eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Hemolytic-Uremic Syndrome

Robert S Gillespie, MD, MPH, Department of Pediatrics, Cook Children's Medical Center
Craig S Wong, MD, MPH, Assistant Professor, Division of Pediatric Nephrology, Department of Pediatrics, University of New Mexico School of Medicine; Director of Pediatric Kidney Transplantation, Division of Pediatric Nephrology, Department of Pediatrics, University of New Mexico Transplant Services, Children's Hospital of New Mexico; Ronald D Prauner, MD, Assistant Professor of Pediatrics, F Edward Herbert School of Medicine, Uniformed Services of the Health Sciences; Chief, Department of Pediatrics, Brooke Army Medical Center; Deputy Chairman, Department of Pediatrics, San Antonio Military Medical Center (SAMMC); Staff Pediatric Hematologist-Oncologist, Brooke Army Medical Center, Wilford Hall Medical Center, CR Darnall Army Medical Center

Updated: Aug 14, 2009

Introduction

Background

Hemolytic-uremic syndrome (HUS) was first described by Gasser in a German publication in 1955. Hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Since 1955, thousands of cases have been reported, and hemolytic-uremic syndrome is recognized as the most common cause of acute renal failure in the pediatric population.

The clinical course of hemolytic-uremic syndrome can vary from subclinical to life threatening. Studies have revealed distinct subgroups of hemolytic-uremic syndrome and have identified several etiologies for the disease. Hemolytic-uremic syndrome is classified as diarrhea-associated (D⁺ hemolytic-uremic syndrome) and non–diarrhea-associated (D^- or atypical hemolytic-uremic syndrome). Within D^- hemolytic-uremic syndrome is another subtype, pneumococcal-associated hemolytic-uremic syndrome (P-hemolytic-uremic syndrome). The distinction is important because the clinical courses, treatments, and prognoses differ for each category. The first reported cases were D^- hemolytic-uremic syndrome; however, D⁺ hemolytic-uremic syndrome is now much more common.

Hemolytic-uremic syndrome shares many features with thrombotic thrombocytopenic purpura (TTP). For more information, see the eMedicine articles in the Neurology and Hematology sections. Both diseases include multiorgan dysfunction due to thrombotic microangiopathy, with active hemolysis and thrombocytopenia. The traditional classification describes patients with predominantly renal disease as having hemolytic-uremic syndrome, and patients with predominantly CNS disease as having TTP. However, hemolytic-uremic syndrome can include severe neurologic impairment, and TTP can involve severe renal failure. Involvement of other organ systems also overlaps. 

Whether these are, in fact, separate diseases remains controversial; some authors describe "hemolytic-uremic syndrome–TTP" as a single disease entity with a diverse spectrum of presentations. In many cases, both nephrologists and hematologists collaborate on the care of patients with these complex illnesses.

Nomenclature for various types of hemolytic-uremic syndrome varies throughout the literature. For consistency, this article uses the following set of terms throughout this review:

• D⁺ hemolytic-uremic syndrome is used to describe diarrhea-positive, classic or typical hemolytic-uremic syndrome, mediated by Shiga toxin (Stx).
• D^- hemolytic-uremic syndrome is used to describe diarrhea-negative, non–diarrhea-associated or atypical hemolytic-uremic syndrome, mediated by abnormalities of the complement system or other heritable factors.
• P-hemolytic-uremic syndrome is used to describe pneumococcal-associated hemolytic-uremic syndrome, mediated by neuraminidase in the presence of infection with Streptococcus pneumoniae.

Pathophysiology

Classic D⁺ hemolytic-uremic syndrome is usually preceded by a colitis caused by Shiga toxin–producing Escherichia coli (STEC). Subsequent inflammation of the colon facilitates systemic absorption of the Stx and lipopolysaccharide (LPS) from the GI tract. The major toxins that cause hemolytic-uremic syndrome, Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2), are similar in structure to the classic Stx. These toxins bind to globotriaosylceramide (Gb3), a glycolipid receptor molecule on the surface of endothelial cells in the gut, kidney, and occasionally other organs. Differential expression of Gb3 on glomerular capillaries compared with other endothelial cells may explain the predominance of renal injury. Damaged endothelial cells of the glomerular capillaries release vasoactive and platelet-aggregating substances. The endothelial cells swell, and fibrin is deposited on the injured vessel walls.

Swelling and microthrombi formation within the glomerular capillaries produce a localized intravascular coagulopathy. The glomerular filtration rate is reduced, and renal insufficiency ensues. Erythrocytes are damaged and fragmented as they traverse the narrowed glomerular capillaries. This leads to the characteristic microangiopathic hemolytic anemia. Hemolysis may also be a result of lipid peroxidation.

Peripheral blood smear in hemolytic-uremic syndrome (HUS) showing many schistocytes and RBC fragments due to hemolysis, and relatively few platelets reflective of thrombocytopenia.

Thrombocytopenia is believed to result from a combination of platelet destruction, increased consumption, sequestration in the liver and spleen, and intrarenal aggregation. Platelets are damaged as they pass through the affected glomerular capillaries. Remaining platelets circulate in a degranulated form and show impaired aggregation. Stx also binds to activated platelets.

Abnormalities of anti–platelet-aggregating agents (eg, prostaglandin I₂ [PGI₂]), platelet-aggregating agents (thromboxane A₂ [TXA₂]) and von Willebrand factor (vWF) multimers are also important factors that contribute to thrombocytopenia. A decrease in PGI₂ during the early stages of hemolytic-uremic syndrome has been noted. Defective PGI₂ production is believed to play a role in D⁺ hemolytic-uremic syndrome; abnormal PGI₂ synthesis is believed to play a role in D^- hemolytic-uremic syndrome.

TXA₂ levels are increased during the acute stage of hemolytic-uremic syndrome, leading to increased platelet aggregation. Another possible cause for increased platelet aggregation is large vWF multimers. In vitro, these large multimers have a greater ability to aggregate platelets than the normal, smaller multimers. Normal plasma contains a vWF-cleaving metalloproteinase (ADAMTS13) that rapidly degrades large vWF multimers. Many cases of TTP are associated with deficient function of ADAMTS13. 

Abnormalities of ADAMTS13 may take the form of decreased quantity or absence of the enzyme, a mutation resulting in normal quantity of a defective enzyme, or an antibody inhibitor of the enzyme. Genetic or acquired defects in this protease have also been reported in patients with D^- hemolytic-uremic syndrome, but less frequently than in patients with TTP. Alterations in ADAMTS13 are not involved in the pathogenesis of D⁺ hemolytic-uremic syndrome. The role of ADAMTS13 in both TTP and, less commonly, D^- hemolytic-uremic syndrome remains incompletely understood.

WBCs are usually elevated in the blood of patients with hemolytic-uremic syndrome. Activated neutrophils are believed to damage endothelial cells by releasing elastase (a catabolic enzyme that promotes endothelial cell detachment) and by producing free radicals. Monocytes may be stimulated to release cytokines (ie, interleukin-1 and tumor necrosis factor [TNF]) that also damage endothelial cells.

