Hemolytic Uremic Syndrome in Emergency Medicine 

Updated: Jun 24, 2021
Author: Audrey J Tan, DO; Chief Editor: Steven C Dronen, MD, FAAEM 

Overview

Practice Essentials

Hemolytic uremic syndrome (HUS) is primarily a disease of infancy and early childhood and is classically characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.[1]  The clinical course of HUS can range from subclinical to life threatening, and the presentation may vary depending on the etiology.[2]

HUS has two variants, typical and atypical. Typical HUS is related to bacteria, with more than 90% following a gastrointestinal infection with Shiga toxin–producing Escherichia coli (STEC). Nomenclature for HUS varies throughout the literature: typical HUS is also called classic HUS, STEC-HUS, and diarrhea-positive (D+) HUS. 

Atypical HUS (aHUS) is HUS not mediated by Shiga toxin. It is also called diarrhea-negative (D-) or non–diarrhea-associated HUS. Most patients with atypical HUS have mutations in one or more of the genes that encode proteins involved in the alternate pathway of complement, which creates a predisposition to the disorder. Atypical HUS may also be due to development of autoantibodies against complement factor H.[3]

HUS may also be initiated by autoimmune disease, transplantation, cancer, infection (eg, with ​Streptococcus pneumoniae, influenza virus), pregnancy, or certain cytotoxic drugs. HUS linked to those clinical entities is sometimes designated as secondary HUS.[3]  For example, in pneumococcal HUS, S pneumoniae damages endothelial cells in the blood vessels, disturbing local complement homeostasis and producing a thrombogenic state.[4, 5]  However, in some cases it may be difficult to determine whether a particular factor is the cause or is the trigger in a patient with an underlying predisposition.[3, 4]

Signs and symptoms of typical HUS include the following::

  • Diarrhea, which becomes hemorrhagic in most cases, usually within 1-2 days
  • Vomiting
  • Fever, in 5-20% of cases
  • After 4-6 days, sudden onset of the clinical manifestations of HUS: pallor and shortness of breath from hemolytic anemia, and reduced or absent urine output due to acute kidney injury
  • Neurologic symptoms in 33% of patients (eg, irritability, seizures, or altered mental status)
  • Diarrhea may improve as the other HUS signs and symptoms begin 

Atypical HUS does not typically begin with a gastrointestinal illness. Patients with pneumococcal HUS may have had a recent respiratory illness. Clinical manifestations of atypical HUS are similar to those of typical HUS, although neurologic involvement is more common. See Presentation.

HUS is primarily a clinical diagnosis coupled with consistent laboratory findings, including the following:

  • Microangiopathic hemolytic anemia, with a hemoglobin level that is typically less than 8 g/dL 
  • Schistocytes on the peripheral blood smear
  • Mild to moderate thrombocytopenia 

See Workup.

Emergency department (ED) care for patients with HUS should focus on the following:

  • Supportive management
  • Correction of blood pressure elevation
  • Red blood cell transfusions
  • Arrangement for prompt dialysis, if necessary

The monoclonal antibodies eculizumab and ravulizumab are approved for treatment of atypical HUS. See Treatment and Medication.

Pathophysiology

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) fall into the broader category of thrombotic microangiopathies (TMA). Thrombotic microangiopathies are characterized by the involvement of widespread occlusive microvascular thromboses resulting in thrombocytopenia, microangiopathic hemolytic anemia, and variable signs and symptoms of end-organ ischemia. Though recent research has revealed that the two disease processes have underlying similarities, HUS and TTP have historically been considered two separate disease entities.

Two predominant types of HUS are identified: one type involves diarrhea (D+) and the other, D- or atypical, does not.

D+ HUS is the classic form, accounting for 95% of cases of hemolytic uremic syndrome in children. This form of HUS occurs predominantly in children and is preceded by a prodrome of diarrhea, most commonly caused by an infection by shiga-toxin producing Escherichia coli.

Specifically, E coli serotype O157:H7 has been associated with more than 80% of infections leading to HUS. The shiga-like toxin affects endothelial cells and initiates intravascular thrombogenesis. After entering the circulation via the gastrointestinal mucosa, the toxin preferentially localizes to the kidneys, inhibiting protein synthesis and eventually leading to cell necrosis or apoptosis.

