Hemolytic Uremic Syndrome Workup
- Author: Robert Stanley Rust, Jr, MD, MA; Chief Editor: Amy Kao, MD more...
See the list below:
- 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: 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).
- Thrombocytopenia: 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.
- 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.
- Severe HUS GI bleeding is associated with consumptive thrombocytopenia.
- Platelet survival time is shortened in HUS.
- Platelet counts may be < 80 X 109/L (< 80,000/mm3).
- Additional findings include the following:
- Microangiopathic changes occur in RBCs.
- The peripheral blood smear reveals fragmented RBCs (eg, schistocytes, spherocytes, segmented RBCs, burr cells, helmet cells).
- Reticulocytosis (proportional to hemolysis) and circulating free hemoglobin may be found, though not when bone marrow response to anemia is impaired.
- Increased serum thrombomodulin levels may be found and are a marker for endothelial injury in HUS.
- Leukocytosis may be found.
- In postdiarrheal cases, moderate leukocytosis typically develops and may be an indicator of renal failure.
- In cases arising after a respiratory prodrome or S pneumoniae sepsis, early and marked leukocytosis may be found with abundant immature forms.
- Because hemolytic anemia is nonimmune, results of Coombs testing is negative.
- 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).
- Full-blown disseminated intravascular coagulation (DIC) is especially likely in S dysenteriae –related postinfectious HUS.
- Of interest, TTP occurring after verotoxigenic E coli O157:H7 infection in adults may provoke changes consistent with DIC.
- Fibrinogen levels may be normal or increased.
- Because of intravascular hemolysis, direct bilirubin values are elevated, where haptoglobin levels are usually low.
- The most sensitive indicator of ongoing intravascular hemolysis is an elevated serum lactate dehydrogenase (LDH) level, and tissue ischemia may further elevate the value.
- Evidence of inflammatory changes may be found in blood and urine.
- Diminished serum concentrations of C'3 is found in approximately half of all cases of verotoxigenic E coli –related HUS.
- 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.
- Elevated concentrations of alpha-1 and beta-2 microglobulins may be found in the urine.
- 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.
- 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.
- 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.
- The relatively uncommon O26, O103:H2, O111:H8, O121, O145, and other serotypes have been identified as Stx+ E coli.
- Culture and other findings
- 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.
- Stx+ S dysenteriae –related HUS more commonly occurs in children younger than 5 than in adults.
- Associated bacteremia is not uncommon.
- Throat cultures may yield S pneumoniae or adenovirus in individuals with a respiratory prodrome.
- Blood cultures may yield S pneumoniae in infants presenting with nondiarrheal sepsis.
- Infants or young children presenting with S dysenteriae postdiarrheal HUS are sometimes septic.
- Stx may be identified in stool in postinfectious HUS with diarrheal prodrome.
- 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.
- 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.
- Microscopic hematuria and proteinuria of 1-2 g/dL develop abruptly as consequences of renal failure in 25% or more of patients with HUS.
- Alpha1- and beta2-microglobulins may be found in the urine of individuals with HUS-associated renal failure.
- The mean glomerular filtration rate for classic Stx-E coli HUS is less than 80 mL/min/1.73 m2 body surface area.
- Marked acidemic uremia may result from the combination of acute renal failure and catabolic state. Approximately one third of these patients become anuric.
- Hypertensive cardiac failure may add prerenal kidney failure to renal failure.
- 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.
- Malignancies associated with the development of sporadic HUS may produce various diagnostically significant changes in the appearance of the blood film and blood counts.
- HUS associated with the use of antineoplastic or immunosuppressive agents may provoke marked leukocytopenia.
- Particularly low platelet counts may be seen in HUS associated with the use of immunosuppressive or antineoplastic drugs.
- Strikingly low platelet counts may be seen in pregnant women with hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) syndrome
- Biochemical changes reflecting the hepatopathy that is another cardinal feature of HELLP may also be found.
- 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.
- Various laboratory abnormalities are seen in cases of HUS that involve the liver. These represent dysfunction associated with hepatic microvascular disease.
- Hypercalcemia is common in HUS.
- Familial non-Stx HUS accounts for less than 3% of all cases of HUS and tends to produce particularly severe microangiopathy and renal failure.
- Remarkably low levels of C'3 may be found. This deficiency may persist during remissions of HUS.
- 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.
