Chapter XIII.5. Hemolytic Uremic Syndrome 
Alicia G. Turlington, MD
October 2013

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Jonathan K. Marr, MD. This current second edition chapter is a revision and update of the original author’s work


A 3 year old male is brought to the ED by his mother with a chief complaint of bloody diarrhea. He has had no fever, ill contacts, or recent exposure to children with diarrhea. He is noted to be pale. His family attended a birthday party 7 days prior where the child had consumed hot dogs and hamburgers.

Exam: VS T 37.7, P 150, R 28, BP 100/45, oxygen saturation 100% in RA. Weight 17 kg (75%ile). He is alert but fussy, pale, and non-toxic appearing. His conjunctiva are pale. His TMs are normal. He has no nasal flaring or palatal petechiae. His oral mucosa is moist and his tongue is pale. His neck is supple without adenopathy. His heart has a regular rhythm with tachycardia 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, with the liver edge palpable 3cm below the RCM. The spleen is non-palpable. His genitalia and anus are normal (no rectal prolapse). His pulses and perfusion are good. There is no edema, rash, or petechiae.

Labs: CBC: WBC 16,000 with 56% segs, 12% bands, 27% lymphs, 3% eos, 2% basos, hemoglobin 8 mg/dL, hematocrit 24.6, platelet count 75,000; peripheral smear shows schistocytes, helmet cells, and polychromasia. Na 133, K 5.9, Cl 96, bicarbonate 16, BUN 45, creatinine 1.3, glucose 145 mg/dL, Ca 7.8, PO4 7.1, uric acid 7.3, and LDH 300. Coagulation studies are normal.


Hemolytic uremic syndrome (HUS) is a heterogeneous group of similar entities that has been reported from most parts of the world since 1955. It is one of the most common causes of community acquired acute renal failure in children. The annual incidence of HUS is one to three cases per 100,000 children (1). It is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency (2). Other systems, such as the central nervous system, may be involved.

The etiologies of HUS include infection-induced, medication-induced, familial or genetic and HUS associated with systemic diseases characterized by microvascular injury (2). The most common form of HUS is diarrhea-associated HUS which is often termed D+ HUS. D+ HUS is characterized by a sudden onset of hemolytic anemia, thrombocytopenia, and acute renal failure after prodromal gastrointestinal enteritis. Other forms of HUS are often labeled atypical HUS or D- HUS (HUS without diarrhea).

Infection-induced HUS is most commonly caused by verotoxin-producing Escherichia coli in Western countries and Shigella dysenteriae type 1 in Asian and southern African countries. Several serotypes of E. coli can produce verotoxin, but O157:H7 is the most common serotype in Western countries. Another infection-induced entity is HUS caused by neuraminidase-producing Streptococcus pneumonia. It usually manifests with acute pneumonia and empyema. Untreated human immunodeficiency virus (HIV) has also been associated with a form of HUS (2).

Approximately 10% of all cases of HUS are classified as atypical. These cases usually portend a worse prognosis, with mortality rates as high as 25% and progression to end-stage renal disease (ESRD) in up to 50% (3). Atypical HUS without a family history, or sporadic atypical HUS, can be medication induced and has been associated with the calcineurin inhibitors (cyclosporine and tacrolimus), cytotoxic and chemotherapeutic agents such as mitomycin C, cisplatin, and gemcitabine, the anti-platelet agents, clopidogrel and ticlopidine, and quinine. Diseases associated with microvascular injury can also trigger HUS. These include malignant hypertension, systemic lupus erythematosus (SLE), antiphospholipid syndrome, primary glomerulopathy, and the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Finally, atypical HUS can be associated with bone marrow and solid organ transplantation as well as cancer (2). Up to 50% of sporadic atypical HUS cases are idiopathic (3).

