eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Hemolytic-Uremic Syndrome

Author: Robert S Gillespie, MD, MPH, Department of Pediatrics, Cook Children's Medical Center
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; 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
Contributor Information and Disclosures

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.

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

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