Chapter XIII.5. Hemolytic Uremic Syndrome
Brooke K.A. Kawamura
October 2022

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The editors and current author would like to thank and acknowledge the significant contributions of the previous authors of this chapter, Dr. Jonathan K. Marr from the 2004 first edition, and Dr. Alicia G. Turlington from the 2013 second edition. This current third edition chapter is a revision and update of their work.

A 3 year old male is brought to the ED by his mother with a chief complaint of bloody diarrhea that started three days ago. His mother denies any fever, recent travel, or exposure to children with illness or diarrhea. His mother notes that he appears pale today. His family attended a birthday party 7 days prior where the child consumed hot dogs and hamburgers.

Exam: VS: T 37.7, HR 150, RR 28, BP 100/45, oxygen saturation 100% on room air. Weight 17 kg (75%ile). He is fussy and pale, but alert and non-toxic appearing. His tympanic membranes are normal. He has no nasal flaring or palatal petechiae. He has moist oral mucosa, but his tongue is pale. His neck is supple without adenopathy. His heart exam reveals tachycardia with regular rhythm and a grade II/VI vibratory systolic ejection murmur at the left sternal border without radiation. No heaves, lifts, thrills, rubs, or gallops are present. His lungs are clear with good aeration. His abdomen is flat, soft, and non-tender. His genitalia and anus are normal (no rectal prolapse). His pulses and perfusion are good.

She is admitted to the hospital for treatment and monitoring. Her immunocompromised grandfather who changes diapers occasionally is informed about her spinal polio and is encouraged to seek medical attention. During her inpatient care, mechanical ventilation is not required and she does not experience any urinary or fecal difficulties. One week after admission, she is discharged with mild residual weakness of her right leg.

Labs: WBC 16,000 with 56% segmented neutrophils, 12% bands, 27% lymphocytes, 3% eosinophils, 2% basophils, hemoglobin 8 mg/dL, hematocrit 24.6%, platelet count 75,000. Peripheral blood smear shows schistocytes and helmet cells. Na 133, K 5.9, Cl 96, bicarbonate 16 mEq/L, BUN 45, creatinine 1.3, glucose 145, Ca 7.8, phosphorus 7.1, uric acid 7.3 mg/dL, and LDH 300. Coagulation studies are normal. Stool culture is obtained.

He is admitted to the general pediatric wards for further evaluation and management. Subsequent labs indicate worsening thrombocytopenia, anemia, and renal function. His stool culture returns positive for Shiga toxin-producing E. coli O157:H7.

Hemolytic uremic syndrome (HUS) is a heterogeneous group of similar entities that have been reported across the world since 1955. It is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). It is one of the most common causes of community-acquired AKI in children. The annual incidence of HUS is approximately 3 cases per 100,000 people (1).

The etiologies of HUS include infection-induced, medication-induced, complement pathway defects, and systemic diseases characterized by microvascular injury (2). The most common form of HUS is diarrhea-associated HUS, which is often referred to as typical HUS. Previously, all other forms of HUS were referred to as atypical HUS; however, a newer classification specifically denotes HUS related to complement pathway defects as atypical HUS. The other forms of HUS are classified by their specific etiology (e.g., medication-induced HUS, HUS with coexisting conditions).

The most common microbe responsible for diarrhea-associated HUS is Shiga toxin-producing Escherichia coli (STEC) in Western countries and Shigella dysenteriae type 1 in Asian and southern African countries. Several serotypes of E. coli can produce Shiga toxin, but E. coli O157:H7 is the most common serotype in Western countries. While STEC-HUS is the most common type of HUS, other infections can cause HUS including other Shiga or Shiga-like toxin-producing bacteria, neuraminidase-producing Streptococcus pneumoniae, and human immunodeficiency virus (HIV) (2). The latter two forms of HUS do not present with prodromal gastroenteritis.

Atypical HUS (related to complement pathway defects) is due to various sporadic or inherited mutations that cause dysregulated, continuous activation of the complement system that results in the HUS triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Mutations identified include mutations in factor H, factor I, MCP (membrane cofactor protein), and thrombomodulin, which normally regulate the complement system. Mutations in C3 and factor B have also been identified (3,4).