Familial atypical HUS has an even worse prognosis than sporadic atypical HUS with a rate of either ESRD or death of 50% to 80% (3). Inherited deficiencies have been identified in von Willebrand factor cleaving protease (ADAMTS13 - ADAM metallopeptidase with thrombospondin type 1 motif 13), complement factor H, 1, and B, and defects in vitamin B12 metabolism (2).

Epidemiologically, the most common form of the HUS syndrome (D+ HUS) occurs predominantly in healthy children one to 10 years of age, and has seasonal variation with peaks in the warmer months, from June to September (1). Occurrences may be sporadic or part of an epidemic. Most cases of D+ HUS occurring during outbreaks are due to ingestion of contaminated, usually undercooked, ground beef. E. coli O157:H7 can also be acquired by consuming fruits or vegetables contaminated by the toxin, drinking unpasteurized milk or apple cider, swimming in contaminated lakes, at petting zoos or farms, and 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 the D+ forms, verotoxin (shiga-like or shiga toxin) directly causes endothelial damage and microvascular injury and activates platelets to promote their aggregation. In the pneumococcal-associated HUS, neuraminidase cleaves sialic acid on the membranes of endothelial cells, platelets, and RBCs to reveal antigens which trigger microvascular injury. In all forms, 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. The microangiopathic hemolytic anemia results from mechanical damage to RBCs as they pass through the damaged microvasculature (2).

Clinically, D+ HUS presents with abdominal pain, vomiting, and diarrhea which may be bloody. The prodromal phase of the illness varies from 1 to 15 days before the onset of HUS. Following the prodrome, there is a sudden onset of pallor, irritability, weakness and lethargy. Petechaie and purpura are uncommon features of HUS and severe bleeding is extremely rare (1). Oliguria may be present but may also be masked by the ongoing diarrhea. Depending on when during the prodromal illness they present, patients may be either dehydrated or volume overloaded (2). 10% of patients may have rectal prolapse with colitis (1). The central nervous system (CNS) is involved in a majority of cases and patients may experience irritability and somnolence, behavioral changes, ataxia, dizziness, nonspecific encephalopathic features and seizures. No presenting features in HUS including laboratory findings can reliably predict the severity of the disease (2).

The differential diagnosis of HUS includes: imflammatory bowel diseases, appendicitis, intussusception, idiopathic rectal prolapse, gastroenteritis, acute bacterial endocarditis, septicemia with disseminated intravascular coagulation, systemic lupus erythematosus, malignant hypertension, and bilateral renal vein thrombosis (1,2).

Thrombotic thrombocytopenic purpura (TTP) is similar to HUS with the features of: microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction, but it tends to have a more gradual onset, and more often includes fever and neurological disturbances than HUS. It is probable that TTP and HUS are part of a continuum of disease (2).

Laboratory criteria for diagnosing HUS include anemia of acute onset with microangiopathic findings on the peripheral blood smear (i.e., schistocytes/helmet cells, and echinocytes) coexisting with findings of renal injury of acute onset (hematuria, proteinuria, or elevated creatinine level). Thrombocytopenia is usually also detected early in the illness but the platelet count can later become normal or even elevated. However, if a platelet count obtained within seven days of onset of an acute gastrointestinal illness is not less than 150,000 per cubic mm , alternative diagnoses should be sought. Other findings in HUS include a negative Coombs’ test as well as evidence of hemolysis including an elevated LDH, elevated reticulocyte count, low serum haptoglobin, and an unconjugated hyperbilirubinemia. Of note, in pneumococcal-induced HUS, the Coombs’ test is usually positive (2). Leukocytosis is generally present and is nonspecific diagnostically. However, leukocytosis has been found to be a valid, independent and reliable early risk factor for predicting progression to HUS in children with E. coli O157:H7 infection. An absence of leukocytosis during the early stages of gastrointestinal illness makes HUS an unlikely event following E. coli O157:H7 infection (4). Coagulation tests are usually normal.