D^- hemolytic-uremic syndrome has several genetic forms. Genetically induced cases are usually not preceded by diarrheal illness, often manifest a recurrent course, and are associated with a more guarded long-term prognosis regarding maintenance of normal kidney function. The best-studied genetic variant of hemolytic-uremic syndrome involves mutations in one of the short consensus repeat segments of the gene for factor H, a protein that regulates complement. Hemolytic-uremic syndrome with factor H mutations usually progresses to end-stage renal disease (ESRD) and has a nearly 100% recurrence rate in renal allografts. 

Mutations in factor I and membrane cofactor protein (MCP), also complement regulatory proteins, are also associated with D^- hemolytic-uremic syndrome. Factor I mutations are associated with a very high rate of recurrence, but patients with MCP mutations may have a more favorable long-term prognosis. Mutations of thrombomodulin, another complement regulatory protein, were identified in 5% of a group of patients with D^- hemolytic-uremic syndrome.¹  Autosomal dominant and autosomal recessive forms of D^- hemolytic-uremic syndrome due to a yet unidentified mutation have also been described.

Pneumococcal-associated hemolytic-uremic syndrome constitutes a distinct subgroup of hemolytic-uremic syndrome. This variant occurs with infections caused by S pneumoniae, usually pneumonia. Because it occurs without diarrhea, it usually falls under the category of D^- hemolytic-uremic syndrome; however, it is actually a distinct entity that has little relation to the D^- hemolytic-uremic syndrome associated with complement factor mutations. The bacterial toxin neuraminidase damages endothelial cells and initiates hemolytic-uremic syndrome in this setting.

As a toxin-mediated disease, pneumococcal-associated hemolytic-uremic syndrome has much in common with D⁺ hemolytic-uremic syndrome mediated by Stx. Bacteria with neuraminidase remove N- acetylneuraminic acid from cell-surface glycoproteins and expose the normally hidden T antigen (Thomsen-Friedenreich antigen) on erythrocytes, platelets, and glomeruli. Serum has anti-T immunoglobulin M (IgM), which can react with the antigen and cause damage to RBCs and the kidneys. Some authors have proposed the term P-hemolytic-uremic syndrome, which is used in this article, to describe this hemolytic-uremic syndrome variant.

Frequency

United States

Between 1982-2002, 354 E coli O157:H7–associated hemolytic-uremic syndrome cases were reported. Transmission route was highest among swimming outbreaks, followed by person-to-person, unknown, animal contact, foodborne, and drinking water–related outbreaks. Daycare centers were the most common person-to-person outbreak setting. Although contaminated ground beef was the most common cause of foodborne outbreaks, produce-associated outbreaks are also common (ie, lettuce, sprouts, cabbage, apple cider, apple juice). These have been attributed to fecal contamination of produce in the fields, from wild animals or from fertilization containing human or animal fecal matter. 

Incidence is increased during the summer and early fall. Outbreaks of diarrhea followed by hemolytic-uremic syndrome have been reported in institutions, boarding schools, and daycare centers. Seasonal variation is not observed in D^- hemolytic-uremic syndrome. D⁺ hemolytic-uremic syndrome is much more common than D^- hemolytic-uremic syndrome.

International

Hemolytic-uremic syndrome occurs worldwide but has a higher incidence in South Africa, Holland, and Argentina.

Mortality/Morbidity

Mortality rates have decreased progressively from near universal fatality in 1955 to only 3-5% during the 1990s. This improvement is attributed to better management during the acute stage of the disease, with aggressive management of hypertension, fluid overload, electrolyte disturbances and nutrition, often requiring dialysis. The mortality rate in underdeveloped countries remains as high as 72%. Patients with hereditary hemolytic-uremic syndrome have a worse prognosis. The vast majority of patients with autosomal dominant or recessive forms of the disease progress to ESRD.

Race

Hemolytic-uremic syndrome occurs in all races; however, it is very rare in blacks. This observation has no explanation.

Sex

Males and females are affected in equal numbers; however, the disease may affect female patients more severely.

Age

A large majority of cases of D⁺ hemolytic-uremic syndrome occur in children aged 7 months to 6 years, although the disease may occur at any age. No age predilection is noted for D^- hemolytic-uremic syndrome. Genetically mediated forms may present as early as birth or the neonatal period.

Clinical

History

Patients with diarrhea-associated hemolytic-uremic syndrome (D⁺ HUS) experience several days of diarrhea, with or without vomiting, followed by sudden onset of symptoms such as irritability and pallor. In more than 80% of patients, the diarrhea is evidently bloody. Other symptoms include restlessness, oliguria, edema, and macroscopic hematuria. In some patients, the prodrome may improve as hemolytic-uremic syndrome symptoms begin. The clinical picture may mimic that of an acute abdomen. In patients infected with a Shiga toxin (Stx)–producing strain of E coli, hemolytic-uremic syndrome occurs in 5-15%. The risk of progression to hemolytic-uremic syndrome is increased in very young or elderly persons, in patients who have been treated with antimotility drugs or antibiotics, and in patients with a fever or a high leukocyte count.

The history should include inquiry about possible recent exposure to E coli, such as consuming undercooked meat, encounters with livestock or petting zoos, contacts with other persons with diarrhea, and attendance at daycare or school. However, most cases of D⁺ hemolytic-uremic syndrome are sporadic, with no clearly identifiable source of infection, even when stool culture yields a toxigenic organism. Outbreaks involving multiple persons more commonly lead to a source.

Non–diarrhea-associated hemolytic-uremic syndrome (D^- HUS) may follow a respiratory illness, especially when caused by S pneumoniae.

Features of all forms of hemolytic-uremic syndrome include the following:

• Hematology
  • Hemolysis occurs in all patients with hemolytic-uremic syndrome. It can proceed rapidly, resulting in a rapid fall of the hematocrit.
  • Platelet counts usually fall below 40,000/mcL. However, the degree of thrombocytopenia does not correlate with the severity of hemolytic-uremic syndrome, and some children can maintain relatively normal kidney function despite severe hematologic abnormalities.
  • Many patients have petechiae, purpura, and oozing from venipuncture sites.
  • Overt bleeding is less common.
• CNS
  • Patients often present with sudden onset of lethargy and irritability.
  • Other findings may include ataxia, coma, seizures, cerebral swelling, hemiparesis, and other focal neurologic signs.
  • CNS changes may be caused by cerebral ischemia from microthrombi, effects of hypertension, hyponatremia, or uremia.
  • D^- hemolytic-uremic syndrome tends to be associated with a greater number of neurologic symptoms than D⁺ hemolytic-uremic syndrome.
• Renal system
  • Acute renal insufficiency usually begins with the onset of hemolysis. Although patients have decreased urine output, frequent diffuse watery stools may mask this sign.
  • If renal insufficiency is not recognized and treated, hyponatremia, hyperkalemia, severe acidosis, ascites, edema, pulmonary edema, and hypertension ensue.
• GI tract: D⁺ hemolytic-uremic syndrome is usually preceded by 3-12 days of watery or bloody diarrhea. Vomiting and crampy abdominal pain are also common. Note that diarrhea may improve as the other hemolytic-uremic syndrome symptoms begin (eg, thrombocytopenia, renal insufficiency). Life-threatening complications include intestinal perforation or necrosis.  Even without these complications, the colitis of hemolytic-uremic syndrome may cause severe abdominal pain which may persist for several days into the illness.
• Infectious signs: Fever is present in 5-20% of patients. The presence of fever, leukocytosis, or both is a prognostic indicator of the risk of developing more severe hemolytic-uremic syndrome.
• Pancreas: Mild pancreatic involvement is common but can be severe on occasion, with necrosis, pseudocysts, or both, which can leave the patient with insulin-dependent diabetes and, on rare occasion, exocrine dysfunction.
• Cardiovascular: Congestive heart failure may occur.