- 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:
- Pregnancy, particularly in individuals with preeclampsia or the syndrome of hemolysis, elevated liver-enzyme levels, and low platelet count (HELLP syndrome)
- Diethylene glycol intoxication
- Use of anticancer drugs (eg, cisplatin, mitomycin, bleomycin, gemcitabine)
- Use of immunomodulatory drugs (eg, cyclosporine, quinidine, interferon, tacrolimus, OKT3)
- Use of antiplatelet drugs (eg, ticlopidine, clopidogrel)
See the list below:
- 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.
- 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.
- 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.
- 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 are listed below.
- 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.
- On fluid-attenuated inversion recovery (FLAIR) imaging, increased signal intensity throughout the subarachnoid spaces is due to increased cellular and protein content in CSF.
- On FLAIR imaging, contrast enhancement in the meninges is due to leak of contrast agent from inflamed blood vessels.
- Abnormalities of the cerebral parenchyma subadjacent to the meninges may be due to inflammation or infarction.
- 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.
See the list below:
- 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.
Biopsy findings are noted above.
Gasser C, Gautier E, Steck A. Haemolotisch-uraemisch syndrome: bilaterale nierindennekrosen bei akuten erworbenen haemolytichen anaemien. Schwiz Med Wochenschr. 1955. 85:174-92.
Lieberman E. Hemolytic-uremic syndrome. J Pediatr. 1972 Jan. 80(1):1-16. [Medline].
Gianantonio CA, Vitacco M, Mendilaharzu F, et al. The hemolytic-uremic syndrome. Nephron. 1973. 11(2):174-92. [Medline].
Vitacco M, Sanchez Avalos J, Gianantonio CA. Heparin therapy in the hemolytic-uremic syndrome. J Pediatr. 1973 Aug. 83(2):271-5. [Medline].
de Chadarevian JP, Kaplan BS. The hemolytic uremic syndrome of childhood. Perspect Pediatr Pathol. 1978. 4:465-502. [Medline].
Silverstein A. Thrombotic thrombocytopenic purpura. The initial neurologic manifestations. Arch Neurol. 1968 Apr. 18(4):358-62. [Medline].
Remuzzi G. HUS and TTP: variable expression of a single entity. Kidney Int. 1987 Aug. 32(2):292-308. [Medline].
Ruggenenti P, Remuzzi G. Thrombotic microangiopathies. Crit Rev Oncol Hematol. 1991 Dec. 11(4):243-65. [Medline].
Wardle EN. Protection against recurrence of acute renal failure. Nephron. 1988. 50(1):81. [Medline].
Drummond KN. Hemolytic uremic syndrome--then and now. N Engl J Med. 1985 Jan 10. 312(2):116-8. [Medline].
Karlsberg RP, Lacher JW, Bartecchi CE. Adult hemolytic-uremic syndrome. Familial variant. Arch Intern Med. 1977 Sep. 137(9):1155-7. [Medline].
Blackall DP, Marques MB. Hemolytic uremic syndrome revisited: Shiga toxin, factor H, and fibrin generation. Am J Clin Pathol. 2004 Jun. 121 Suppl:S81-8. [Medline].
Martin DL, MacDonald KL, White KE, et al. The epidemiology and clinical aspects of the hemolytic uremic syndrome in Minnesota. N Engl J Med. 1990 Oct 25. 323(17):1161-7. [Medline].
Gianviti A, Tozzi AE, De Petris L, et al. Risk factors for poor renal prognosis in children with hemolytic uremic syndrome. Pediatr Nephrol. 2003 Dec. 18(12):1229-35. [Medline].
Miliwebsky ES, Balbi L, Gomez D, Wainsztein R, Cueto Rua M, Roldan C, et al. Síndrome uremico hemolitico en ninos de Argentina: asociacion con la infección por Escherichia coli productor de toxina Shiga. Bioq Patol Clin. 1999. 63:113-21.
Rivas M, Sosa-Estani S, Rangel J, Caletti MG, Valles P, Roldan CD, et al. Risk factors for sporadic Shiga toxin-producing Escherichia coli infections in children, Argentina. Emerg Infect Dis. 2008 May. 14(5):763-71. [Medline].
Riley LW, Remis RS, Helgerson SD, et al. Hemorrhagic colitis associated with a rare Escherichia coli serotype. N Engl J Med. 1983 Mar 24. 308(12):681-5. [Medline].