Endothelial cell damage subsequently potentiates renal microvascular thrombosis by promoting activation of the blood coagulation cascade. Platelet aggregation results in a consumptive thrombocytopenia. Microangiopathic hemolytic anemia results from mechanical damage to red blood cells circulating through partially occluded microcirculation.

E coli O157:H7 is not normally found in human intestinal flora but is present in 1% of healthy cattle. Thus, meat may become contaminated during animal slaughter and processing. The most common form of transmission to children in the United States is ingestion of undercooked meat containing viable bacteria. Ingesting unpasteurized fruits and juices, coming into contact with unchlorinated water, and person-to-person transmission in daycare or long-term care facilities are alternate routes of transmission.

D- HUS accounts for the remaining 5% of cases of hemolytic uremic syndrome and its etiology, age at onset, and clinical presentations are far more varied.[6] Unlike D+ HUS, D- HUS is not preceded by an identifiable gastrointestinal infection. The pathogenesis of D- HUS has been the focus of current research and has, thus far, been associated with complement dysregulation in up to 50% of cases.[7] Specifically, mutations in complement regulatory protein factor H, factor I, or factor B or autoantibodies against factor H have all been implicated.[7] These mutations result in inability to suppress complement activation and for reasons that are not completely understood, the glomerular endothelium is particularly susceptible to these changes.

Clinically, D- HUS has been associated with various nonenteric infections, viruses, drugs, malignancies, transplantation, pregnancy, and other underlying medical conditions such as scleroderma and antiphospholipid syndrome. Infections caused by Streptococcus pneumoniae has been linked to 40% of D- HUS cases. Categories of drugs that have been most frequently associated with D- HUS include the following:

  • Anticancer molecules (mitomycin, cisplatin, bleomycin, and gemcitabine)
  • Immunotherapeutics (cyclosporine, tacrolimus, OKT3, interferon, and quinidine)
  • Antiplatelet agents (ticlopidine and clopidogrel)

Malignancies found in conjunction with HUS include prostatic, gastric, and pancreatic cancers. Familial forms of D- HUS exist but account for fewer than 3% of cases. Unlike D+ HUS, only 4.7% of D-HUS cases in the United States involve children.

In contrast to hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) presents with the classic pentad of microangiopathic hemolytic anemia, thrombocytopenia, prominent neurologic symptoms, fever and a milder form of renal failure. The pathophysiology of thrombotic thrombocytopenic purpura is different in that, as opposed to endothelial cell injury, thrombotic thrombocytopenic purpura is thought to be caused by a deficiency in the metalloprotease ADAMTS13, which is involved in the regulation of von Willebrand factor. A lack of this protein results in spontaneous platelet aggregation and the widespread deposition of platelet-rich thrombi in the microvasculature of various organs, most notably the heart, brain, and kidneys.

Current research has demonstrated that, though a deficiency of ADAMTS13 clearly diagnoses thrombotic thrombocytopenic purpura, patients with D- HUS also share this finding. Current research suggests that these two illnesses share a similar pathophysiology and may be variants of the same disease spectrum.

Epidemiology

The overall incidence of D+ HUS is estimated to be approximately 2.1 cases per 100,000 persons per year, with a peak incidence in children who are younger than 5 years (6.1 cases per 100,000 per year). The lowest rate is in adults aged 50-59 years (0.5 cases per 100,000 per year).[8]

Incidence tends to parallel the seasonal fluctuation of E coli O157:H7 infection, which peaks between June and September.[8]

 D+ HUS is typically observed in infants and children, especially those aged 6 months to 4 years. D- HUS is variable in its age of presentation. Incidence of D- HUS in children is approximately 2 cases per year per 100,000 total population.[8]

Hemolytic uremic syndrome has no predilection for a specific race or for either sex.

Prognosis

With supportive care, approximately 85% of patients recover and regain normal renal function. The overall mortality rate of hemolytic uremic syndrome (HUS) is 5-15%. In D+ HUS, the mortality rate is between 3% and 5%. Older children and adults often have poorer prognoses. Death is nearly always associated with severe extrarenal disease, including severe central nervous system (CNS) involvement. Approximately two thirds of children with D+ HUS require dialysis.[9]  In cases of D- HUS, overall mortality rate approaches 26%.