Physical

• Blood pressure may be elevated unless the patient is volume depleted (eg, from diarrhea.)
• Child appears ill and pale.
• Abdominal pain and tenderness may be present, possibly severe.
• Peripheral edema may be present.
• Petechiae, purpura, or oozing from venipuncture sites may be present.

Causes

The causes of D⁺ hemolytic-uremic syndrome and D^- hemolytic-uremic syndrome differ.

• D⁺ hemolytic-uremic syndrome
  • GI tract infection with Stx–producing E coli (STEC) precedes most cases of typical D⁺ hemolytic-uremic syndrome. Stx1 is identical to the Stx produced by Shigella dysenteriae. Stx2 has a 55-60% amino acid homology with Stx. They injure the gut and lead to hemorrhagic colitis. Most cases worldwide are associated with STEC 0157:H7 infection. This organism is very resilient; viable bacteria has been reported in environments up to 10 months following initial contamination. Aside from Stx production, this bacteria produces virulence factors that mediate tight adherence to the host cell, facilitating transluminal transport of the toxins into the systemic circulation. Cattle are the major reservoir for human infection. The use of antimotility agents, antidiarrheal agents, and antibiotics has been reported to increase the risk of developing hemolytic-uremic syndrome.
  • Other causes of hemolytic-uremic syndrome include infection by the following:
    • S dysenteriae (established as an etiologic agent)
    • Salmonella typhi (established as an etiologic agent)
    • Campylobacter jejuni (established as an etiologic agent)
    • Yersinia species
    • Pseudomonas species
    • Bacteroides species
    • Entamoeba histolytica
    • Aeromonas hydrophilia
    • Organisms of the class Microtatobiotes
• D^- hemolytic-uremic syndrome
  • Inherited (eg, mutations in the gene for factor H, a complement regulatory protein)
  • S pneumoniae (neuraminidase-associated)
  • Portillo virus
  • Coxsackie virus
  • Influenza virus
  • Epstein-Barr virus
  • Pregnancy: Hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura (TTP) are associated with pregnancy; pre-eclampsia and HELLP syndrome also have features in common and should be part of the differential diagnosis.
  • Drugs (eg, chemotherapy, oral contraceptives, cyclosporine, tacrolimus)
  • Bone marrow or hematopoietic stem cell transplantation
  • Malignancy
  • Idiopathic
  • Systemic lupus erythematosus (SLE)
  • Glomerulonephritis, especially membranoproliferative glomerulonephritis
  • Malignant hypertension

Differential Diagnoses

Other Problems to Be Considered

Thrombotic thrombocytic purpura (TTP) due to ADAMTS13 deficiency or inhibitor
Idiopathic TTP
Drug-induced TTP
Hematopoietic stem cell transplant-associated TTP
Disseminated intravascular coagulation (DIC)
Bilateral renal vein thrombosis
Henoch-Schönlein purpura
Immune hemolytic anemia and thrombocytopenia
Sepsis

Workup

Laboratory Studies

• Hematology
  • Classic findings in hemolytic-uremic syndrome (HUS) include anemia and thrombocytopenia, with fragmented RBCs (eg, schistocytes, helmet cells, burr cells).
    
    

    

    Peripheral blood smear in hemolytic-uremic syndrome (HUS) showing many schistocytes and RBC fragments due to hemolysis, and relatively few platelets reflective of thrombocytopenia.

    
    
  • WBC differential may reveal a left shift (ie, immature WBCs, including bands, myelocytes, metamyelocytes). Patients with diarrhea-associated hemolytic-uremic syndrome (D⁺ HUS) may have extremely high WBC counts, in the range of 50-60,000/mcL.
  • Coombs test results are negative, except with S pneumoniae –associated hemolytic-uremic syndrome.
  • Reticulocyte count is elevated.
  • Levels of serum haptoglobin, which binds hemoglobin, are decreased.
  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal.
  • Fibrin degradation products are increased.
  • Fibrinogen levels are increased or within reference range.
• Serum chemistry testing
  • BUN and creatinine levels are elevated.
  • Various electrolyte and ion derangements may be present due to vomiting, diarrhea, dehydration and renal failure; these may include hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acidosis. Phosphorous concentration is elevated.
  • Uric acid level may be increased because of acute renal failure, dehydration, and cell breakdown.
  • Protein and albumin levels may be mildly decreased.
  • Bilirubin and aminotransferase levels are typically elevated.
  • Lactate dehydrogenase (LDH) level is elevated. Serial measurements of LDH help track the approximate level of hemolytic activity.
• Urinalysis
  • Protein
  • Heme
  • Bilirubin
  • RBCs (dysmorphic)
  • WBCs
  • Casts - Cellular, granular, pigmented, hyaline
• Stool testing
  • Culture: Usually, culture yield is low after 7 days of diarrhea. The standard method used to detect and isolate Shigella toxin (Stx)–producing E coli (STEC) involves sorbitol MacConkey (SMAC) agar plates that enable identification of characteristic sorbitol nonfermenting colonies of STEC O157:H7.
    • E coli 0157:H7 does not grow on agar plates used for routine stool cultures. Notify the laboratory and request specific testing for this organism when hemolytic-uremic syndrome is suspected.
    • Even patients with documented bloody diarrhea and other classic features of D+ hemolytic-uremic syndrome often do not yield a causative organism on stool culture. This reflects the limited sensitivity of stool culture, not the absence of disease. The diagnosis of hemolytic-uremic syndrome is a clinical one and is not excluded by a negative stool culture.
  • Stx may be detected using specific antibody testing, gene studies, and enzyme-linked immunosorbent assay (ELISA).
  • Stool leukocytes have little value in detecting E coli 0157:H7. They are absent in approximately 50% of cases.
• Other tests
  • A test for serum antibodies to STEC 0157:H7 is available, but its clinical use is not well defined.
  • Complement C3 may be decreased in patients with genetic forms of hemolytic-uremic syndrome.
  • Genetic testing for complement factor mutations is available from a limited number of laboratories, in some cases only on a research basis. For a list of some laboratories offering such testing see Special Concerns. Consult with an expert in this area before ordering such tests.
    • Genetic tests may take weeks or months to perform, so they are not useful in the immediate management of a patient with hemolytic-uremic syndrome, and acute treatment decisions should not be delayed while awaiting results.
    • Results may be helpful in determining long-term prognosis (eg, the presence of factor H mutations portends a very poor renal prognosis).
    • Tests done on a fee basis may be very expensive.
    • Tests done on a research basis require informed consent. Check with the facility regarding applicable policies for research testing.

Imaging Studies

• Consider performing chest radiography to evaluate for pulmonary congestion or edema, if clinically indicated.
• Renal ultrasound typically reveals nonspecific findings (eg, increased echogenicity) and is of little use. Ultrasonography may be helpful if the diagnosis is uncertain or if one needs evaluation of blood flow in the large renal vessels.
• Abdominal ultrasonography or CT scanning may help if clinical findings raise suspicion of intestinal obstruction or perforation.
• Non-contrast CT scanning or MRI of the head is indicated in patients with CNS symptoms or acute mental status changes. Avoid iodinated contrast or gadolinium in patients with decreased renal function.