Manning SD, Motiwala AS, Springman AC, Qi W, Lacher DW, Ouellette LM, et al. Variation in virulence among clades of Escherichia coli O157:H7 associated with disease outbreaks. Proc Natl Acad Sci U S A. 2008 Mar 25. 105(12):4868-73. [Medline].
Lindqvist R, Antonsson AK, Norling B, et al. The prevalence of verocytotoxin-producing Escherichia coli (VTEC) and E. coli O157:H7 in beef in Sweden determined by PCR assays and an immuno-magnetic separation (IMS) method. Food Microbiology. 1998 Dec. 15(6):591-601.
Cimolai N, Carter JE. Gender and the progression of Escherichia coli O157:H7 enteritis to haemolytic uraemic syndrome. Arch Dis Child. 1991 Jan. 66(1):171-2. [Medline].
Joh K. Predictive indicators for progression to severe complications(hemolytic-uremic syndrome and encephalopathy) and their prevention in enterohemorrhagic Escherichia coli infection [in Japanese]. Nippon Rinsho. 1997 Mar. 55(3):700-5. [Medline].
te Loo DM, Monnens LA, van Der Velden TJ, Vermeer MA, Preyers F, Demacker PN, et al. Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome. Blood. 2000 Jun 1. 95(11):3396-402. [Medline].
Te Loo DM, van Hinsbergh VW, van den Heuvel LP, Monnens LA. Detection of verocytotoxin bound to circulating polymorphonuclear leukocytes of patients with hemolytic uremic syndrome. J Am Soc Nephrol. 2001 Apr. 12(4):800-6. [Medline].
Malbrain ML, Lambrecht GL, Brans B. Acute renal failure in non-fulminant hepatitis A. Clin Nephrol. 1994 Mar. 41(3):180-1. [Medline].
Remuzzi G, Bertani T. Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and acute cortical necrosis. Diseases of the Kidney. 1988. 2301.
Tzipori S, Sheoran A, Akiyoshi D, Donohue-Rolfe A, Trachtman H. Antibody therapy in the management of shiga toxin-induced hemolytic uremic syndrome. Clin Microbiol Rev. 2004 Oct. 17(4):926-41, table of contents. [Medline].
Nagayama K. [A novel marker of development of HUS associated with enterohemorrhagic Escherichia coli infection--thrombomodulin levels in the blood]. Nippon Rinsho. 1997 Mar. 55(3):747-50. [Medline].
Chandler WL, Jelacic S, Boster DR, et al. Prothrombotic coagulation abnormalities preceding the hemolytic-uremic syndrome. N Engl J Med. 2002 Jan 3. 346(1):23-32. [Medline].
Tsai HM. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. J Mol Med. 2002 Oct. 80(10):639-47. [Medline].
Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Arch Pathol Lab Med. 2003 Jul. 127(7):834-9. [Medline].
Chow TW, Turner NA, Chintagumpala M, et al. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol. 1998 Apr. 57(4):293-302. [Medline].
Tsai HM, Rice L, Sarode R, et al. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med. 2000 May 16. 132(10):794-9. [Medline].
Tsai HM. Deficiency of ADAMTS-13 in thrombotic and thrombocytopenic purpura. J Thromb Haemost. 2003 Sep. 1(9):2038-40; discussion 2040-5. [Medline].
Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998 Nov 26. 339(22):1585-94. [Medline].
Siegler RL, Pysher TJ, Lou R, Tesh VL, Taylor FB Jr. Response to Shiga toxin-1, with and without lipopolysaccharide, in a primate model of hemolytic uremic syndrome. Am J Nephrol. 2001 Sep-Oct. 21(5):420-5. [Medline].
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. 2000 Jun 29. 342(26):1930-6. [Medline].
Barnham M, Weightman N. Clostridium septicum infection and hemolytic uremic syndrome. Emerg Infect Dis. 1998 Apr-Jun. 4(2):321-4. [Medline].
Richardson SE, Jagadha V, Smith CR, Becker LE, Petric M, Karmali MA. Annual Meeting of the American Society for Microbiology, Atlanta, 1-6 March 1987 (abstract). Pathological effects on injected H.30 verotoxin (VT) in rabbits.
Tzipori S, Chow CW, Powell HR. Cerebral infection with Escherichia coli O157:H7 in humans and gnotobiotic piglets. J Clin Pathol. 1988 Oct. 41(10):1099-103. [Medline].
