Laboratory Studies
Hemolytic uremic syndrome (HUS) is fundamentally a microangiopathic nonimmune hemolytic anemia associated with a variety of complications. Microangiopathic Coombs-negative hemolytic anemia and acute renal failure with microscopic hematuria and proteinuria (1–2 g/dL) abruptly mark the onset of HUS in nearly all patients.
Hematologic and associated serologic findings of HUS thrombotic microangiopathy (TMA) (and thrombotic thrombocytopenic purpura [TTP]) include the following:
Anemia is an invariable finding and usually severe, whether HUS occurs after postinfectious verocytotoxin-related colitis (eg, due to E coli or S dysenteriae) or in HUS without a diarrheal prodrome (eg, related to S pneumoniae pneumonia or sepsis).
Platelet counts tend to be somewhat higher in HUS TMA than in TTP because they are not consumed quickly by clot formation. However, in some cases of HUS, thrombocytopenia may be severe.
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The microcirculatory clots of TTP are formed in large part from platelets, whereas those that develop in HUS consist chiefly of red blood cells. The HUS clots are fibrin rich but contain relatively few platelets.
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Severe HUS GI bleeding is associated with consumptive thrombocytopenia.
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Platelet survival time is shortened in HUS.
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Platelet counts may be < 80 X 109/L (< 80,000/mm3).
Additional findings include the following:
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Microangiopathic changes occur in RBCs.
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The peripheral blood smear reveals fragmented RBCs (eg, schistocytes, spherocytes, segmented RBCs, burr cells, helmet cells).
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Reticulocytosis (proportional to hemolysis) and circulating free hemoglobin may be found, though not when bone marrow response to anemia is impaired.
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Increased serum thrombomodulin levels may be found and are a marker for endothelial injury in HUS.
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Leukocytosis may be found.
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In postdiarrheal cases, moderate leukocytosis typically develops and may be an indicator of renal failure.
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In cases arising after a respiratory prodrome or S pneumoniae sepsis, early and marked leukocytosis may be found with abundant immature forms.
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Because hemolytic anemia is nonimmune, results of Coombs testing is negative.
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HUS is more likely than TTP to manifest changes consistent with disseminated intravascular coagulopathy (elevated fibrin split products, prolongation of the activated partial thromboplastin time, and low antithrombin III levels). [65]
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Full-blown disseminated intravascular coagulation (DIC) is especially likely in S dysenteriae –related postinfectious HUS.
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Of interest, TTP occurring after verotoxigenic E coli O157:H7 infection in adults may provoke changes consistent with DIC.
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Fibrinogen levels may be normal or increased.
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Because of intravascular hemolysis, direct bilirubin values are elevated, where haptoglobin levels are usually low.
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The most sensitive indicator of ongoing intravascular hemolysis is an elevated serum lactate dehydrogenase (LDH) level, and tissue ischemia may further elevate the value.
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Evidence of inflammatory changes may be found in blood and urine.
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Diminished serum concentrations of C'3 is found in approximately half of all cases of verotoxigenic E coli –related HUS.
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In the acute situation, the extent to which low levels of C'3 reflect a heritable defect of complement C3 or factor H may not be clear.
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Elevated concentrations of alpha-1 and beta-2 microglobulins may be found in the urine.
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In HUS with a diarrheal prodrome, bacterial or viral stool cultures may yield verotoxigenic E coli, S dysenteriae, coxsackie virus, echovirus, Salmonella enteritis, or Yersinia species.
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In North America or Europe, at least 70% of all cases of postinfectious HUS with diarrheal prodrome are due to E coli enteritis. This can be confirmed with stool cultures, and the specific serotype may be identified. Most of these cases occur in children younger than 5 years.
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O157:H7 is the most common Stx-elaborating serotype of E coli. Absence of sorbitol fermentation of the subcultured E coli is a strong indication of this serotype, which may be confirmed with specific serotyping.
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The relatively uncommon O26, O103:H2, O111:H8, O121, O145, and other serotypes have been identified as Stx+ E coli.
Culture and other findings
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In Asia, North Africa, and many developing nations in tropical or temperate zones, cultures may demonstrate enteric infection with Stx-elaborating S dysenteriae. Serotype 1 is by far the most common cause of HUS.
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Stx+ S dysenteriae –related HUS more commonly occurs in children younger than 5 than in adults.
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Associated bacteremia is not uncommon.
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Throat cultures may yield S pneumoniae or adenovirus in individuals with a respiratory prodrome.
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Blood cultures may yield S pneumoniae in infants presenting with nondiarrheal sepsis.
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Infants or young children presenting with S dysenteriae postdiarrheal HUS are sometimes septic.
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Stx may be identified in stool in postinfectious HUS with diarrheal prodrome.
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Hematochezia is common in verotoxigenic HUS (related to E coli or especially S dysenteriae), particularly when consumptive coagulopathy is severe. This enteric bleeding is presumably due to the microangiopathy with associated thrombosis of enteric circulation.
