasma hemoglobin levels, are diagnostic of hemolytic anemia, along with schistocytes on peripheral smear. A Coombs test result should be negative, except in HUS caused by Streptococcus pneumoniae. Up to 20% of patients have elevated amylase and lipase levels due to pancreatic damage, which may be accompanied by hyperglycemia.[Pediatric Kidney Disease. Postinfectious Hemolytic Uremic Syndrome] A stool sample should be collected to test for Shiga toxin whenever diarrhea is present. The results may be negative for Shiga toxin if it has been cleared or avidly bound to the endothelium. If clinically indicated, testing for S dysenteriae and S pneumoniae should also be performed. 

Low complement levels are suggestive of, but not specific to, aHUS, because typical HUS can also cause immune system abnormalities.[7] Patients may have hyponatremia, hyperkalemia, and other electrolyte abnormalities from acute kidney injury as the disease progresses. Genetic testing can also be ordered to evaluate for genetic causes of aHUS.

An ADAMTS13 test should be ordered to rule out TTP. Abnormal coagulation test results, such as prolonged prothrombin time, activated partial thromboplastin time, elevated D-dimer levels, and elevated fibrin degradation products, are suggestive of disseminated intravascular coagulation. All of the above tests have therapeutic value. However, if clinical suspicion is high, treatment should not be delayed while awaiting all test results, as early initiation is associated with improved outcomes.

Treatment / Management

The management of typical STEC-associated HUS is generally supportive. Patients are often volume-depleted, and inadequate volume resuscitation has been linked to an increased need for renal replacement therapy, which half of all patients require.[4][15] Blood transfusions are provided as clinically indicated, and platelet transfusions should be administered sparingly to minimize the risk of thrombotic complications. Antimotility agents and antibiotics are avoided in typical STEC-associated HUS because they are associated with poorer outcomes, likely due to heightened exposure to Shiga toxin. Conversely, if Shigella dysenteriae or Streptococcus pneumoniae is present, early antibiotic administration is associated with improved outcomes.[Pediatric Kidney Disease. Postinfectious Hemolytic Uremic Syndrome] (B3)

In aHUS, prompt initiation of therapy is critical to reduce the risk of end-stage renal disease and mortality. First-line treatment is complement inhibition with eculizumab, whereas plasma exchange is considered a second-line or adjunctive therapy.[24] Eculizumab is a recombinant monoclonal antibody that targets the C5 component of complement activation by preventing its cleavage; early administration improves its effectiveness.[9][24] The advent of eculizumab has reduced progression to end-stage renal disease or death in both children and adults.[7] (B2)

Ravulizumab is a C5 inhibitor approved for use in the US in 2019 and the European Union in 2020. Ravulizumab also binds to C5, preventing cleavage, and has similar efficacy to eculizumab but with a half-life 4 times as long.[11] Before eculizumab, plasma exchange was the standard of care for HUS and is still used when eculizumab is unavailable or as an adjunct when clinically indicated.(B3)

One ongoing question is how to treat patients who develop end-stage renal disease due to aHUS because patients with aHUS and kidney failure often require a kidney transplant, and recurrence rates of aHUS in the transplanted kidney are high. Studies suggest that prophylactic administration of eculizumab in patients at high risk of aHUS recurrence prolongs graft survival and may also be cost-effective in these high-risk groups, despite the drug's high cost.[9][24] Adverse effects of eculizumab include infections caused by encapsulated organisms, such as S pneumoniae and Haemophilus influenzae; all patients should receive appropriate vaccines and be monitored closely.[9] (B2)

Treatment for secondary HUS is largely dependent on treatment of the underlying condition. Small studies have shown eculizumab to have some efficacy in treating pregnancy-related secondary HUS; however, many of these patients have an underlying genetic component predisposing them to aHUS as well.[13][25] In another small study, patients with secondary HUS who had worsening renal function despite treatment of the underlying disease were administered eculizumab, resulting in improvement in renal and extrarenal symptoms.[25]

Differential Diagnosis

Initially, HUS may present like other thrombotic microangiopathies, such as TTP, disseminated intravascular coagulation, HELLP syndrome, and systemic vasculitis. Clinical signs and laboratory test results often help exclude other causes.

Thrombotic Thrombocytopenic Purpura 

TTP is a thrombotic microangiopathy characterized by a pentad of hemolytic anemia, thrombocytopenia, renal dysfunction, fever, and neurological dysfunction. TTP is caused by a deficiency or mutation in the disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13) and usually presents with adult-onset symptoms.

Disseminated Intravascular Coagulation 

Disseminated intravascular coagulation is the systemic activation of the coagulation cascade. This type of microangiopathy is characterized by abnormal coagulation test results, including prolonged prothrombin time and activated partial thromboplastin time, elevated D-dimer levels, and elevated fibrin degradation products, which are usually normal in HUS. Patients with DIC usually have serious underlying illnesses such as septic shock, trauma, or malignant neoplasm.

HELLP Syndrome

HELLP syndrome is observed in pregnant women in the third trimester or immediately postpartum, and is characterized by hemolysis of red blood cells, elevated liver enzymes, and a low platelet count, usually occurring with preeclampsia.

Systemic Vasculitis

Patients with systemic vasculitis typically present with inflammatory signs such as fever, rash, and arthralgia, and do not have prodromal diarrhea. Patients generally have a markedly elevated erythrocyte sedimentation rate.

Prognosis

The prognosis of typical HUS is generally good, with overall mortality estimated at 5%.[26][27][28] However, up to 25% of patients with HUS develop long-term renal sequelae, including reduced glomerular filtration rate less than 80 mL/min/1.73 m², hypertension, or proteinuria, which may predispose them to progressive renal impairment. The strongest predictor of chronic kidney disease is the duration of dialysis, with an increased risk of complications in patients requiring dialysis for more than 2 to 3 weeks.[4] In contrast to children, adults older than 60 years account for most fatalities.[14] The course of aHUS has traditionally been much less benign than that of typical HUS. However, the advent of eculizumab therapy has reduced progression to end-stage renal disease or death from 30% to 50% to 9% in children and from 60% to 6% to 15% in adults.[7] 

Complications

HUS can affect any organ system, but renal, neurologic, and gastrointestinal tract manifestations are the most common. Cardiac complications have also been reported. Older patients are more likely to experience long-term consequences than children, but early recognition is key to preventing long-term damage in all patients.[16]

Although eculizumab has significantly improved long-term survival in patients with aHUS, a serious complication is Neisseria meningitidis infection. Patients must receive meningococcal vaccines against both serogroups ACWY and B at least 2 weeks before the first dose, unless the risk of delaying complement inhibitor therapy outweighs the risk of developing meningococcal disease. For unvaccinated patients in whom therapy cannot be delayed, as is often the case in acute aHUS, antimicrobial prophylaxis (eg, penicillin) should be given alongside meningococcal vaccination and continued for at least 2 weeks after vaccination.[6][29]