History

Patients with Shiga toxin–producing E coli hemolytic-uremic syndrome (STEC-HUS) typically 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 visibly 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 STEC-HUS 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.

Atypical hemolytic-uremic syndrome (aHUS) 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/µL. 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. aHUS tends to be associated with a greater number of neurologic symptoms than STEC-HUS.
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: STEC-HUS 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 type 1 diabetes and, on rare occasion, exocrine dysfunction.
Cardiovascular: Congestive heart failure may occur.

Physical Examination

Blood pressure may be elevated unless the patient is volume depleted (eg, from diarrhea). The 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.

Differential Diagnoses

Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet. 2017 Aug 12. 390 (10095):681-696. [QxMD MEDLINE Link].
Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr. 2013 Apr. 25(2):203-8. [QxMD MEDLINE Link].
Loos S, Ahlenstiel T, Kranz B, Staude H, Pape L, Härtel C, et al. An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children. Clin Infect Dis. 2012 Sep. 55(6):753-9. [QxMD MEDLINE Link].
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. 2008 Mar. 51(3):435-44. [QxMD MEDLINE Link].
Gitiaux C, Krug P, Grevent D, Kossorotoff M, Poncet S, Eisermann M, et al. Brain magnetic resonance imaging pattern and outcome in children with haemolytic-uraemic syndrome and neurological impairment treated with eculizumab. Dev Med Child Neurol. 2013 May 10. [QxMD MEDLINE Link].
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. 2005 Jun. 115(6):e673-80. [QxMD MEDLINE Link].
Ardissino G, Tel F, Possenti I, Testa S, Consonni D, Paglialonga F, et al. Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome. Pediatrics. 2016 Jan. 137 (1):[QxMD MEDLINE Link].
Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol. 2004 Dec. 19(12):1394-9. [QxMD MEDLINE Link].
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. 2004 Aug. 32(8):1771-6. [QxMD MEDLINE Link].
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. 2000 Apr. 28(4):1161-5. [QxMD MEDLINE Link].
Murphy EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. 2005 Jun. 33(3):311-22. [QxMD MEDLINE Link].
Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004 Nov. 28(5):497-504. [QxMD MEDLINE Link].
[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. 2009 Apr. 24(4):687-96. [QxMD MEDLINE Link].
Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016 Jan. 31 (1):15-39. [QxMD MEDLINE Link].
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. 2009 Feb. 53(2):259-72. [QxMD MEDLINE Link].
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. 2008 Feb. 48(2):349-57. [QxMD MEDLINE Link].
von Baeyer H. Plasmapheresis in thrombotic microangiopathy-associated syndromes: review of outcome data derived from clinical trials and open studies. Ther Apher. 2002 Aug. 6(4):320-8. [QxMD MEDLINE Link].
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. 2004 Aug. 19(8):908-11. [QxMD MEDLINE Link].
Saland JM, Ruggenenti P, Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2009 May. 20(5):940-9. [QxMD MEDLINE Link].
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. 2009 Jan. 4(1):201-6. [QxMD MEDLINE Link]. [Full Text].
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. 2008 Jan. 8(1):216-21. [QxMD MEDLINE Link].
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. 2006 Aug. 6(8):1948-52. [QxMD MEDLINE Link].
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. 2007 Aug. 18(8):2392-400. [QxMD MEDLINE Link].
Zimmerhackl LB, Besbas N, Jungraithmayr T, et al. Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost. 2006 Mar. 32(2):113-20. [QxMD MEDLINE Link].
Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol. 2011 Aug. 26(8):1325-9. [QxMD MEDLINE Link].
Krid S, Roumenina LT, Beury D, Charbit M, Boyer O, Frémeaux-Bacchi V, et al. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant. 2012 Jul. 12(7):1938-44. [QxMD MEDLINE Link].
Xie L, Nester CM, Reed AI, Zhang Y, Smith RJ, Thomas CP. Tailored eculizumab therapy in the management of complement factor H-mediated atypical hemolytic uremic syndrome in an adult kidney transplant recipient: a case report. Transplant Proc. 2012 Dec. 44(10):3037-40. [QxMD MEDLINE Link].
Benoit SW, Fukuda T, VandenHeuvel K, Witte D, Fuller C, Willis J, et al. Case Report: Atypical HUS Presenting With Acute Rhabdomyolysis Highlights the Need for Individualized Eculizumab Dosing. Front Pediatr. 2022. 10:841051. [QxMD MEDLINE Link].