Signs of renal dysfunction include elevated serum levels of creatinine, potassium, phosphorus, and uric acid. Elevations in BUN and creatinine may initially reflect volume depletion because of dehydration, but are later the result of renal failure. Sodium, calcium, and albumin may be low from initial diarrhea losses and later from volume overload because of renal failure. Pancreatic insufficiency is manifested by elevations in amylase and lipase or glucose intolerance. Hyperkalemia may be severe and life threatening due to the rapidly developing renal failure as well as severe ongoing hemolysis. Renal biopsy is rarely clinically indicated for D+ HUS (2).

The presence or absence of toxigenic organisms in the stool culture has little role in making the diagnosis of HUS as 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 as the presence of toxigenic enteropathic organisms has important public health implications and HUS is a reportable disease (1).

HUS disease progression varies. It can be relatively mild or it can progress to severe, multisystem disease. Renal insufficiency can be mild or can be rapidly worsening with oliguria or anuria developing. Half of all patients will require dialysis. Volume overload, hypertension, electrolyte abnormalities and severe anemia can precipitate heart failure and arrhythmias. Severe CNS involvement can occur in <20% of cases and results from focal ischemia. Rarely, larger strokes or intracranial hemorrhages can occur. Intestinal complications are also possible and include severe inflammatory colitis, ischemic enteritis, bowel perforation, intestinal strictures, intussusception, and pancreatitis (1,2).

Treatment for infection-induced HUS is supportive. Careful monitoring of fluid balance is critical. Dehydration should be corrected, but over hydration should be avoided if oliguric renal failure occurs. Hyperkalemia, hyperphosphatemia, and severe metabolic acidosis must be managed medically. Packed red blood cells should be transfused if the hemoglobin falls below 6g/dL or for symptomatic anemia. Platelet transfusions are rarely administered since generalized bleeding is uncommon and the infused platelets are almost immediately consumed. Hypertension must also be treated (2).

Peritoneal or hemodialysis should be considered when fluid and electrolyte imbalances cannot be corrected by medical management, or when fluid overload compromises cardiac or pulmonary function. In general, the indications for dialysis are similar to other forms of acute renal failure. This includes: hyperkalemia (potassium concentration higher than 6.5 mEq/L with electrocardiographic changes); serum urea concentrations higher than 100 mg/dL, persistent acidosis (bicarbonate concentration less than 10 mEq/L); hypertension from volume overload not responding to medical therapies; volume overload leading to cardiac or respiratory compromise; oliguria or anuria as a limiting factor for nutritional support; and the need for blood transfusions in patients with poorly controlled hypertension (5). Non-oliguric patients generally do not need dialysis.

There is no evidence to support any therapy directed at arresting the disease process in D+ HUS. Anticoagulants, antiplatelet agents, fibrinolytic therapy, immune globulin, plasmapharesis, steroids, and Shiga-toxin binding agents have not been found to be beneficial (1,2). A 2009 systematic review of the literature which evaluated seven randomized control trials concluded that none of the included treatments were superior to supportive care alone. Bleeding complications were significantly higher in studies involving anticoagulation (6).

In atypical HUS and TTP, plasmapharesis has been found to be beneficial (1,3). Such therapies have been associated with a decrease in mortality from 50% to 25% (3). Kidney transplantation for patients with ESRD and atypical HUS is usually associated with poor results: 50% have disease recurrence resulting in a 80% to 90% rate of graft failure; however, this varies widely depending on the etiology and even the specific genetic mutation involved. There are a few case reports illustrating the possible benefit of eculizumab, an anti-complement monoclonal antibody, for patients in whom plasmapharesis is no longer beneficial (3).

Antibiotic therapy during D+ HUS is generally discouraged due to the potential to increase toxin release from lysed bacteria (1). A 2002 meta-analysis of nine studies suggested that the data on increased risk of developing HUS after antibiotic administration for diarrhea was conflicting (7). However, in 2012, a prospective cohort study of 259 children with E. coli O157:H7 found that antibiotic use is associated with a higher rate of subsequent HUS (8). Another age-matched case-case comparison study done in 2012 did not find an increase risk from antibiotics overall but did show a significant increase of HUS in patients given bactericidal antibiotics, in particular Beta-lactams (9). Similarly, antimotility agents used to treat diarrhea have also been discouraged (1). Antibiotics are most definitely indicated in the treatment of pneumoccocal associated HUS cases, however (2).