Other Tests

• Patients with hyperkalemia may require EKG monitoring.

Histologic Findings

• Renal biopsy is not usually necessary for diagnosis and may be contraindicated due to thrombocytopenia. Histologic analysis of kidney specimens reveals thrombotic microangiopathy, with swollen glomerular endothelial cells and red cells and platelets in the capillaries. Accumulation of fibrinlike material in the subendothelial space creates a thickened appearance to the capillary walls. Thrombi may be observed in the glomerular capillaries and arterioles. These findings can progress to acute cortical necrosis involving both glomeruli and convoluted tubules.
  
  

  

  Peripheral blood smear in hemolytic-uremic syndrome (HUS) showing many schistocytes and RBC fragments due to hemolysis, and relatively few platelets reflective of thrombocytopenia.

  
  
• Tissue section of the gut shows microangiopathy, with endothelial cell injury, and thrombosis, with submucosal edema and hemorrhage.
• Microthrombi may be observed in other organs, including the lungs, liver, heart, adrenal glands, brain, thyroid, pancreas, thymus, lymph nodes, and ovaries.

Treatment

Medical Care

Successful management of hemolytic-uremic syndrome (HUS) begins with early recognition of the disease and supportive care. Management includes good control of volume status, electrolyte abnormalities, hypertension, and anemia. Supportive care measures apply to both diarrhea-associated hemolytic-uremic syndrome (D⁺ HUS) and non–diarrhea-associated hemolytic-uremic syndrome (D^- HUS). Additional special considerations for D^- hemolytic-uremic syndrome are listed at the end of this section.