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Because of the particular predilection for involvement of renal microvascular circulation, acute renal failure is routinely found in Stx+ or non-Stx HUS with resulting elevation of blood urea nitrogen (BUN) and creatinine levels.
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Microscopic hematuria and proteinuria of 1–2 g/dL develop abruptly as consequences of renal failure in 25% or more of patients with HUS.
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Alpha1- and beta2-microglobulins may be found in the urine of individuals with HUS-associated renal failure.
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The mean glomerular filtration rate for classic Stx-E coli HUS is less than 80 mL/min/1.73 m2 body surface area.
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Marked acidemic uremia may result from the combination of acute renal failure and catabolic state. Approximately one third of these patients become anuric.
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Hypertensive cardiac failure may add prerenal kidney failure to renal failure.
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HUS associated with illnesses other than verotoxigenic infections, sepsis, or other infectious processes may provide additional clues to the pathogenesis. However, many patients with such symptomatic have a premorbid history of such conditions.
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Malignancies associated with the development of sporadic HUS may produce various diagnostically significant changes in the appearance of the blood film and blood counts.
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HUS associated with the use of antineoplastic or immunosuppressive agents may provoke marked leukocytopenia.
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Particularly low platelet counts may be seen in HUS associated with the use of immunosuppressive or antineoplastic drugs.
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Strikingly low platelet counts may be seen in pregnant women with hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) syndrome
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Biochemical changes reflecting the hepatopathy that is another cardinal feature of HELLP may also be found.
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Among non-Stx (sporadic) cases of HUS, immune-mediated forms are associated with a decrease in the serum concentration of C'3 at the onset of disease. This decrease may be particularly striking when HUS occurs in association with an identifiable systemic inflammatory disease, such as SLE or scleroderma.
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Various laboratory abnormalities are seen in cases of HUS that involve the liver. These represent dysfunction associated with hepatic microvascular disease.
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Hypercalcemia is common in HUS.
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Familial non-Stx HUS accounts for less than 3% of all cases of HUS and tends to produce particularly severe microangiopathy and renal failure.
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Remarkably low levels of C'3 may be found. This deficiency may persist during remissions of HUS.
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Any of more than 50 mutations of the HF1 (factor H) gene (on chromosomal region 1q32) may be found in up to 40% of all cases of familial non-Stx HUS and in as many as 13–17% of all cases of sporadic non-Stx+ HUS. In the latter case, it probably occurs as an acquired autoimmune HF1 defect due to anti–factor H antibodies.
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Factor H is an important regulator of the alternative pathway of complement. It is a cofactor for the cleavage of C3b by C3b convertase. Of interest, defects in HF1 are observed in some cases of thrombotic TTP.
Other causes of non-Stx+ (sporadic) HUS that can be diagnosed with various laboratory tests. These causes include S pneumoniae (40% of all cases of non-Stx+ HUS), Neisseria meningitidis, and other bacteria. Systemic viral infections may be diagnosed by using blood, oropharyngeal, or rectal cultures and/or viral titers.
Particular tests may reveal non-Stx (sporadic) HUS due to systemic autoimmunity. Important examples are SLE, antiphospholipid antibody syndrome, and scleroderma.
Other conditions that may provoke the development of non-Stx (sporadic) HUS are usually identified based on the clinical history. These conditions may have their own associated clinical or laboratory changes or abnormalities in addition to those characteristic of HUS. These conditions include the following:
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Pregnancy, particularly in individuals with preeclampsia or the syndrome of hemolysis, elevated liver-enzyme levels, and low platelet count (HELLP syndrome)
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Diethylene glycol intoxication
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Use of anticancer drugs (eg, cisplatin, mitomycin, bleomycin, gemcitabine)
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Use of immunomodulatory drugs (eg, cyclosporine, quinidine, interferon, tacrolimus, OKT3)
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Use of antiplatelet drugs (eg, ticlopidine, clopidogrel)
Imaging Studies
Overview
The organs and system most likely to show imaging changes in association with HUS are the kidneys and the GI tract.
Patients with neurologic abnormalities may or may not have imaging abnormalities initially, though initial or follow-up studies may show a variety of changes.
Abnormalities in organs other than the kidneys and those of the GI tract may be observed initially, during acute illness, or with delayed onset during the recuperative period.
Enteric abnormalities
Marked thickening of the intestinal wall may be observed during the enteritic, or especially the enterohemorrhagic, phase of illness, which usually precedes acute renal failure.
Such changes are usually observed when serious enteropathy is initially suspected and when the diagnosis of HUS or related entities is considered. At this time, typically 4-6 days after the onset of diarrhea, initial enteric imaging is usually undertaken.
Abdominal imaging with barium enema may show thumb-printing of the large bowel due to the combination of edema of the bowel wall and submucosal hemorrhage. These changes are usually most striking in the ascending or transverse colon.
HUS rarely occurs after Clostridium perfringens sepsis with multiple organ failure, in which case imaging abnormalities are particularly severe and fulminant. In such cases, imaging findings may suggest regional enteritis of the Crohn type.