Palomeque Rico A, Pastor Durán X, Molinero Egea C, Roca González A. [Hemolytic uremic syndrome. Evaluation of clinical and prognostic factors]. An Esp Pediatr. 1993 Nov. 39(5):391-4. [Medline].
Upadhyaya K, Barwick K, Fishaut M, Kashgarian M, Siegel NJ. The importance of nonrenal involvement in hemolytic-uremic syndrome. Pediatrics. 1980 Jan. 65(1):115-20. [Medline].
Kovacs MJ, Roddy J, Gregoire S, et al. Thrombotic thrombocytopenic purpura following hemorrhagic colitis due to Escherichia coli O157:H7. Am J Med. 1990 Feb. 88(2):177-9. [Medline].
Warwicker P, Goodship JA, Goodship TH. Factor H--US?. Nephrol Dial Transplant. 1998 Aug. 13(8):1921-3. [Medline].
Noris M, Ruggenenti P, Perna A, et al. Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. Italian Registry of Familial and Recurrent Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Pur. J Am Soc Nephrol. 1999 Feb. 10(2):281-93. [Medline].
Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, et al. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet. 2003 Nov 8. 362(9395):1542-7. [Medline].
Cooper M, McGraw ME, Unsworth DJ, Mathieson P. Familial mesangio-capillary glomerulonephritis with initial presentation as haemolytic uraemic syndrome. Nephrol Dial Transplant. 2004 Jan. 19(1):230-3. [Medline].
Pérez-Caballero D, González-Rubio C, Gallardo ME, Vera M, López-Trascasa M, Rodríguez de Córdoba S, et al. Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet. 2001 Feb. 68(2):478-84. [Medline].
Richards A, Goodship JA, Goodship TH. The genetics and pathogenesis of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Curr Opin Nephrol Hypertens. 2002 Jul. 11(4):431-5. [Medline].
Galbusera M, Noris M, Rossi C, et al. Increased fragmentation of von Willebrand factor, due to abnormal cleavage of the subunit, parallels disease activity in recurrent hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and discloses predisposition in families. The Italian R. Blood. 1999 Jul 15. 94(2):610-20. [Medline].
Rodríguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P. The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol. 2004 Jun. 41(4):355-67. [Medline].
Fortin MC, Schürch W, Cardinal H, Hébert MJ. Complement factor H deficiency in acute allograft glomerulopathy and post-transplant hemolytic uremic syndrome. Am J Transplant. 2004 Feb. 4(2):270-3. [Medline].
Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet. 2004 Jun. 41(6):e84. [Medline].
Elliott MK, Jarmi T, Ruiz P, Xu Y, Holers VM, Gilkeson GS. Effects of complement factor D deficiency on the renal disease of MRL/lpr mice. Kidney Int. 2004 Jan. 65(1):129-38. [Medline].
Rougier N, Kazatchkine MD, Rougier JP, et al. Human complement factor H deficiency associated with hemolytic uremic syndrome. J Am Soc Nephrol. 1998 Dec. 9(12):2318-26. [Medline].
Goldstein MH, Churg J, Strauss L, Gribetz D. Hemolytic-uremic syndrome. Nephron. 1979. 23(6):263-72. [Medline].
Lin CC, King KL, Chao YW, Yang AH, Chang CF, Yang WC. Tacrolimus-associated hemolytic uremic syndrome: a case analysis. J Nephrol. 2003 Jul-Aug. 16(4):580-5. [Medline].
Kinney JS, Gross TP, Porter CC, Rogers MF, Schonberger LB, Hurwitz ES. Hemolytic-uremic syndrome: a population-based study in Washington, DC and Baltimore, Maryland. Am J Public Health. 1988 Jan. 78(1):64-5. [Medline].
Cummings KC, Mohle-Boetani JC, Werner SB, Vugia DJ. Population-based trends in pediatric hemolytic uremic syndrome in California, 1994-1999: substantial underreporting and public health implications. Am J Epidemiol. 2002 May 15. 155(10):941-8. [Medline].
Tarr PI, Neill MA, Allen J, et al. The increasing incidence of the hemolytic-uremic syndrome in King County, Washington: lack of evidence for ascertainment bias. Am J Epidemiol. 1989 Mar. 129(3):582-6. [Medline].
Olotu AI, Mithwani S, Newton CR. Haemolytic uraemic syndrome in children admitted to a rural district hospital in Kenya. Trop Doct. 2008 Jul. 38(3):165-7. [Medline].