• Fluid therapy
  • Early and ample hydration with intravenous isotonic saline is associated with a lower risk of progression to oligoanuric hemolytic-uremic syndrome in patients with diarrhea (see Deterrence/Prevention).²  Studies on fluid therapy in patients with established hemolytic-uremic syndrome are lacking; however, based on the data above, the authors recommend that patients with hemolytic-uremic syndrome continue to receive intravenous isotonic saline to maintain a euvolemic state.
  • Monitor hydration status closely and frequently. This includes serial and frequent measurements of body weight, fluid intake and output, heart rate, and blood pressure. Renal function may rapidly decline, so laboratory test results obtained in the morning may not reflect the patient's renal function or electrolyte status later in the day. Patients may develop fluid overload or hyperkalemia if not carefully managed.
  • Monitor electrolytes. Testing may need to be performed frequently in the early stages of disease or while children are on dialysis. In children in whom kidney function is stable, testing may be performed daily.
  • Use potassium-free fluids until renal function has stabilized. Mild hypokalemia is tolerable and much less critical than hyperkalemia. Treat severe or symptomatic hypokalemia with very cautious potassium replacement.
  • Once fluid deficits have been replaced, restrict fluid replacement to insensible losses plus actual output.
• Management of acute renal failure
  • Approximately 50% of patients with D⁺ hemolytic-uremic syndrome require a period of dialysis. Consider early dialysis if the patient develops fluid overload, hyperkalemia, acidosis, hyponatremia, or oligoanuria that is unresponsive to diuretics.
  • Any type of dialysis or related technique (eg, hemofiltration) may be used, depending on local availability and individual patient factors. Suitable techniques include peritoneal dialysis, hemodialysis, or continuous renal replacement therapies (CRRT).
    • Peritoneal dialysis is widely used for pediatric patients. Peritoneal dialysis is usually well tolerated, and is technically easier, especially in small infants.
    • Hemodialysis is also suitable for children. Hemodialysis may be preferable in patients with severe abdominal pain, in whom intestinal edema and pain may reduce achievable fill volumes. The intense visceral inflammation may lead to ultrafiltration failure. Omentectomy and placement of a peritoneal catheter may worsen their pain and complicate evaluation of continued pain. 
    • Abdominal pain is more complex to assess in patients with a new peritoneal catheter. Pain could be due to a catheter-related complication, dialysis-associated peritonitis, or critical complications of hemolytic-uremic syndrome, such as intestinal perforation.
    • CRRT may be preferable for hemodynamically unstable patients. CRRT allows very precise control of volume status. CRRT also circumvents the issue of abdominal pain discussed above.
    • A growing body of evidence from critically ill patients shows that volume overload is a major contributor to morbidity and mortality.^3,4 Initiate dialysis promptly if patient has, or is approaching, a state of fluid overload.
    • Dialysis does not alter the course of the disease; it only supports the patient while awaiting resolution of the illness. Early dialysis as a preventive or therapeutic measure is not justified. Current data do not support a previous theory that peritoneal dialysis could improve outcomes by removal of plasminogen-activator inhibitor type 1 (PAI-1). However, several studies support early use of dialysis when indicated to optimize fluid, electrolyte or nutritional status.
  • Patients who require dialysis usually need 5-7 days of therapy, although this number widely varies.
• Management of hematologic abnormalities
  • Most children with hemolytic-uremic syndrome require packed RBC (PRBC) transfusions. PRBCs may be administered for symptomatic anemia (eg, tachycardia, orthostatic changes in blood pressure or heart rate, congestive heart failure) or if the hematocrit falls rapidly. The authors try to maintain the hemoglobin at approximately 7 g/dL, or the lowest amount required to prevent symptomatic anemia. Maintaining a relatively anemic state keeps the blood less viscous, theoretically helping prevent further thrombus formation.  
  • Transfuse platelets if the patient has active bleeding. Other indications for platelet transfusion remain controversial. Most physicians try to avoid platelet transfusion because it may promote platelet aggregation and thrombus formation, worsening the disease. A commonly used threshold is to transfuse as needed to maintain a platelet count near 20,000/mcL. Platelets may also be given just before a surgical or catheter placement procedure.
• Management of hypertension
  • A wide range of antihypertensive medications are available, and treatment should be individualized.  
  • Calcium channel blockers such as amlodipine or isradipine are commonly used in pediatrics. 
  • ACE inhibitors are very effective but should be used with caution in individuals with a decreased glomerular filtration rate (GFR) or with hyperkalemia.
  • Treatment is covered separately in Hypertension.
• Nutritional support
  • Providing adequate protein and energy intake enterally or parenterally is important to prevent catabolism and promote healing. Initiating dialysis, if needed, to provide adequate nutrition is preferred than to withhold nutrition in the hopes of avoiding the need for dialysis.
  • Patients may require intravenous hyperalimentation due to prolonged diarrhea, colitis, abdominal pain, intestinal ileus, or anorexia. 
  • Lipid infusion may have to be limited if hypertriglyceridemia is present.
  • Patients receiving CRRT may require additional nutrition due to amino acid removal by CRRT.⁵  Patients receiving hyperalimentation while on CRRT may require 3-4 g/kg/d of protein. Consult a dietician with renal expertise for assistance.
• Pain management
  • D⁺ hemolytic-uremic syndrome causes an intense colitis that can be extremely painful. Abdominal pain may mimic that of an acute abdomen.  Severe pain or acute changes in pain should be evaluated as a surgical emergency just as with any other patient.  
  • Acetaminophen may be used.
  • Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) because of their nephrotoxicity, which is particularly risky in an acutely injured kidney.
  • Many patients will require opioid medication. Observe special precautions when using opioids in patients with renal insufficiency or failure. Start with a low dose, titrate to effect, and observe carefully for signs of toxicity.^6,7
    • Fentanyl has no active metabolites and is an excellent choice for patients with renal dysfunction. It has a rapid onset of action but a relatively short duration.
    • Hydromorphone has active metabolites but they do not consistently cause symptoms in renal impairment. Most authors consider hydromorphone to be relatively safe in renal patients, with cautious monitoring for side effects, most commonly neuro-excitation.
    • Methadone has metabolites that are excreted primarily through stool.  Methadone is a good analgesic in renal impairment, but due to its slower onset of action and long half-life, it is less suitable for acute pain.
    • Do not use morphine, codeine, or meperidine in patients with decreased renal function. The human body converts these drugs into numerous metabolites that have no analgesic function but cause many side effects. Patients with renal failure cannot excrete these metabolites; thus, they accumulate and cause nausea, vomiting, altered mental status, hallucinations, and other deleterious effects.
    • Little data are available on the use of most other opioid analgesics in patients with renal failure. Use other agents with caution because the drug or its metabolites may have very different effects in patients with renal failure as opposed to those with normal renal function.
  • Patients should receive adequate pain control. Patients with renal disease require special care and vigilance, but renal failure is not a valid reason to withhold appropriate pain management. 
• Special considerations for D^- hemolytic-uremic syndrome 
  • Management of D^- hemolytic-uremic syndrome is very difficult and remains poorly understood. Clinicians caring for patients with D^- hemolytic-uremic syndrome should search recent literature and confer with physicians with expertise in this disorder.⁸
  • Discontinue offending agent if a drug-associated cause is identified.
  • Treat bacterial infections (eg, S pneumoniae) promptly and aggressively.
  • The role of plasma therapy in pneumococcal hemolytic-uremic syndrome (P-HUS) or neuraminidase-mediated hemolytic-uremic syndrome remains controversial. Plasma may contain antibodies to the T antigen, which, in theory, could worsen the hemolytic process. Alternately, plasma exchange may remove neuraminidase and decrease the amount of circulating anti–T antibody. Some authors advocate plasma exchange using albumin replacement.
  • Plasma therapies form the mainstay of treatment for most forms of D^- hemolytic-uremic syndrome. These therapies use donor plasma products to replace the deficient or abnormal von Willebrand factor (vWF) metalloproteinase or complement factors.   
  • No treatment has been found to be more effective than therapeutic plasma exchange (TPE), which is also called plasmapheresis.⁹
    • TPE is the most effective therapy for D^- hemolytic-uremic syndrome. TPE removes the patient's plasma and replaces it with fresh frozen plasma (FFP) or a similar product. Albumin should not be used for replacement because it does not contain the vWF metalloproteinase or complement factors, except in the case of P-hemolytic-uremic syndrome or neuraminidase mediated hemolytic-uremic syndrome (see above).
    • This can be done using cell a separator device or a special plasma filter used on a CRRT machine, both of which require specially trained staff to operate. Both methods work well, and local availability is the main selection factor. TPE requires a central venous catheter for vascular access.
    • No consensus or evidence-based guidelines guide therapy dose or schedule. Most clinicians use a tapering schedule, with several daily sessions followed by alternate-day treatments. Intervals between treatments are extended based on patient response. Individual regimens widely vary. Some authors advocate twice-daily TPE for refractory cases but note that the benefit of this approach cannot be confirmed.¹⁰
    • TPE can lower the serum creatinine because it removes the patient's serum and replaces it with serum from donors with a normal creatinine value. This does not necessarily mean the patient's renal function is improving. Platelet count is a more reliable marker of response. 
    • In theory, FFP may contain some large vWF multimers. Some authors advocate using cryoprecipitate-reduced plasma. However, multiple TPE sessions with cryoprecipitate-reduced plasma alone may deplete other coagulation factors and put the patient at risk for bleeding. Consider using FFP for at least some exchanges.
  • Plasma infusion
    • Plasma infusion consists of simply infusing donor plasma, such as FFP or cryoprecipitate-reduced plasma. In theory, this delivers the absent or abnormal vWF metalloproteinase or complement factors.
    • The sole advantage of plasma infusion is its simplicity because it can be performed in almost any medical facility and does not require specialized equipment, central venous access, or specially trained staff. Studies have found superior outcomes with TPE.¹¹
    • Infusions typically consist of 20-30 mL of FFP or cryoprecipitate-reduced plasma per kg. One case report found 40-45 mL/kg infusions necessary.¹²
    • Volume overload may complicate plasma infusion, especially in patients with reduced renal function. For example, a 50-kg child receiving 40 mL/kg of plasma would require a 2000 mL infusion, approximately equal to the entire daily fluid requirement for a patient with normal renal function. The risk of volume overload may limit the volume administered, reducing the effectiveness of the therapy.
    • Hyperproteinemia, as shown by elevated serum total protein, has been reported in a patient receiving chronic plasma infusion.
    • In theory, one can use exclusively cryoprecipitate-reduced plasma for plasma infusion because the patient's own coagulation factors are not removed.
• Management of end-stage renal disease (ESRD)
  • Patients who develop permanent renal failure due to D⁺ hemolytic-uremic syndrome have a low risk of recurrence and can proceed to renal transplantation similar to patients with most other renal diseases.
  • Renal transplantation in patients with D- hemolytic-uremic syndrome is more difficult because of the high risk of recurrence and allograft loss, with success rates of only 18-33% reported.^13,14  
  • The risk of recurrence varies with the complement mutation identified; such testing is essential is planning and counseling patients about transplant options:
    • Factor H mutation: 80-100% recurrence
    • Factor I mutation:  80% recurrence
    • Membrane cofactor protein mutation:  10-20% recurrence
    • No (known) mutation identified:  30% recurrence
  • Combined liver-kidney transplant has been reported in patients with high-risk mutations such as factor H.^15,16,17,18 Liver transplant alone is an option for patients without renal failure.¹⁵

Surgical Care

• Supportive medical care is the mainstay of treatment of hemolytic-uremic syndrome.
• Obtain surgical consultation if the patient has severe abdominal pain or other abdominal findings, which may be similar to an acute abdomen. 
• Surgery may also be required for placement of a dialysis catheter.

Consultations

• Nephrologist: Most patients with hemolytic-uremic syndrome require assistance, if not primary management, from a nephrologist.
• Hematologist/oncologist: Consult with a hematologist or oncologist if needed for assistance with transfusion management. Patients with D^- hemolytic-uremic syndrome have findings very similar to thrombotic thrombocytopenic purpura (TTP), which is traditionally considered a hematologic disorder, and a hematologist/oncologist may provide assistance with evaluation and management.
• Cardiologist: Consult with a cardiologist if the patient has cardiac failure or other abnormalities.
• Neurologist: Consult with a neurologist if the patient has seizures or other CNS findings.
• Endocrinologist: Consult with an endocrinologist if the patient develops diabetes due to pancreatitis.
• Surgeon: Consult with a surgeon for evaluation of abdominal pain or placement of dialysis access.
• Social worker: Consult with a social worker for patient and family support with school, financial, and coping/adjustment issues.
• Child life specialist: Consult with this specialist to help child understand medical care and find age-appropriate strategies to facilitate treatments.
• Psychologist/psychiatrist: Consult with this specialist if the patient has depression, anxiety, or adjustment issues related to disease.
• Dietician: Consult with a dietician to help manage nutrition, especially in patients with inadequate oral intake.
• Physical therapist: Patients with hemolytic-uremic syndrome may be bedridden for a prolonged time due to pain, CRRT, and a generally ill state. Physical therapy can help patients maintain strength, reduce muscle wasting, and prevent deep venous thromboses.