Primary prevention of D+ HUS is through avoidance of consuming undercooked beef and unpasteurized dairy and fruit juice products and taking care not to contaminate 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 degrees F (71 degrees C) for cooked hamburger and also 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 (10). Infected people must avoid swimming at recreational venues for 2 weeks after symptoms resolve. Infected children must be excluded from day care centers until diarrhea has resolved and they have two negative stool cultures for E. coli O157:H7 (11).

Prognosis for HUS has improved due to early recognition of the disease, monitoring for potential complications, and excellent supportive care. The mortality rate for D+ HUS is now <5%. Pneumococcal associated HUS, unfortunately, has a higher mortality of up to 20%. Most patients with D+HUS recover with little risk of long-term sequelae. Of the 50% who require dialysis, 5% remain on dialysis and 20% to 30% will have some level of chronic renal insufficiency. If after one year, patients have no hypertension, renal insufficiency, or residual urinary abnormalities, they are unlikely to manifest any long-term effects (2). Atypical HUS generally portends a poorer prognosis.


Questions

1. What is the likely bacterial etiology of D+ HUS?

2. What 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. What is the strongest indication for dialysis? 
. . . . . a. Serum sodium of 120 
. . . . . b. Initial bicarbonate of 14 
. . . . . c. Serum BUN 120 mg/dL 
. . . . . d. Initial K of 5.2 

5. True/False: The absence of leukocytosis in E. coli O157:H7 infection makes HUS an unlikely sequelae.

6. 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 of the findings above could be due to HUS instead.


References

1. Razzaq S. Hemolytic-Uremic Syndrome: An Emerging Health Risk. Am Fam Physician 2006;74(6):991-6.

2. Van Why S, Avner E. Chapter 512 - Hemolytic-Uremic Syndrome. In: Kliegman R, et al (eds). Nelson Textbook of Pediatrics, 19th edition. 2011, Philadelphia: Saunders, pp. 1791-1794.

3. Noris M and Remuzzi G. Atypical Hemolytic-Uremic Syndrome. N Engl J Med. 2009 Oct 22;361(17):1676-87.

4. Anjay MA, Anoop P, Britland A. Leukocytosis as a predictor for progression to haemolytic uraemic syndrome in Escherichia coli O157:H7 infection. Arch Dis Child. 2007 Sep;92(9):820-3.

5. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005 Mar 19-25;365(9464):1073-86.

6. Michael M et al. Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003595.

7. Safdar N et al. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis. JAMA. 2002 Aug 28;288(8):996-1001.

8. Wong CS et al. Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis. Clin Infect Dis. 2012 Jul;55(1):33-41.

9. Smith KE et al. Antibiotic treatment of Escherichia coli O157 infection and the risk of hemolytic uremic syndrome, Minnesota. Pediatr Infect Dis J. 2012 Jan;31(1):37-41.

10. National Center for Emerging and Zoonotic Infectious Diseases. E coli Infection. Centers for Disease Control and Prevention. http://www.cdc.gov/Features/EcoliInfection/. (Accessed March 31, 2013).

11. American Academy of Pediatrics. Escherichia coli Diarrhea (Including Hemolytic Uremic Syndrome). Red Book: 2012 Report of the Committee on Infectious Diseases. Pickering LK, ed. 29th ed. Elk Grove Village, IL. American Academy of Pediatrics, 2012. [The following section is for the answers to questions]


Answers to questions

1. E. coli O157:H7

2. Microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.

3. D. Schistocytes

4. C. Serum BUN >100

5. True

6. Crampy abdominal pain (due to colitis), crying with puffy eyes (due to abdominal cramps, fluid retention due to renal failure 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 renal failure).


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