For unknown reasons, younger children who present in the summer with the typical diarrheal prodrome tend to do better than older children who develop HUS during the colder months of the year.

Adults with HUS generally have a poorer prognosis than children. In one study, 14% of adults with HUS succumbed to the disease. Adults who undergo kidney transplantation because of HUS are at much higher risk of graft loss than patients undergoing transplantation for other reasons.[10]  Patients with atypical HUS have a poorer prognosis with high mortality and >50% of patients developing end-stage renal disease. However, since the introduction of eculizumab, these outcomes have greatly improved.[11]  

Complications of hemolytic uremic syndrome include the following:

  • Hypertension

  • Chronic renal failure

  • Neurologic dysfunction including seizures, coma, stroke, hemiparesis, and cortical blindness: Severe CNS involvement is associated with significant mortality.

  • GI involvement, including any area from the esophagus to the anus: This can include hemorrhagic colitis, bowel necrosis/perforation, or intussusception.

  • Cardiac dysfunction, possibly precipitated by uremia and fluid overload

  • Complications involving the pancreas are seen in fewer than 10% of patients and can include glucose intolerance. Frank diabetes mellitus is rare.

  • Liver complications including hepatomegaly and/or increased serum transaminases levels are not uncommon.

  • In severe cases, death may be an inevitable outcome if the disease has progressed too far prior to presentation.

 

Presentation

History

The presentation in patients with hemolytic uremic syndrome (HUS) may vary with the etiology. Typical HUS (ie, Shiga toxin–related) presents as follows:

  • Recent history may include such risk factors as eating rare hamburger, a trip to a petting zoo, or contact with persons with diarrhea
  • Diarrhea, which becomes hemorrhagic in 70% of cases, usually within 1-2 days
  • Vomiting, in 30-60% of cases
  • Fever, in 5-20% of cases
  • After 4-6 days, sudden onset of the clinical manifestations of HUS: pallor and shortness of breath from hemolytic anemia, and reduced or absent urine output due to acute kidney injury
  • Neurologic symptoms in 33% of patients (eg, irritability, seizures, or altered mental status)
  • Diarrhea may improve as the other HUS signs and symptoms begin 

Atypical HUS does not typically begin with a gastrointestinal (GI) illness. Patients with pneumococcal HUS may have had a recent respiratory illness. Clinical manifestations of atypical HUS are similar to those of typical HUS, although neurologic involvement is more common.

Physical Examination

Findings in patients with hemolytic uremic syndrome reflect those of the inciting prodromal illness and the end organ in which thrombogenesis is occurring, as follows:

  • Gastrointestinal: GI bleeding is often noted. GI involvement may lead to symptoms of an acute abdomen, with occasional peritonitis.
  • Cardiac involvement may lead to congestive heart failure (CHF) and arrhythmias.
  • Microinfarcts in the pancreas may cause pancreatitis or rarely, insulin-dependent diabetes mellitus.
  • Ocular involvement may lead to retinal or vitreous hemorrhages.
  • Hypertension and oliguria are typical findings consistent with renal compromise.
 

DDx

Diagnostic Considerations

Other problems to be considered include the following:

  • Aspergillosis

  • Catastrophic antiphospholipid antibody syndrome (CAPS)

  • Intussusception

  • Ischemic colitis

  • Preeclampsia

  • Vasculitis

Differential Diagnoses

 

Workup

Laboratory Studies

Hemolytic uremic syndrome (HUS) is primarily a clinical diagnosis coupled with consistent laboratory findings. HUS produces a microangiopathic hemolytic anemia with a hemoglobin level that is typically less than 8 g/dL. This is a consistent finding and is necessary to establish the diagnosis.

The hallmark of HUS in the peripheral smear is the presence of schistocytes. These consist of fragmented, deformed, irregular, or helmet-shaped red blood cells (RBCs), as shown in the image below. They reflect the partial destruction of RBCs that occurs as they traverse vessels partially occluded by platelet and hyaline microthrombi. The peripheral smear may also contain giant platelets. This is due to the reduced platelet survival time resulting from the peripheral consumption/destruction. A consumptive coagulopathy is typically not present.

Peripheral smear in hemolytic uremic syndrome (HUS Peripheral smear in hemolytic uremic syndrome (HUS), with findings of microangiopathic hemolytic anemia. Note schistocytes/helmet cells as well as decrease in platelets. Image courtesy of Emma Z. Du, MD.