Other causes of HUS include medication-induced HUS and HUS with coexisting conditions. Calcineurin inhibitors (e.g., cyclosporine, tacrolimus), cytotoxic and chemotherapeutic agents (e.g., mitomycin C, cisplatin, gemcitabine), and antiplatelet agents (e.g., clopidogrel, ticlopidine, quinine) are some medications that can cause HUS. Systemic diseases including systemic lupus erythematosus (SLE), antiphospholipid syndrome, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, primary glomerulopathies, and cancer can cause HUS. HUS has also been seen in patients after bone marrow and solid organ transplantation, likely through microvascular injury.

Epidemiologically, STEC-HUS makes up more than 90% of all HUS cases worldwide. STEC-HUS occurs predominantly in healthy children less than 5 years old and has higher incidences in warmer months (1). Occurrences may be sporadic or part of an epidemic. Most outbreaks of STEC-HUS are due to ingestion of contaminated, undercooked ground beef. STEC can also be acquired by consuming fruits or vegetables contaminated by the toxin or toxin secreting organisms, drinking unpasteurized milk or apple cider, swimming in contaminated lakes, contact with infected animals at petting zoos and farms, or via person-to-person contact (1,2).

The pathogenesis of all forms of HUS is understood to be microvascular injury through endothelial cell damage. In diarrhea-associated HUS, circulating Shiga-toxin directly causes endothelial damage and microvascular injury and activates platelets to promote their aggregation. In pneumococcal-associated HUS, neuraminidase cleaves sialic acid on the membranes of endothelial cells, platelets, and red blood cells to reveal antigens, which trigger microvascular injury. In atypical HUS, there is continuous activation of the complement cascade leading to the formation of the membrane attack complex (MAC) which results in endothelial damage. In all forms of HUS, progressive damage to endothelial cells in the kidneys leads to localized thrombosis, particularly in the glomeruli resulting in renal insufficiency. Progressive platelet aggregation in areas of endothelial injury leads to consumptive thrombocytopenia. Microangiopathic hemolytic anemia results from mechanical damage to red blood cells as they pass through thromboses in damaged microvasculature (2).

Clinically, STEC-HUS presents with a prodromal phase of abdominal pain, vomiting, and/or diarrhea (often bloody) that lasts from 2 to 14 days before the onset of HUS. HUS then presents with a sudden onset of pallor, irritability, weakness, and lethargy as the gastroenteritis manifestations resolve (1). Petechiae and purpura are uncommon features of HUS and severe bleeding is rare. Oliguria may be present but may also be masked by ongoing diarrhea. Depending on when the patient presents, patients may be either dehydrated (from ongoing losses from diarrhea) or volume overloaded (from AKI) (2). Rectal prolapse and colitis are rare complications in the acute phase. The central nervous system (CNS) can be involved; patients may experience irritability, somnolence, behavioral changes, ataxia, dizziness, nonspecific encephalopathic features, and even seizures (5).

The differential diagnosis of HUS includes septicemia with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and systemic vasculitis (1,2). TTP is like HUS as they both have features of microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction, but TTP tends to have a more gradual onset and more often includes fever and neurological disturbances than HUS. Some experts consider TTP and HUS to be part of a continuum of disease (6).

Laboratory criteria for diagnosing HUS include thrombocytopenia (platelet count less than 150,000 per mm3), anemia (hemoglobin < 10 g/dL) of acute onset with microangiopathic findings on the peripheral blood smear (e.g., schistocytes, helmet cells), and evidence of acute kidney injury (e.g., elevated creatinine, hematuria, proteinuria). Other findings in HUS include elevated LDH, elevated reticulocyte count, low serum haptoglobin, and unconjugated hyperbilirubinemia due to ongoing hemolysis. Coagulation tests are usually normal. In STEC-HUS, the Coombs’ test should be negative; however, in pneumococcal-induced HUS, the Coombs’ test is usually positive (1,2).

Signs of renal dysfunction include elevated serum levels of BUN, creatinine, potassium, phosphorus, and uric acid. Hyperkalemia may be severe and life-threatening due to rapidly developing kidney injury as well as ongoing hemolysis (1). Elevations in BUN and creatinine may initially reflect volume depletion because of dehydration but are later the result of kidney injury (1,2). Sodium, calcium, and albumin may be low from initial diarrhea losses and later from volume overload because of kidney injury (7). Pancreatic insufficiency may manifest as elevations in amylase and lipase or glucose intolerance (5).