Ardissino G, Tel F, Testa S, Marzano AV, Lazzari R, Salardi S, et al. Skin Involvement in Atypical Hemolytic Uremic Syndrome. Am J Kidney Dis. 2013 Nov 26. [Medline].
Fong JS, de Chadarevian JP, Kaplan BS. Hemolytic-uremic syndrome. Current concepts and management. Pediatr Clin North Am. 1982 Aug. 29(4):835-56. [Medline].
Wang R, Zhang Y, Li S, Chen H, Zeng C, Chen H, et al. Hemolytic uremic syndrome complicated with IgA nephropathy: a case report and literature review. Clin Nephrol. 2013 Dec 2. [Medline].
Steinborn M, Leiz S, Rüdisser K, Griebel M, Harder T, Hahn H. CT and MRI in haemolytic uraemic syndrome with central nervous system involvement: distribution of lesions and prognostic value of imaging findings. Pediatr Radiol. 2004 Oct. 34(10):805-10. [Medline].
Remuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int. 1995 Jul. 48(1):2-19. [Medline].
Ruggenenti P, Remuzzi G. Treatment of adult hemolytic-uremic syndrome. Adv Nephrol Necker Hosp. 2000. 30:83-94. [Medline].
Arenson EB, August CS. Preliminary report: treatment of the hemolytic-uremic syndrome with aspirin and dipyridamole. J Pediatr. 1975 Jun. 86(6):957-61. [Medline].
Misiani R, Appiani AC, Edefonti A, et al. Haemolytic uraemic syndrome: therapeutic effect of plasma infusion. Br Med J (Clin Res Ed). 1982 Nov 6. 285(6351):1304-6. [Medline].
Soliris (eculizumab) [package insert]. Cheshire, CT: Alexion Pharmaceuticals. Sept 2011. Available at [Full Text].
Verweyen HM, Karch H, Allerberger F, Zimmerhackl LB. Enterohemorrhagic Escherichia coli (EHEC) in pediatric hemolytic-uremic syndrome: a prospective study in Germany and Austria. Infection. 1999 Nov-Dec. 27(6):341-7. [Medline].
Loirat C, Babu S, Furman R, Sheerin N, Cohen D, Gaber O, et al. Eculizumab Efficacy and Safety in Patients With Atypical Hemolytic Uremic Syndrome (aHUS) Resistant to Plasma Exchange/Infusion [poster]. Presented at the 16th Congress of European Hematology Association (EHA). 2011. London, UK.
Loirat C, Muus P, Legendre C, Douglas K, Hourmant M, Delmas Y, et al. A Phase II Study of Eculizumab in Patients With Atypical Hemolytic Uremic Syndrome Receiving Chronic Plasma Exchange/Infusion [poster]. Presented at the 16th Congress of European Hematology Association (EHA). 2011. London, UK.
Hu H, Nagra A, Haq MR, Gilbert RD. Eculizumab in atypical haemolytic uraemic syndrome with severe cardiac and neurological involvement. Pediatr Nephrol. 2013 Dec 8. [Medline].
Vitacco M, Sanchez Avalos J, Gianantonio CA. Heparin therapy in the hemolytic-uremic syndrome. J Pediatr. 1973 Aug. 83(2):271-5. [Medline].
Van Damme-Lombaerts R, Proesmans W, Van Damme B, Eeckels R, Binda ki Muaka P, Mercieca V. Heparin plus dipyridamole in childhood hemolytic-uremic syndrome: a prospective, randomized study. J Pediatr. 1988 Nov. 113(5):913-8. [Medline].
Armstrong GD, Rowe PC, Goodyer P, Orrbine E, Klassen TP, Wells G. A phase I study of chemically synthesized verotoxin (Shiga-like toxin) Pk-trisaccharide receptors attached to chromosorb for preventing hemolytic-uremic syndrome. J Infect Dis. 1995 Apr. 171(4):1042-5. [Medline].
Van Dyck M, Proesmans W. Renoprotection by ACE inhibitors after severe hemolytic uremic syndrome. Pediatr Nephrol. 2004 Jun. 19(6):688-90. [Medline].
Greinacher A, Friesecke S, Abel P, Dressel A, Stracke S, Fiene M, et al. Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial. Lancet. 2011 Sep 24. 378(9797):1166-73. [Medline].
Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA. 2003 Sep 10. 290(10):1360-70. [Medline].
Siegler RL. Postdiarrheal Shiga toxin-mediated hemolytic uremic syndrome. JAMA. 2003 Sep 10. 290(10):1379-81. [Medline].
Baker KR, Moake JL. Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. Curr Opin Pediatr. 2000 Feb. 12(1):23-8. [Medline].
Banatvala N, Griffin PM, Greene KD, et al. The United States National Prospective Hemolytic Uremic Syndrome Study: microbiologic, serologic, clinical, and epidemiologic findings. J Infect Dis. 2001 Apr 1. 183(7):1063-70. [Medline].
Bassani CE, Ferraris J, Gianantonio CA, et al. Renal transplantation in patients with classical haemolytic-uraemic syndrome. Pediatr Nephrol. 1991 Sep. 5(5):607-11. [Medline].
Beattie TJ, Murphy AV, Willoughby ML, Belch JJ. Prostacyclin infusion in haemolytic-uraemic syndrome of children. Br Med J (Clin Res Ed). 1981 Aug 15. 283(6289):470. [Medline].
Beattie TJ, Murphy AV, Willoughby ML, et al. Plasmapheresis in the haemolytic-uraemic syndrome in children. Br Med J (Clin Res Ed). 1981 May 23. 282(6277):1667-8. [Medline].
Blaker F, Altrogge H, Hellwege HH, et al. Treatment of severe haemolytic-uraemic syndrome by dialysis [in German]. Dtsch Med Wochenschr. 1978 Aug 4. 103(31):1229-32. [Medline].
Bohle A, Helmchen U, Grund KE, et al. Malignant nephrosclerosis in patients with hemolytic uremic syndrome (primary malignant nephrosclerosis). Curr Top Pathol. 1977. 65:81-113. [Medline].
Bukowski RM, Hewlett JS, Harris JW, et al. Exchange transfusions in the treatment of thrombotic thrombocytopenic purpura. Semin Hematol. 1976 Jul. 13(3):219-32. [Medline].
Byrnes JJ, Moake JL. Thrombotic thrombocytopenic purpura and the haemolytic-uraemic syndrome: evolving concepts of pathogenesis and therapy. Clin Haematol. 1986 May. 15(2):413-42. [Medline].
Caprioli A, Luzzi I, Rosmini F, et al. Hemolytic-uremic syndrome and Vero cytotoxin-producing Escherichia coli infection in Italy. The HUS Italian Study Group. J Infect Dis. 1992 Jul. 166(1):154-8. [Medline].
Caprioli A, Tozzi AE, Rizzoni G, Karch H. Non-O157 Shiga toxin-producing Escherichia coli infections in Europe. Emerg Infect Dis. 1997 Oct-Dec. 3(4):578-9. [Medline].
Cimolai N, Basalyga S, Mah DG, et al. A continuing assessment of risk factors for the development of Escherichia coli O157:H7-associated hemolytic uremic syndrome. Clin Nephrol. 1994 Aug. 42(2):85-9. [Medline].
Cimolai N, Carter JE. Antimotility agents for paediatric use. Lancet. 1990 Oct 6. 336(8719):874. [Medline].
Cimolai N, Carter JE. Bacterial genotype and neurological complications of Escherichia coli O157:H7-associated haemolytic uraemic syndrome. Acta Paediatr. 1998 May. 87(5):593-4. [Medline].
Cimolai N, Carter JE, Morrison BJ, Anderson JD. Risk factors for the progression of Escherichia coli O157:H7 enteritis to hemolytic-uremic syndrome. J Pediatr. 1990 Apr. 116(4):589-92. [Medline].
Cimolai N, Morrison BJ, Carter JE. Risk factors for the central nervous system manifestations of gastroenteritis-associated hemolytic-uremic syndrome. Pediatrics. 1992 Oct. 90(4):616-21. [Medline].
Coad NA, Marshall T, Rowe B, Taylor CM. Changes in the postenteropathic form of the hemolytic uremic syndrome in children. Clin Nephrol. 1991 Jan. 35(1):10-6. [Medline].
Decludt B, Bouvet P, Mariani-Kurkdjian P, et al. Haemolytic uraemic syndrome and Shiga toxin-producing Escherichia coli infection in children in France. The Societe de Nephrologie Pediatrique. Epidemiol Infect. 2000 Apr. 124(2):215-20. [Medline].