Thrombocytopenia is noted and is typically mild to moderate in severity with platelet counts of less than 60,000 per mL. In spite of this finding, neither purpura nor active bleeding is typically seen.

Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen are within the reference ranges, thus differentiating HUS and thrombotic thrombocytopenic purpura from disseminated intravascular coagulation (DIC).

Elevation of lactate dehydrogenase (LDH) and indirect bilirubin levels reflects intravascular hemolysis. Bilirubin rarely exceeds 2-3 mg/dL. Haptoglobin is very low, as it is consumed by free hemoglobin released by the destroyed RBCs.

Blood urea nitrogen (BUN) and creatinine measurements are markedly elevated. However, there is no correlation between the severity of anemia and the severity of the kidney disease.

Other laboratory findings are as follows:

  • Urine may contain protein and RBCs
  • D-dimer and fibrinogen levels are usually within the reference range
  • The reticulocyte count should be elevated
  • Coombs test results are negative, indicating that the anemia is not immunologically mediated
  • A moderate leukocytosis may be present but rarely more than 20,000/mL
  • Plasma contains free hemoglobin that can often be observed with the naked eye; the degree correlates with the severity of the anemia
  • Bone marrow reveals erythroid hyperplasia and increased megakaryocytes
  • Blood cultures are negative in Escherichia coli–mediated disease, since only the Shiga toxin circulates in the blood, while the organisms remain in the intestinal lumen
  • Stool cultures typically detect Shiga toxin–producing E coli

Imaging Studies

Imaging studies are not indicated for the diagnosis of hemolytic uremic syndrome unless a viscus perforation is suspected. At that point, plain films or computed tomography will aid in the diagnosis.

 

Treatment

Emergency Department Care

Emergency department (ED) care for patients with hemolytic uremic syndrome (HUS) should focus on supportive management, correction of blood pressure elevation, blood transfusions, and if necessary, arrangement for prompt dialysis.

Avoid unnecessary use of antibiotics or antimotility agents during diarrheal illness. The use of these agents has been shown to increase the incidence of HUS because as motility slows, the gut is exposed to the toxins for a longer period of time. Additionally, antibiotic-induced injury to the bacterial membrane favors the acute release of large amounts of toxins. Use of antibiotics has been shown to increase the risk of full-blown HUS by 17-fold, and thus, the recommendation is to avoid its use, except in cases of sepsis.

Maintain fluid balance. In light of the diarrheal illness, fluid resuscitation is important, although one must avoid fluid overload. Watch for and treat hyperkalemia. If indicated, treat acute kidney injury aggressively with hemodialysis.

A study of children with HUS from Shiga toxin–producing Escherichia coli (STEC-HUS) found that fluid infusion soon after diagnosis led to a significantly better short-term outcome, with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = 0.06), less need for renal replacement therapy (26.3% vs 57.9%, P = 0.01) or intensive care support (2.0 vs. 8.5 days, P = 0.02), and fewer days of hospitalization (9.0 vs 12.0 days, P = 0.03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = 0.01).[12]

Treat hypertension with standard antihypertensive agents.

Plasma exchange (plasmapheresis combined with fresh-frozen plasma replacement) is currently the treatment of choice. Plasma exchange is performed daily until remission is obtained. However, because 85% of children with hemolytic uremic syndrome recover after supportive therapy alone, plasma exchange is generally reserved for the most severe cases.

The U.S. Food and Drug Administration (FDA) has approved two monoclonal antibodies for the treatment of atypical HUS (aHUS): eculizumab and ravulizumab. These monoclonal antibodies inhibit complement-mediated thrombotic microangiopathy. Both of these agents carry black box warnings regarding meningococcal infection, which include a recommendation to immunize patients with meningococcal vaccines at least 2 weeks before starting treatment.[13, 14]

Eculizumab

Eculizumab (Soliris) is the first treatment approved by the US Food and Drug Administration (FDA) (September, 2011) for adults and children with atypical hemolytic uremic syndrome (aHUS). Approval was based on data from adults and children who were resistant or intolerant to, or receiving, long-term plasma exchange/infusion. Data also included children (aged 2 mo to 17 y) who received eculizumab with or without prior plasma exchange/infusion. Eculizumab demonstrated significant improvement in platelet count from baseline (P = 0.0001). Thrombotic microangiopathy events were reduced, and maintained or improved kidney function was also reported.[13, 15, 16]