The presence or absence of toxigenic organisms in the stool culture has little role in making the diagnosis of HUS since most patients infected with such organisms do not develop HUS and those with HUS may have already cleared the organism when they present with signs of HUS (2). However, stool cultures should still be obtained since the presence of toxigenic enteropathic organisms have important public health implications and are reportable diseases (8).

HUS disease progression varies. It can be relatively mild or progress to severe, multisystem disease. Renal insufficiency can be mild or can rapidly worsen with oliguria or anuria. Half of HUS patients will require dialysis. Volume overload, hypertension, electrolyte abnormalities, and severe anemia can precipitate heart failure and arrhythmias. Severe CNS involvement occurs in less than 20% of cases and results from focal ischemia. Rarely, larger strokes or intracranial hemorrhages can occur. Intestinal complications are also possible, including severe inflammatory colitis, ischemic enteritis, bowel perforation, intestinal strictures, intussusception, and pancreatitis (2).

Treatment for STEC-HUS is supportive. Careful monitoring of fluid balance is critical. Dehydration should be corrected, but overhydration should be avoided if oliguric kidney injury occurs. Antihypertensives may be required. Hyperkalemia, hyperphosphatemia, and severe metabolic acidosis must be managed medically. Packed red blood cells should be transfused if the hemoglobin falls below 7 g/dL. Platelet transfusions are rarely administered since generalized bleeding is uncommon and the infused platelets are almost immediately consumed (1,2).

Peritoneal or hemodialysis should be considered for patients with significant AKI. The indications for dialysis include hyperkalemia (potassium concentration higher than 6.5 mEq/L or any hyperkalemia with electrocardiographic changes), serum blood urea nitrogen (BUN) higher than 100 mg/dL, persistent acidosis, volume overload leading to cardiac or respiratory compromise, hypertension from volume overload not responding to medical therapies, oliguria or anuria as a limiting factor for nutritional support, and the need for blood transfusions in patients with poorly controlled hypertension (9).

There is no evidence to support any therapy directed at arresting the disease process in STEC-HUS. Anticoagulants, antiplatelet agents, fibrinolytic therapy, immune globulin, plasmapheresis, corticosteroids, and Shiga-toxin binding agents have not been found to be beneficial (2). Various studies have been conducted to determine the efficacy of multiple Shiga toxin-specific therapies in preventing systemic disease progression. However, it has been concluded that, thus far, these therapies would need to be administered before the onset of thrombotic microangiopathy to be most effective (10). Anticoagulation, antiplatelet, and fibrinolytic therapies are contraindicated due to the increased risk of serious hemorrhage (2).

In atypical HUS, plasmapheresis has been found to be beneficial (11). However, this varies widely depending on the etiology and even the specific genetic mutation involved (3). Eculizumab, an anti-C5 monoclonal antibody, has been FDA approved as a therapy for atypical HUS (2). In the last decade, the use of eculizumab has helped to reduce mortality rates, but up to 50% of patients still develop chronic kidney disease (12).

Antibiotic therapy is contraindicated in the treatment of STEC-HUS due to the risk of Shiga toxin release and exacerbation of HUS symptoms (12). However, this matter is still up for debate, since some studies have reported conflicting findings (13). Antibiotics are most definitely indicated in the treatment of pneumococcal-associated HUS cases (9).

Primary prevention of STEC-HUS is through avoiding the consumption of undercooked beef and unpasteurized beverages, and ensuring there is no contamination of raw fruits and vegetables with raw meats during food preparation. The Centers for Disease Control recommends cooking ground beef until there is a minimum internal temperature of 160°F (70°C) for a cooked hamburger and states that the color of the meat is not a reliable indicator of safety. The most effective means of preventing person-to-person spread is through proper hand hygiene (14).