Fakhouri F, Fila M, Provôt F, Delmas Y, Barbet C, Châtelet V, et al. Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation. Clin J Am Soc Nephrol. 2017 Jan 6. 12 (1):50-59. [QxMD MEDLINE Link].
Baskin E, Fidan K, Gulhan B, Gulleroglu K, Canpolat N, Yilmaz A, et al. Eculizumab treatment and discontinuation in pediatric patients with atypical hemolytic uremic syndrome: a multicentric retrospective study. J Nephrol. 2022 Jan 21. [QxMD MEDLINE Link].
Fakhouri F, Fila M, Hummel A, et al. Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study. Blood. 2021 May 6. 137 (18):2438-2449. [QxMD MEDLINE Link].
McNamara LA, Topaz N, Wang X, Hariri S, Fox L, MacNeil JR. High Risk for Invasive Meningococcal Disease Among Patients Receiving Eculizumab (Soliris) Despite Receipt of Meningococcal Vaccine. MMWR Morb Mortal Wkly Rep. 2017 Jul 14. 66 (27):734-737. [QxMD MEDLINE Link].
Mbaeyi SA, Bozio CH, Duffy J, Rubin LG, Hariri S, Stephens DS, et al. Meningococcal Vaccination: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Recomm Rep. 2020 Sep 25. 69 (9):1-41. [QxMD MEDLINE Link].
Tanaka K, Adams B, Aris AM, Fujita N, Ogawa M, Ortiz S, et al. The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab. Pediatr Nephrol. 2021 Apr. 36 (4):889-898. [QxMD MEDLINE Link].
Wang Y, Johnston K, Popoff E, Myren KJ, Cheung A, Faria C, et al. A US cost-minimization model comparing ravulizumab versus eculizumab for the treatment of atypical hemolytic uremic syndrome. J Med Econ. 2020 Dec. 23 (12):1503-1515. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Iijima K, Kamioka I, Nozu K. Management of diarrhea-associated hemolytic uremic syndrome in children. Clin Exp Nephrol. 2008 Feb. 12(1):16-9. [QxMD MEDLINE Link].
Monet-Didailler C, Godron-Dubrasquet A, Madden I, Delmas Y, Llanas B, Harambat J. Long-term outcome of diarrhea-associated hemolytic uremic syndrome is poorly related to markers of kidney injury at 1-year follow-up in a population-based cohort. Pediatr Nephrol. 2018 Oct 27. [QxMD MEDLINE Link].
Uslu-Gökceoglu A, Dogan CS, Comak E, Koyun M, Akman S. Atypical Hemolytic Uremic Syndrome due to Factor H Autoantibody. Turk J Pediatr. 2013 Jan-Feb. 55(1):86-9. [QxMD MEDLINE Link].
Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Jul 23. 361(4):345-57. [QxMD MEDLINE Link].
Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, et al. Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med. 2011 Jun 30. 364(26):2561-3. [QxMD MEDLINE Link].
Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C, et al. Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry. Nephrol Dial Transplant. 2012 Oct. 27(10):3807-15. [QxMD MEDLINE Link].
Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, et al. Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ. 2012 Jul 19. 345:e4565. [QxMD MEDLINE Link]. [Full Text].
Trachtman H, Austin C, Lewinski M, Stahl RA. Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol. 2012 Nov. 8(11):658-69. [QxMD MEDLINE Link].
Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015 May. 87 (5):1061-73. [QxMD MEDLINE Link].
Soliris (eculizumab) [package insert]. Cheshire, CT: Alexion Pharmaceutical. 2011. Available at [Full Text].
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.
Gulleroglu K, Fidan K, Hançer VS, Bayrakci U, Baskin E, Soylemezoglu O. Neurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab. Pediatr Nephrol. 2013 May. 28(5):827-30. [QxMD MEDLINE Link].
Salvadori M, Bertoni E. Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations. World J Nephrol. 2013 Aug 6. 2(3):56-76. [QxMD MEDLINE Link]. [Full Text].
Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012 Nov. 8(11):643-57. [QxMD MEDLINE Link].
Ardissino G, Testa S, Possenti I, Tel F, Paglialonga F, Salardi S, et al. Discontinuation of Eculizumab Maintenance Treatment for Atypical Hemolytic Uremic Syndrome: A Report of 10 Cases. Am J Kidney Dis. 2014 Mar 19. [QxMD MEDLINE Link].
Palma LM, Langman CB. Critical appraisal of eculizumab for atypical hemolytic uremic syndrome. J Blood Med. 2016. 7:39-72. [QxMD MEDLINE Link].
Greenbaum LA, Fila M, Ardissino G, Al-Akash SI, Evans J, Henning P, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016 Mar. 89 (3):701-11. [QxMD MEDLINE Link].
Kreuzer M, Sollmann L, Ruben S, Leifheit-Nestler M, Fischer DC, Pape L, et al. Endothelial dysfunction during long-term follow-up in children with STEC hemolytic-uremic syndrome. Pediatr Nephrol. 2017 Jun. 32 (6):1005-1011. [QxMD MEDLINE Link].
Loos S, Oh J, Kemper MJ. Eculizumab in STEC-HUS: need for a proper randomized controlled trial. Pediatr Nephrol. 2018 Aug. 33 (8):1277-1281. [QxMD MEDLINE Link].
Ultomiris (ravulizumab) [package insert]. Boston, MA: Alexion Pharmaceuticals, Inc. October 2019. Available at [Full Text].