Drews RE, Weinberger SE. Thrombocytopenic disorders in critically ill patients. Am J Respir Crit Care Med. 2000 Aug. 162(2 Pt 1):347-51. [Medline].
Ekberg M, Holmberg L, Denneberg T. Hemolytic uremic syndrome. Results of treatment with hemodialysis. Acta Paediatr Scand. 1977 Nov. 66(6):693-8. [Medline].
Elliott MA, Nichols WL. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Mayo Clin Proc. 2001 Nov. 76(11):1154-62. [Medline].
Fakhouri F, Vincent F, Legendre C. Pathological and therapeutic distinctions in HUS/TTP. Lancet. 2000 Feb 5. 355(9202):497; author reply 497-8. [Medline].
Fitzpatrick MM, Walters MD, Trompeter RS, et al. Atypical (non-diarrhea-associated) hemolytic-uremic syndrome in childhood. J Pediatr. 1993 Apr. 122(4):532-7. [Medline].
Fong JS, Kaplan BS. Impairment of platelet aggregation in hemolytic uremic syndrome: evidence for platelet "exhaustion". Blood. 1982 Sep. 60(3):564-70. [Medline].
Fremeaux-Bacchi V, Kemp EJ, Goodship JA, et al. The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts. J Med Genet. 2005 Nov. 42(11):852-6. [Medline].
Furlan M, Lammle B. Haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura--new insights into underlying biochemical mechanisms. Nephrol Dial Transplant. 2000 Aug. 15(8):1112-4. [Medline].
Gallo EG, Gianantonio CA. Extrarenal involvement in diarrhoea-associated haemolytic-uraemic syndrome. Pediatr Nephrol. 1995 Feb. 9(1):117-9. [Medline].
Gianviti A, Perna A, Caringella A, et al. Plasma exchange in children with hemolytic-uremic syndrome at risk of poor outcome. Am J Kidney Dis. 1993 Aug. 22(2):264-6. [Medline].
Griffin PM, Tauxe RV. The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E. coli, and the associated hemolytic uremic syndrome. Epidemiol Rev. 1991. 13:60-98. [Medline].
Hammond D, Lieberman E. The hemolytic uremic syndrome. Renal cortical thrombotic microangiopathy. Arch Intern Med. 1970 Nov. 126(5):816-22. [Medline].
Heusser. hemolytic uremic syndrome. 1966.
Jeong YK, Kim IO, Kim WS, et al. Hemolytic uremic syndrome: MR findings of CNS complications. Pediatr Radiol. 1994. 24(8):585-6. [Medline].
Kakishita E. Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Int J Hematol. 2000 Jun. 71(4):320-7. [Medline].
Kaplan BS, Thomson PD. Hyperuricemia in the hemolytic-uremic syndrome. Am J Dis Child. 1976 Aug. 130(8):854-6. [Medline].
Kaplan BS, Thomson PD, de Chadarevian JP. The hemolytic uremic syndrome. Pediatr Clin North Am. 1976 Nov. 23(4):761-77. [Medline].
Karmali MA, Petric M, Lim C, et al. The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis. 1985 May. 151(5):775-82. [Medline].
Lieberman E, Heuser E, Donnell GN, et al. Hemolytic-uremic syndrome. Clinical and pathological considerations. N Engl J Med. 1966 Aug 4. 275(5):227-36. [Medline].
Loirat C, Beaufils F, Sonsino E, et al. Treatment of childhood hemolytic-uremic syndrome with urokinase. Cooperative controlled trial [in French]. Arch Fr Pediatr. 1984 Jan. 41(1):15-9. [Medline].
Loirat C, Niaudet P. The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children. Pediatr Nephrol. 2003 Nov. 18(11):1095-101. [Medline].
Lopez EL, Devoto S, Fayad A, et al. Association between severity of gastrointestinal prodrome and long-term prognosis in classic hemolytic-uremic syndrome. J Pediatr. 1992 Feb. 120(2 Pt 1):210-5. [Medline].
Marques MB, Mayfield CA, Blackall DP. Thrombotic thrombocytopenic purpura: from platelet aggregates to plasma. Am J Clin Pathol. 2004 Jun. 121 Suppl:S89-96. [Medline].
Ohali M, Shalev H, Schlesinger M, et al. Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H. Pediatr Nephrol. 1998 Oct. 12(8):619-24. [Medline].