Diet

• In the acute stage of illness, limit fluid intake to replace insensible losses and urine output.
• A low-salt diet helps prevent fluid retention and elevated blood pressure.
• Patients should be encouraged to eat as tolerated if there is no contraindication to doing so. Supplemental formulas orally or by nasogastric tube may be used if oral intake is poor. Consult a dietician early in the course of illness.
• Many patients require intravenous hyperalimentation.

Activity

• Encourage activity as tolerated. 
• Even minor activity such as moving out of bed to a chair is beneficial. 
• Consider physical therapy to help patients maintain strength and activity.

Medication

Supportive care remains the mainstay of therapy for hemolytic-uremic syndrome (HUS). Medications such as antihypertensives, diuretics, anticonvulsants, and analgesics are indicated to treat specific symptoms or complications of hemolytic-uremic syndrome. No medications are clearly demonstrated to alter the disease process. 

Unfortunately, several agents that in theory should ameliorate hemolytic-uremic syndrome have failed to do so in clinical trials. These include thrombolytic agents (eg, heparin, urokinase), platelet inhibitors (eg, aspirin, dipyridamole), and a Shiga toxin (Stx)–binding agent (ie, Synsorb-Pk). Current evidence does not support use of these medications.

Corticosteroids are not useful in diarrhea-associated hemolytic-uremic syndrome (D⁺ HUS). They may be of value in non–diarrhea-associated hemolytic-uremic syndrome (D^- HUS) if the patient has an autoimmune-produced inhibitor of ADAMTS13. Clinical testing for inhibitors is available but has a long turnaround time. Corticosteroid therapy may be initiated presumptively in patients with unexplained D^- hemolytic-uremic syndrome. 

Limited case reports describe using intravenous immune globulin (IVIG) in patients with D^- hemolytic-uremic syndrome associated with organ transplantation. IVIG does not have a role in hereditary D^- hemolytic-uremic syndrome or in D⁺ hemolytic-uremic syndrome.

Plasma therapies are covered in Treatment. They are indicated only for treatment of D^- hemolytic-uremic syndrome, or possibly D⁺ hemolytic-uremic syndrome with associated CNS involvement.

Studies have shown that antibiotics given to patients with diarrhea due to E coli 0157:H7 increase the risk of developing hemolytic-uremic syndrome.¹⁹  A theory proposed to explain this finding is that antibiotic therapy causes rapid large-scale bacterial lysis with massive release of Stx, overwhelming host defense mechanisms. Whether antibiotics affect the course of established hemolytic-uremic syndrome remains unknown. Patients with E coli 0157 colitis usually clear the infection spontaneously. 

Most pediatric nephrologists do not routinely use antibiotics in patients with D⁺ hemolytic-uremic syndrome, based on a theoretical concern it could exacerbate the disease process.²⁰  However, antibiotics should be used when indicated according to clinical judgment. Examples include patients having suspected or documented bacteremia, urinary tract infection, or sepsis.

Follow-up

Further Outpatient Care

• Diarrhea-associated hemolytic-uremic syndrome (D⁺ HUS)
  • Patients recovering from D⁺ hemolytic-uremic syndrome should have regular follow-up until their symptoms have resolved and their hemoglobin, platelet counts and renal function have returned to normal.
  • Beyond that, no consensus is noted regarding frequency of follow-up or testing required. Preliminary data suggest many survivors may have persistent, subclinical renal injury, putting them at risk for future development of hypertension, proteinuria, and/or chronic renal disease.
    • All patients should have their blood pressure checked at each medical encounter.
    • The authors suggest annual follow-up with a nephrologist, with consideration of annual urinalysis, urine microalbumin, serum creatinine, and fasting glucose levels on an annual basis.
    • Counsel patients on the importance of a healthy lifestyle, with regular exercise, healthy diet, and avoidance of tobacco and obesity. These measures are beneficial for all patients but especially those at higher risk for future renal disease.
• Non–diarrhea-associated hemolytic-uremic syndrome (D^- HUS)
  • Patients with streptococcal-associated hemolytic-uremic syndrome have a low risk of recurrence and should have follow-up as outlined for D⁺ hemolytic-uremic syndrome above.
  • Patients with idiopathic or genetically mediated D^- hemolytic-uremic syndrome usually have a persistent and relapsing course, and most require frequent and lifelong nephrology follow-up.

Inpatient & Outpatient Medications

• Patients with persistent hypertension require antihypertensives.

Transfer

• Transfer may be required if the patient requires care or services not available at the patient's facility, such as pediatric specialist consultation, pediatric intensive care, dialysis or plasma exchange.

Deterrence/Prevention

• General preventive measures
  • Avoid ingestion of raw or undercooked meat.
  • Avoid unpasteurized milk and cheese.
  • Practice good hand-washing technique, especially during outbreaks of diarrhea.
  • Wash hands well after touching livestock, farm animals or "petting zoo" animals.  Supervise children to ensure good technique.
  • Avoid taking antidiarrheal or antimotility agents for diarrhea. Avoid taking antibiotics for diarrhea unless under the management of a physician.
  • Seek medical care immediately for bloody diarrhea.
• Preventive measures for medical practitioners
  • Avoid antibiotic treatment of patients with possible GI E coli 0157:H7 infection, unless other clinical factors require antibiotic therapy.¹⁹
  • Use ample parenteral volume expansion with isotonic ("normal") saline in patients with suspected E coli 0157:H7 infection (eg, those with bloody diarrhea). Early recognition is important. 
  • A study has shown that early and ample rehydration with isotonic saline is associated with a lower risk of developing oligoanuric renal failure.²  
    • Many patients who received this therapy still developed hemolytic-uremic syndrome, but they had a less severe course, with shorter lengths of stay and fewer patients requiring dialysis.
    • Ake and colleagues recommend that patients with suspected E coli 0157:H7 infection be admitted for inpatient therapy, using intravenous isotonic saline for both maintenance and replacement fluid requirements, avoiding use of hypotonic fluids. 
    • The authors of this article concur with this advice. 
    • Trials of oral rehydration, normally an appropriate practice, should be avoided in this situation due to the risk of prolonged renal hypoperfusion.   
  • Monitor fluid status, intake and output closely because renal function may change rapidly, requiring adjustments to fluid therapy. Use potassium supplementation with great caution.