Media Gallery

Peripheral blood smear in hemolytic-uremic syndrome (HUS) showing many schistocytes and RBC fragments due to hemolysis, and relatively few platelets reflective of thrombocytopenia.
Micrograph of a glomerulus in hemolytic-uremic syndrome, showing thrombi and red blood cell fragments in the capillary space. Courtesy of Xin J (Joseph) Zhou, MD, Renal Path Diagnostics, Pathologists BioMedical Labs.

of 2

Author

Robert S Gillespie, MD, MPH Senior Consultant, Medical Director, Nephrology and Kidney Transplantation, Cook Children's Medical Center

Disclosure: Received consulting fee from Alexion Pharmaceuticals for consulting.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Luther Travis, MD Professor Emeritus, Departments of Pediatrics, Nephrology and Diabetes, University of Texas Medical Branch School of Medicine

Luther Travis, MD is a member of the following medical societies: Alpha Omega Alpha, American Federation for Medical Research, International Society of Nephrology, Texas Pediatric Society

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD Tenured Professor of Pediatrics, The First Isaac A Abt, MD, Professor of Kidney Diseases (Emeritus), Northwestern University, The Feinberg School of Medicine; Staff Nephrologist, The Ann and Robert H Lurie Children’s Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Clinical Research, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Pediatric Nephrology, Association of Clinical Scientists, Cochrane Collaboration, International Bone and Mineral Society, International Conferences on Calcium Regulating Hormones, International Pediatric Nephrology Association, International Society of Nephrology, International Society of Renal Nutrition and Metabolism, Midwest Society for Pediatric Research, Pediatric Academic Societies, ROCK (Research on Calculus Kinetics) Society, Society for Pediatric Research

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Horizon Pharmaceuticals); ; Dicerna Pharmaceuticals<br/>Incyte Pharmaceuticals; Eli Lilly for: Federation bio; Dicerna pharmaceuticals.

Additional Contributors

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 and Dental Associations, Florida Medical Association, International Society for Peritoneal Dialysis, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Shock Society, Sigma Xi, The Scientific Research Honor Society, Southern Medical Association, Southern Society for Pediatric Research, Southwest Pediatric Nephrology Study Group

Disclosure: Nothing to disclose.

Ronald D Prauner, MD Assistant Professor of Pediatrics, F Edward Herbert School of Medicine, Uniformed Services of the Health Sciences; Assistant Deputy Commander for Medicine; Fort Belvoir Community Hospital, Fort Belvoir, VA; Consultant to the Army Surgeon General for Pediatric Subspecialties; Staff Pediatric Hematologist-Oncologist, Fort Belvoir Community Hospital

Ronald D Prauner, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Christian Medical and Dental Associations, Children's Oncology Group

Disclosure: Nothing to disclose.

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, American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Acknowledgements

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