Olinsky A, Thomson P, Kaplan B, Abrahams C. Analysis of 10 cases of the haemolytic-uraemic syndrome seen at the Transvaal Memorial Hospital for Children in the 18-month period January 1970 to June 1971. S Afr Med J. 1972 Jun 17. 46(25):848. [Medline].
Ostroff SM, Tarr PI, Neill MA, et al. Toxin genotypes and plasmid profiles as determinants of systemic sequelae in Escherichia coli O157:H7 infections. J Infect Dis. 1989 Dec. 160(6):994-8. [Medline].
Pichette V, Querin S, Schurch W, et al. Familial hemolytic-uremic syndrome and homozygous factor H deficiency. Am J Kidney Dis. 1994 Dec. 24(6):936-41. [Medline].
Ray PE, Liu XH. Pathogenesis of Shiga toxin-induced hemolytic uremic syndrome. Pediatr Nephrol. 2001 Oct. 16(10):823-39. [Medline].
Remis RS, MacDonald KL, Riley LW, et al. Sporadic cases of hemorrhagic colitis associated with Escherichia coli O157:H7. Ann Intern Med. 1984 Nov. 101(5):624-6. [Medline].
Remuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int Suppl. 1998 May. 66:S54-7. [Medline].
Remuzzi G, Zoja C, de Gaetano G, Rossi EC. Prostacyclin and hemolytic uremic syndrome: from the laboratory to an international registry. Int J Artif Organs. 1987 Nov. 10(6):337-40. [Medline].
Renaud C, Niaudet P, Gagnadoux MF, et al. Haemolytic uraemic syndrome: prognostic factors in children over 3 years of age. Pediatr Nephrol. 1995 Feb. 9(1):24-9. [Medline].
Rizzoni G, Claris-Appiani A, Edefonti A, et al. Plasma infusion for hemolytic-uremic syndrome in children: results of a multicenter controlled trial. J Pediatr. 1988 Feb. 112(2):284-90. [Medline].
Ruggenenti P, Remuzzi G. The pathophysiology and management of thrombotic thrombocytopenic purpura. Eur J Haematol. 1996 Apr. 56(4):191-207. [Medline].
Sheth KJ, Swick HM, Haworth N. Neurological involvement in hemolytic-uremic syndrome. Ann Neurol. 1986 Jan. 19(1):90-3. [Medline].
Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr. 2005 Apr. 17(2):200-4. [Medline].
Siegler RL, Milligan MK, Burningham TH, et al. Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome. J Pediatr. 1991 Feb. 118(2):195-200. [Medline].
Siegler RL, Pavia AT, Christofferson RD, Milligan MK. A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in Utah. Pediatrics. 1994 Jul. 94(1):35-40. [Medline].
Siegler RL, Pavia AT, Hansen FL, et al. Atypical hemolytic-uremic syndrome: a comparison with postdiarrheal disease. J Pediatr. 1996 Apr. 128(4):505-11. [Medline].
Spizzirri FD, Rahman RC, Bibiloni N, et al. Childhood hemolytic uremic syndrome in Argentina: long-term follow-up and prognostic features. Pediatr Nephrol. 1997 Apr. 11(2):156-60. [Medline].
Tarr PI, Tsai HM, Chandler WL. Thrombotic microangiopathies. N Engl J Med. 2002 Dec 26. 347(26):2171-3; author reply 2171-3. [Medline].
Tozzi AE, Caprioli A, Minelli F, et al. Shiga toxin-producing Escherichia coli infections associated with hemolytic uremic syndrome, Italy, 1988-2000. Emerg Infect Dis. 2003 Jan. 9(1):106-8. [Medline].
Trompeter RS, Schwartz R, Chantler C, et al. Haemolytic-uraemic syndrome: an analysis of prognostic features. Arch Dis Child. 1983 Feb. 58(2):101-5. [Medline].
Walters MD, Matthei IU, Kay R, et al. The polymorphonuclear leucocyte count in childhood haemolytic uraemic syndrome. Pediatr Nephrol. 1989 Apr. 3(2):130-4. [Medline].
Wells JG, Davis BR, Wachsmuth IK, et al. Laboratory investigation of hemorrhagic colitis outbreaks associated with a rare Escherichia coli serotype. J Clin Microbiol. 1983 Sep. 18(3):512-20. [Medline].