Renal findings
At the onset of acute renal failure, which occurs in 55-70% of cases of HUS, a variety of imaging techniques may be used to evaluate the etiology and nature of renal impairment. Most abnormalities observed are not specific for HUS; hence, considering the changes observed in the context of the case history and available laboratory results is important.
Increased brightness of the kidney may be detected on renal ultrasonography.
In patients with HUS, ultrasonography combined with Doppler imaging may demonstrate the association of 2 findings: diminished parenchymal perfusion and an increased resistance index (RI). This combination is found not only in HUS but also in TTP, panarteritis nodosa, and other vasculitic nephropathies. [68]
Cortical necrosis of the kidney is observed in many instances of severe HUS, as seen in association with S dysenteriae or S pneumoniae infections.
Neurologic findings
In patients with neurologic manifestations associated with HUS, various abnormalities may be observed on brain images.
In North America and in Europe, most patients with clinical and radiographic abnormalities involving the nervous system will have had verocytogenic E coli HUS. Approximately one third of these patients have serious neurologic symptoms or signs.
MRI of the brain may reveal focal areas of infarction with swelling and, in some cases, hemorrhage, especially in areas such as the internal capsule and deep gray nuclei. Whether changes observed on images are due to cerebral microangiopathy or hypertension and metabolic disarray is not always clear.
Limited evidence shows that approximately 60% of patients with chiefly verotoxigenic E coli and clinically significant neurologic findings have abnormalities on brain CT or MRI during the acute phase. However, in 40% of patients, CT and MRI images are entirely normal.
The most common sites of abnormality on CT or MRI during the acute phase of HUS are the thalami, brainstem, or cerebellum. In one series, 1 or more of these locations were involved in 60% of cases of HUS with MRI abnormalities. In approximately 20%, abnormalities were in 1 or both thalami; in 20%, in the cerebellum; and in 10%, in the brainstem. In some instances, lesions contained hemorrhage. [69]
In 1 small series, all abnormalities resolved in nearly one half of all children with good clinical outcomes after verotoxigenic E coli HUS; slightly more than one half had partial resolution at the time of imaging follow-up. [69]
Favorable clinical and imaging improvement may be seen, even in patients with severe initial clinical and imaging abnormalities. On follow-up imaging, a hemorrhagic component in an area of acute abnormality may be the best predictor of a residual imaging abnormality.
The prevalence of neurologic involvement with associated imaging abnormalities is clearly lower in HUS after verotoxigenic E coli enteritis than after the comparatively rare HUS related to S pneumoniae infection.
Although little pertinent information is available, imaging techniques are least likely to show improvement in HUS after verotoxigenic S dysenteriae enteritis among all types of postinfectious HUS.
Verotoxigenic S dysenteriae HUS is by far the most prevalent type of HUS in developing nations, where CT and MRI may not be readily available.
In S pneumoniae–related HUS, the risk for CNS involvement is high. MRI is more sensitive than CT for detecting brain abnormalities. The findings are usually associated with acute bacterial meningitis, which is the cause of death in most patients with S pneumoniae–related HUS. Examples of such findings include the following:
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MRIs obtained with a long repetition time (TR) and a short echo time (TE) (intermediate) show abnormal hyperintensity in the brain cisterns and near the base of the brain.
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On fluid-attenuated inversion recovery (FLAIR) imaging, increased signal intensity throughout the subarachnoid spaces is due to increased cellular and protein content in CSF.
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On FLAIR imaging, contrast enhancement in the meninges is due to leak of contrast agent from inflamed blood vessels.
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Abnormalities of the cerebral parenchyma subadjacent to the meninges may be due to inflammation or infarction.
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Subdural effusions may be observed.
Pulmonary findings
Several types of lung abnormalities have been described in individuals with HUS.
Acute pneumonia is commonly found in patients with non-Stx (sporadic) HUS related to S pneumoniae.
One 20-month-old Italian infant developed pulmonary hemorrhage after the acute phase of postdiarrheal HUS, although he had greater degrees of thrombocytopenia and coagulative abnormality during the acute phase that had resolved.
Procedures
In kidney biopsy specimens obtained from patients with acute Stx+ HUS, the predominant finding is in the glomerular tuft. These changes apparently develop early in the course of illness. Changes include microvascular endothelial swelling with an accumulation of proteinaceous material and cellular debris in the subendothelial layer (between the inner endothelial cell membrane and the subadjacent basement membrane).
Microthromboses may be found in the involved microcirculation of the kidney near the glomerular tuft. These microthromboses include fibrin thrombi that may occlude the glomerular tuft. In some instances thrombi extend likely because of retrograde propagation of clot into the arterioles.
Renal cortical ischemic disease may be found in severe cases of Shigella dysenteriae or HUS related to S pneumoniae.
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Peripheral smear in hemolytic uremic syndrome, with findings of microangiopathic hemolytic anemia. Note schistocytes/helmet cells, as well as decrease in platelets. Image courtesy of Emma Z Du, MD.