Complications

• Renal system
  • Renal insufficiency
  • Renal failure
  • Hypertension
• CNS
  • Mental retardation
  • Seizures
  • Focal motor deficit
  • Optic atrophy
  • Cortical blindness
  • Learning disability
• Endocrine system
  • Diabetes mellitus
  • Pancreatic exocrine insufficiency
• GI system - Intestinal necrosis
• Cardiac system - Congestive heart failure

Prognosis

• D⁺ hemolytic-uremic syndrome 
  • Most patients with D⁺ hemolytic-uremic syndrome who receive the appropriate treatment have a good recovery. Recurrence is very rare.  Poor prognostic indicators include the following:
    • Elevated WBC count at diagnosis
    • Prolonged anuria
    • Severe prodromal illness
    • Severe hemorrhagic colitis with rectal prolapse or colonic gangrene
    • Severe multisystemic involvement
    • Persistent proteinuria
  • The long-term prognosis for survivors of childhood D⁺ hemolytic-uremic syndrome remains unknown. A five-year follow-up of a cohort of patients showed no difference in blood pressure and slightly higher rates of microalbuminuria compared with controls.²¹ The patients also had lower glomerular filtration rates (GFRs) as measured by cystatin C but not as measured by serum creatinine levels. Other studies have shown similar findings. Continued long-term follow-up studies are needed to help determine whether survivors have residual subclinical renal injury that could manifest itself later in life. At present, patients should be counseled on avoiding risk factors for renal disease (eg, tobacco use, obesity, hypertension) and the importance of continued medical follow-up.
• D^- hemolytic-uremic syndrome: The prognosis is more guarded than for D⁺ hemolytic-uremic syndrome. Patients with D^- hemolytic-uremic syndrome typically have frequent relapses and a higher risk of progression to end-stage renal disease (ESRD).

Patient Education

• Diet
  • Low-salt diet to decrease risk of hypertension
  • Diet high in iron and folic acid content to help recover from anemia
  • High-energy diet to help patient regain lost weight
• Social worker or psychologist consultation to help the family cope with the illness

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize the disease
• Failure to recognize and treat fluid overload
• Failure to monitor electrolytes and correct imbalances as needed
• Failure to recognize when to begin dialysis
• Failure to recognize and treat symptomatic anemia
• Failure to recognize and treat symptomatic thrombocytopenia
• Failure to select medications and adjust doses based on renal function

Special Concerns

• Laboratories offering specialized genetic, ADAMTS13, and/or complement testing are listed below. This is not intended to be an exclusive listing; other laboratories may also offer these services.
• For additional details, contact the laboratories; information on some laboratories is also summarized in the guidelines from Ariceta et al, which is cited in the references.⁸
  
  Service d’Immunologie Biologique
  Hospital Europeén George Pompidou
  20–40 rue Leblanc
  75908 Paris cedex 15
  France
  veronique.fremeaux-bacchi@egp.aphp.fr
  
  The Northern Genetics Service
  Institute of Human Genetics
  Newcastle upon Tyne Hospitals
  NHS Foundation Trust
  International Centre for Life
  Newcastle upon Tyne NE1 3BZ
  UK
  lisa.strain@nuth.nhs.uk
  
  Mario Negri Institute for Pharmacological Research
  Via Gavazzeni 11
  24125 Bergamo
  Italy
  gremuzzi@marionegri.it
  noris@marionegri.it
  
  Department of Biological Infection
  Leibniz Institute for Natural Product Research and Infection Biology
  Hans Knoell Institute for Natural Product Research
  Beutenbergstr. 11a
  07745 Jena
  Germany
  peter.zipfel@hki-jena.de
  
  Department of Pediatrics
  BMC C14
  Lund University,
  Klinikgatan 28, 22184 Lund, Sweden
  diana.karpman@med.lu.se
  
  Laboratory for Paediatrics and Neurology
  Radboud University Nijmegen Medical Center
  Postbus 9101
  6500 HB Nijmegen
  Geert Grooteplein 10 6525 GA Nijmegen
  The Netherlands
  B.vandenHeuvel@cukz.umcn.nl
  
  Immunology Unit and Research Unit
  Hospital Universitario La Paz
  Paseo de la Castellana 261
  28046 Madrid
  Spain
  srdecordoba@cib.csic.es
  psanchez.hulp@salud.madrid.org
  
  Laboratory of Complement Genetics
  Centro de Investigaciones Biológicas
  Ramiro de Maeztu 9
  28040 Madrid
  Spain.
  srdecordoba@cib.csic.es
  psanchez.hulp@salud.madrid.org
  
  U770 INSERM
  Hopital de Bicetre
  80 rue du General Leclerc
  94276 Le Kremlin-Bicetre cedex
  France
  agnes.veyradier@abc.aphp.fr
  
  Haemostasis Research Unit
  Haematology Department
  University College London
  1st floor
  51 Chenies Mews
  London WC1E 6HX
  UK
  i.Mackie@ucl.ac.uk
  g.purdy@ucl.ac.uk
  
  University Medical Center Hamburg-Eppendorf
  Department of Pediatric Hematology and Oncology
  Molecular Genetics Laboratory
  Martinistrasse 52
  20246 Hamburg
  Germany
  schneppenheim@uke.de
  f.oyen@uke.de
  
  Molecular Otolaryngology Research Laboratories
  University of Iowa
  Telephone: 319-335-7997
  Address: 5270 CBRB Otolaryngology—Head & Neck Surgery
  University of Iowa
  Iowa City, Iowa 52242
  E-mail: carla-nishimura@uiowa.edu
  E-mail:nic-meyer@uiowa.edu

Multimedia

Media file 1: Peripheral blood smear in hemolytic-uremic syndrome (HUS) showing many schistocytes and RBC fragments due to hemolysis, and relatively few platelets reflective of thrombocytopenia.

References

1. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. Jul 23 2009;361(4):345-57. [Medline].

2. Ake JA, Jelacic S, Ciol MA, Watkins SL, Murray KF, Christie DL. Relative nephroprotection during Escherichia coli O157:H7 infections: association with intravenous volume expansion. Pediatrics. Jun 2005;115(6):e673-80. [Medline].

3. Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol. Dec 2004;19(12):1394-9. [Medline].

4. Foland JA, Fortenberry JD, Warshaw BL, Pettignano R, Merritt RK, Heard ML. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med. Aug 2004;32(8):1771-6. [Medline].

5. Maxvold NJ, Smoyer WE, Custer JR, Bunchman TE. Amino acid loss and nitrogen balance in critically ill children with acute renal failure: a prospective comparison between classic hemofiltration and hemofiltration with dialysis. Crit Care Med. Apr 2000;28(4):1161-5. [Medline].

6. Murphy EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. Jun 2005;33(3):311-22. [Medline].

7. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. Nov 2004;28(5):497-504. [Medline].

8. [Guideline] Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. Apr 2009;24(4):687-96. [Medline].

9. [Best Evidence] Michael M, Elliott EJ, Craig JC, Ridley G, Hodson EM. Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis. Feb 2009;53(2):259-72. [Medline].

10. Nguyen L, Li X, Duvall D, Terrell DR, Vesely SK, George JN. Twice-daily plasma exchange for patients with refractory thrombotic thrombocytopenic purpura: the experience of the Oklahoma Registry, 1989 through 2006. Transfusion. Feb 2008;48(2):349-57. [Medline].

11. von Baeyer H. Plasmapheresis in thrombotic microangiopathy-associated syndromes: review of outcome data derived from clinical trials and open studies. Ther Apher. Aug 2002;6(4):320-8. [Medline].

12. Filler G, Radhakrishnan S, Strain L, Hill A, Knoll G, Goodship TH. Challenges in the management of infantile factor H associated hemolytic uremic syndrome. Pediatr Nephrol. Aug 2004;19(8):908-11. [Medline].

13. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. Aug 2007;18(8):2392-400. [Medline].

14. Zimmerhackl LB, Besbas N, Jungraithmayr T, et al. Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost. Mar 2006;32(2):113-20. [Medline].

15. Saland JM, Ruggenenti P, Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol. May 2009;20(5):940-9. [Medline].

16. Saland JM, Shneider BL, Bromberg JS, et al. Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. Jan 2009;4(1):201-6. [Medline].

17. Jalanko H, Peltonen S, Koskinen A, et al. Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H. Am J Transplant. Jan 2008;8(1):216-21. [Medline].

18. Saland JM, Emre SH, Shneider BL, et al. Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant. Aug 2006;6(8):1948-52. [Medline].

19. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. Jun 29 2000;342(26):1930-6. [Medline].

20. Iijima K, Kamioka I, Nozu K. Management of diarrhea-associated hemolytic uremic syndrome in children. Clin Exp Nephrol. Feb 2008;12(1):16-9. [Medline].

21. Garg AX, Salvadori M, Okell JM, et al. Albuminuria and estimated GFR 5 years after Escherichia coli O157 hemolytic uremic syndrome: an update. Am J Kidney Dis. Mar 2008;51(3):435-44. [Medline].

22. Blaser MJ. Bacteria and diseases of unknown cause: hemolytic-uremic syndrome. J Infect Dis. Feb 1 2004;189(3):552-5. [Medline].

23. Brunner K, Bianchetti MG, Neuhaus TJ. Recovery of renal function after long-term dialysis in hemolytic uremic syndrome. Pediatr Nephrol. Feb 2004;19(2):229-31. [Medline].

24. Kaplan BS, Cleary TG, Obrig TG. Recent advances in understanding the pathogenesis of the hemolytic uremic syndromes. Pediatr Nephrol. May 1990;4(3):276-83. [Medline].

25. Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. Jun 1998;9(6):1126-33. [Medline].

26. Milford DV, Taylor CM. New insights into the haemolytic uraemic syndromes. Arch Dis Child. Jul 1990;65(7):713-5. [Medline].

27. Nathan DG, Orkin SH, eds. Nathan and Oski's Hematology of Infancy and Childhood. Vol 1. 5^th ed. Harcourt Health Sciences; 1998:531-6.

28. Pickering LK, Obrig TG, Stapleton FB. Hemolytic-uremic syndrome and enterohemorrhagic Escherichia coli. Pediatr Infect Dis J. Jun 1994;13(6):459-75; quiz 476. [Medline].

29. Rangel JM, Sparling PH, Crowe C, et al. Epidemiology of Escherichia coli O157:H7 outbreaks, United States, 1982-2002. Emerg Infect Dis. Apr 2005;11(4):603-9. [Medline].

30. Robson WL, Leung AK, Kaplan BS. Hemolytic-uremic syndrome. Curr Probl Pediatr. Jan 1993;23(1):16-33. [Medline].

31. Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr. Apr 2005;17(2):200-4. [Medline].

32. Stewart CL, Tina LU. Hemolytic uremic syndrome. Pediatr Rev. Jun 1993;14(6):218-24. [Medline].

33. Trachtman H, Christen E. Pathogenesis, treatment, and therapeutic trials in hemolytic uremic syndrome. Curr Opin Pediatr. Apr 1999;11(2):162-8. [Medline].

34. Varade WS. Hemolytic uremic syndrome: reducing the risks. Contemp Pediatr. 2000;17:54-64.

Keywords

hemolytic-uremic syndrome, HUS, schistocytic hemolytic anemia with severe thrombocytopenia, hemolytic anemia, uremia, thrombocytopenia, acute renal failure, Shiga toxin, Shiga toxin 1, Shiga toxin 2, Stx, Stx1, Stx2, diarrhea-associated HUS, D⁺ HUS, non–diarrhea-associated HUS, D^- HUS, Streptococcus pneumoniae, end-stage renal disease, oliguria, edema, and macroscopic hematuria, hyponatremia, hyperkalemia, severe acidosis, ascites, edema, pulmonary edema, hypertension, intestinal perforation, necrosis, diabetes, congestive heart failure, treatment, diagnosis, Salmonella typhi, Campylobacter jejuni, Yersinia species , Pseudomonas species, Bacteroides species, Entamoeba histolytica, Aeromonas hydrophilia, influenza, Epstein-Barr virus, bone marrow transplantation, hematopoietic stem cell transplantation, systemic lupus erythematosus, glomerulonephritis

Contributor Information and Disclosures

Author

Robert S Gillespie, MD, MPH, Department of Pediatrics, Cook Children's Medical Center
Robert S Gillespie, MD, MPH is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology, and Texas Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Craig S Wong, MD, MPH, Assistant Professor, Division of Pediatric Nephrology, Department of Pediatrics, University of New Mexico School of Medicine; Director of Pediatric Kidney Transplantation, Division of Pediatric Nephrology, Department of Pediatrics, University of New Mexico Transplant Services, Children's Hospital of New Mexico
Craig S Wong, MD, MPH is a member of the following medical societies: American Society of Nephrology and American Society of Pediatric Nephrology
Disclosure: Nothing to disclose.

Ronald D Prauner, MD, Assistant Professor of Pediatrics, F Edward Herbert School of Medicine, Uniformed Services of the Health Sciences; Chief, Department of Pediatrics, Brooke Army Medical Center; Deputy Chairman, Department of Pediatrics, San Antonio Military Medical Center (SAMMC); Staff Pediatric Hematologist-Oncologist, Brooke Army Medical Center, Wilford Hall Medical Center, CR Darnall Army Medical Center
Ronald D Prauner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Blood Banks, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Association of Pediatric Program Directors, Children's Oncology Group, and Christian Medical & Dental Society
Disclosure: Nothing to disclose.

Medical Editor

Richard Neiberger, MD, PhD, Director of Pediatric Renal Stone Disease Clinic, Associate Professor, Department of Pediatrics, Division of Nephrology, University of Florida College of Medicine and Shands Hospital
Richard Neiberger, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Medical Association, American Society of Nephrology, American Society of Pediatric Nephrology, Christian Medical & Dental Society, Florida Medical Association, International Society for Peritoneal Dialysis, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Shock Society, Sigma Xi, Southern Medical Association, Southern Society for Pediatric Research, and Southwest Pediatric Nephrology Study Group
Disclosure: The Osler Institute Honoraria Speaking and teaching

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Luther Travis, MD, William W Glauser Professor of Pediatrics and Pediatric Nephrology, Department of Pediatrics, Divisions of Nephrology and Diabetes, University of Texas Medical Branch and Children's Hospital
Luther Travis, MD is a member of the following medical societies: Alpha Omega Alpha, American Federation for Medical Research, International Society of Nephrology, and Texas Pediatric Society
Disclosure: Nothing to disclose.

CME Editor

Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine
Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD, The Isaac A Abt, MD, Professor of Kidney Diseases, Feinberg School of Medicine, Northwestern University; Division Head of Kidney Diseases, Children's Memorial Hospital, Chicago
Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology
Disclosure: Amgen Grant/research funds None; Altus Pharmaceuticals Grant/research funds None; Genzyme Grant/research funds None; Merck Grant/research funds None; NIH Grant/research funds None

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Tamara Biega, MD, to the original writing and development of this article.

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