The prognosis for HUS has improved due to early recognition of the disease, monitoring for potential complications, and excellent supportive care. The mortality rate for STEC-HUS is now less than 5%. Most patients with STEC-HUS recover with little risk of long-term sequelae. Of the 50% who require acute dialysis, 5% remain on dialysis chronically and approximately 30% will have some level of chronic renal insufficiency. If patients have no hypertension, renal insufficiency, or residual urinary abnormalities after one year, they are unlikely to manifest any long-term effects. Unfortunately, pneumococcal-associated HUS has higher mortality of up to 20% and atypical HUS has an even higher mortality of up to 25%. Up to 50% of atypical HUS patients progress to end-stage renal disease (ESRD); however, the prognosis for atypical HUS has improved in the last decade and should continue to improve as the accessibility to eculizumab increases (3,4).

1. What is the most likely bacterial etiology of STEC-HUS?

2. What triad defines HUS?

3. What types of blood cells would be most consistent with a diagnosis of HUS in a 3 year old child with bloody diarrhea?
   a. Atypical lymphocytes
   b. Elliptocytes
   c. Myeloblasts
   d. Schistocytes
   e. Spherocytes

4. Name the indications of dialysis in HUS patients.

5. A 3 year old girl presents with signs and symptoms of intussusception which include crampy intermittent abdominal pain, crying with puffy eyes, currant jelly diarrhea, pallor, dehydration, and oliguria. Could this patient have HUS? Explain how all the findings above could be due to HUS instead.

1. Bhandari J, Sedhai YR. StatPearls. Hemolytic Uremic Syndrome. Accessed July 30, 2022.
2. Devarajan P. Chapter 538. Multisystem Disease Associated with Hematuria. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp: 2728-2736.
3. National Organization for Rare Disorders. Atypical Hemolytic Uremic Syndrome. Accessed July 30, 2022.
4. Raina R, Krishnappa V, Blaha T, Kann T, et al. Atypical Hemolytic-Uremic Syndrome: An Update on Pathophysiology, Diagnosis, and Treatment. Ther Apher Dial 2019; 23(1):4-21.
5. Khalid M, Andreoli S. Extrarenal manifestations of the hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC HUS). Pediatr Nephrol 2019;34(12):2495-2507.
6. Zini G, De Cristofaro R. Diagnostic Testing for Differential Diagnosis in Thrombotic Microangiopathies. Turk J Haematol 2019;36(4):222-229.
7. Cobenas CJ, Lombardi LL, Pereyra P, De Rosa E, et al. Hypoalbuminemia: a risk factor in patients with STEC-associated hemolytic uremic syndrome. Pediatr Nephrol 2021;36(9):2739-2746.
8. Centers for Disease Control and Prevention. Hemolytic Uremic Syndrome, Post-diarrheal (HUS) 1995 Case Definition. Accessed July 30, 2022.
9. Phadke K, Goodyer P, Bitzan M. Manual of Pediatric Nephrology, 2014th edition. 2014. Springerlink, Manhattan.
10. Cody EM, Dixon BP. Hemolytic Uremic Syndrome. Pediatr Clin North Am 2019; 66(1): 235-246.
11. Chen YY, Sun X, Huang W, et al. Therapeutic apheresis in kidney diseases: an updated review. Ren Fail 2022;44(1):842-857.
12. Sperati J. Hemolytic-Uremic Syndrome (Clinical Overview). Clinical Key (Elsevier Database). Elsevier 2022.!/content/derived_clinical_overview/76-s2.0-B9780323755702004197#hl0000205
13. Detzner J, Pohlentz G, Muthing J. Enterohemorrhagic Escherichia coli and a Fresh View on Shiga Toxin-Binding Glycosphingolipids of Primary Human Kidney and Colon Epithelial Cells and Their Toxin Susceptibility. Int J Mol Sci 2022;23(13):6884.
14. Centers for Disease Control and Prevention. Escherichia coli: Prevention. Accessed July 31, 2022.

Answers to questions
1. E. coli O157:H7
2. Microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.
3. d. Schistocytes
4. Hyperkalemia, uremia, persistent acidosis, volume overload leading to cardiac or respiratory compromise, hypertension from volume overload, and oliguria or anuria as a limiting factor for nutritional support.
5. Yes. Crampy abdominal pain (due to colitis), crying with puffy eyes (due to abdominal cramps, fluid retention due to kidney injury causing puffy eyes), currant jelly diarrhea (actually bloody diarrhea due to E. coli O157:H7), pallor (due to hemolytic anemia), dehydration (due to diarrhea), oliguria (due to kidney injury).

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