Treatment with eculizumab consists of weekly infusions in the initial phase (up to 4 weeks) followed by eculizumab infusions every 14–21 days depending on the body weight of the patient, potentially their entire life. However, there are no studies that provide strong evidence in favor of lifelong treatment with eculizumab. This, together with the high cost of eculizumab, has caused a debate regarding duration of treatment.[11]

In a study of 11 children (median age 22 months, range 11-175) with enterohemorrhagic E coli–positive HUS requiring dialysis, Pape and colleagues reported that early use of eculizumab appears to improve neurological outcome. All the study patients had seizures and/or were in a stupor or coma. Three patients died and of the surviving 8 patients, none experienced further seizures after the first dose of eculizumab. Three patients showed mild neurological impairment at discharge, while the remaining 5 showed no impairment.[17]

Optimal duration of eculizumab therapy is not yet known. Because of the potential risk of developing TMA following discontinuation of treatment, lifelong treatment has been suggested.  Menne and colleagues confirmed the efficacy and safety of eculizumab with a long-term observational study over 6 years of 93 patients from 0-80 years old who participated in eculizumab trials and received at least one eculizumab infusion. Among the 42 patients that discontinued eculizumab, 50% (21) patients reinstated therapy.  Discontinuation of eculizumab was associated with higher risk of TMA and decreases in renal function. Patients at highest risk for TMA following discontinuation included those with pediatric disease onset, identified genetic or autoimmune complement abnormalities, and a history of multiple TMAs.[18]  

Ravulizumab

Ravulizumab (Ultomiris) was approved by the FDA in 2019 for the treatment of aHUS in adult and pediatric patients aged 1 month and older. Like eculizumab, ravlizumab is a monoclonal antibody that inhibits complement-mediated thrombotic microangiopathy (TMA)[14]  

Approved was based on data from 2 ongoing single-arm open-label studies that evaluated the efficacy of ravulizumab in pediatric (n=13) and adult (n=56) patients with aHUS. The studies demonstrated a complete TMA response in 71% of children and 54% of adults during the initial 26-week treatment period, as evidenced by normalization of hematological parameters (platelet count and LDH level) and ≥25% improvement in serum creatinine from baseline. Additionally, ravulizumab treatment resulted in reduced thrombocytopenia in 93% of children and 84% of adults; reduced hemolysis in 86% of children and 77% of adults; and improved kidney function in 79% of children and 59% of adults.[19]   

Consultations

Consult a hematologist and a nephrologist to help manage the case and an intensivist to admit the patient to an ICU setting, if necessary. In severe cases, consider consulting the renal transplant service if renal dysfunction persists.

 

Medication

Medication Summary

For hemolytic uremic syndrome (HUS) related to Shiga toxin (ie, typical HUS), supportive care only is used. Medications for supportive care may include angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) for control of hypertension, or phenytoin for prevention of seizures. For complement-mediated HUS (ie, atypical HUS), two monoclonal antibodies that block complement component C5 have been approved for use: eculizumab and ravulizumab.

Refractory cases have been treated with vincristine or cyclosporine. Steroids are of questionable benefit, as are antiplatelet agents such as aspirin or dipyridamole. Fibrinolytic therapy is not only ineffective but it also increases the risk of bleeding. 

Complement Inhibitors

Class Summary

Two monoclonal antibodies that block complement C5 are approved for use in atypical hemolytic uremic syndrome (HUS).  These agents may block the formation of membrane attack complex, which can stabilize hemoglobin and reduce the need for RBC transfusions.

Eculizumab (Soliris)

Monoclonal blocking antibody to complement protein C5; inhibits cleavage to C5a and C5b, thus preventing terminal complement complex C5b-9, thereby preventing RBC hemolysis. Inhibits terminal complement mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.

Ravulizumab (Ravulizumab-cwvz, Ultomiris)

Ravulizumab is a monoclonal blocking antibody to complement protein C5; it inhibits cleavage to C5a and C5b, thus preventing terminal complement complex C5b-9, thereby preventing RBC hemolysis. It inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy in patients with aHUS.