Pediatric Nephrology

, Volume 28, Issue 11, pp 2097–2105 | Cite as

Long-term outcomes of Shiga toxin hemolytic uremic syndrome

  • Joann M. Spinale
  • Rebecca L. Ruebner
  • Lawrence Copelovitch
  • Bernard S. Kaplan
Educational Review


Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) is an important cause of acute kidney injury (AKI). The outcomes of STEC HUS have improved, and the acute mortality rate in children is 1–4 %. About 70 % of patients recover completely from the acute episode and the remainder have varying degrees of sequelae. Only a few retrospective studies have reviewed these patients over long periods. Methodological flaws include a lack of strict definitions, changing modes of treatment, ascertainment bias and loss of subjects to follow-up. The kidneys bear the brunt of the long-term damage: proteinuria (15–30 % of cases); hypertension (5–15 %); chronic kidney disease (CKD; 9–18 %); and end-stage kidney disease (ESKD; 3 %). A smaller number have extra-renal sequelae: colonic strictures, cholelithiasis, diabetes mellitus or brain injury. Most renal sequelae are minor abnormalities, such as treatable hypertension and/or variable proteinuria. Most of the patients who progress to ESKD do not recover normal renal function after the acute episode. Length of anuria (more than 10 days) and prolonged dialysis are the most important risk factors for a poor acute and long-term renal outcome. After the acute episode all patients must be followed for at least 5 years, and severely affected patients should be followed indefinitely if there is proteinuria, hypertension or a reduced glomerular filtration rate (GFR).


Hemolytic uremic syndrome Long-term outcomes Prognosis STEC HUS D+HUS 



  1. 1.
    Gerber A, Karch H, Allerberger F, Verweyen HM, Zimmerhackl LB (2002) Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997–2000, in Germany and Austria: a prospective study. J Infect Dis 186:493–500PubMedCrossRefGoogle Scholar
  2. 2.
    Siegler RL (2003) Postdiarrheal Shiga toxin-mediated hemolytic uremic syndrome. JAMA 290:1379–1381PubMedCrossRefGoogle Scholar
  3. 3.
    Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP, Salvadori M, Haynes RB, Clark WF (2003) Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: A systematic review, meta-analysis, and meta-regression. JAMA 290:1360–1370PubMedCrossRefGoogle Scholar
  4. 4.
    Gagnadoux MF, Habib R, Gubler MC, Bacri JL, Broyer M (1996) Long-term (15–25 years) outcome of childhood hemolytic-uremic syndrome. Clin Nephrol 46:39–41PubMedGoogle Scholar
  5. 5.
    Kaplan BS, Katz J, Krawitz S, Lurie A (1971) An analysis of the results of therapy in 67 cases of the hemolytic-uremic syndrome. J Pediatr 78:420–425PubMedCrossRefGoogle Scholar
  6. 6.
    Gianantonio C, Vitacco M, Mendilaharzu F, Rutty A, Mendilaharzu J (1964) The Hemolytic-Uremic Syndrome. J Pediatr 64:478–491PubMedCrossRefGoogle Scholar
  7. 7.
    Kaplan BS, Thomson PD, de Chadarevian JP (1976) The hemolytic uremic syndrome. Pediatr Clin North Am 23:761–777PubMedGoogle Scholar
  8. 8.
    Grisaru S, Midgley JP, Hamiwka LA, Wade AW, Samuel SM (2011) Diarrhea-associated hemolytic uremic syndrome in southern Alberta: A long-term single-centre experience. Paediatr Child Health 16:337–340PubMedGoogle Scholar
  9. 9.
    Robson WL, Fick GH, Wilson PC (1988) Prognostic factors in typical postdiarrhea hemolytic-uremic syndrome. Child Nephrol Urol 9:203–207PubMedGoogle Scholar
  10. 10.
    Kaplan BS, Meyers KE, Schulman SL (1998) The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol 9:1126–1133PubMedGoogle Scholar
  11. 11.
    Oakes RS, Siegler RL, McReynolds MA, Pysher T, Pavia AT (2006) Predictors of fatality in postdiarrheal hemolytic uremic syndrome. Pediatrics 117:1656–1662PubMedCrossRefGoogle Scholar
  12. 12.
    Schieppati A, Ruggenenti P, Cornejo RP, Ferrario F, Gregorini G, Zucchelli P, Rossi E, Remuzzi G (1992) Renal function at hospital admission as a prognostic factor in adult hemolytic uremic syndrome. The Italian Registry of Haemolytic Uremic Syndrome. J Am Soc Nephrol 2:1640–1644PubMedGoogle Scholar
  13. 13.
    Siegler RL, Milligan MK, Burningham TH, Christofferson RD, Chang SY, Jorde LB (1991) Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome. J Pediatr 118:195–200PubMedCrossRefGoogle Scholar
  14. 14.
    Huseman D, Gellermann J, Vollmer I, Ohde I, Devaux S, Ehrich JH, Filler G (1999) Long-term prognosis of hemolytic uremic syndrome and effective renal plasma flow. Pediatr Nephrol 13:672–677PubMedCrossRefGoogle Scholar
  15. 15.
    Robson WL, Leung AK, Brant R (1993) Relationship of the recovery in the glomerular filtration rate to the duration of anuria in diarrhea-associated hemolytic uremic syndrome. Am J Nephrol 13:194–197PubMedCrossRefGoogle Scholar
  16. 16.
    Tonshoff B, Sammet A, Sanden I, Mehls O, Waldherr R, Scharer K (1994) Outcome and prognostic determinants in the hemolytic uremic syndrome of children. Nephron 68:63–70PubMedCrossRefGoogle Scholar
  17. 17.
    Oakes RS, Kirkham JK, Nelson RD, Siegler RL (2008) Duration of oliguria and anuria as predictors of chronic renal-related sequelae in post-diarrheal hemolytic uremic syndrome. Pediatr Nephrol 23:1303–1308PubMedCrossRefGoogle Scholar
  18. 18.
    Rosales A, Hofer J, Zimmerhackl LB, Jungraithmayr TC, Riedl M, Giner T, Strasak A, Orth-Holler D, Wurzner R, Karch H (2012) Need for long-term follow-up in enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to late-emerging sequelae. Clin Infect Dis 54:1413–1421PubMedCrossRefGoogle Scholar
  19. 19.
    Otukesh H, Hoseini R, Golnari P, Fereshtehnejad SM, Zamanfar D, Hooman N, Tabarroki A (2008) Short-term and long-term outcome of hemolytic uremic syndrome in Iranian children. J Nephrol 21:694–703PubMedGoogle Scholar
  20. 20.
    Trompeter RS, Schwartz R, Chantler C, Dillon MJ, Haycock GB, Kay R, Barratt TM (1983) Haemolytic-uraemic syndrome: An analysis of prognostic features. Arch Dis Child 58:101–105PubMedCrossRefGoogle Scholar
  21. 21.
    Kelles A, Van Dyck M, Proesmans W (1994) Childhood haemolytic uraemic syndrome: Long-term outcome and prognostic features. Eur J Pediatr 153:38–42PubMedCrossRefGoogle Scholar
  22. 22.
    Bos AP, Donckerwolcke RA, van Vught AJ (1985) The hemolytic-uremic syndrome: Prognostic significance of neurological abnormalities. Helv Paediatr Acta 40:381–389PubMedGoogle Scholar
  23. 23.
    Brandt JR, Joseph MW, Fouser LS, Tarr PI, Zelikovic I, McDonald RA, Avner ED, McAfee NG, Watkins SL (1998) Cholelithiasis following Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr Nephrol 12:222–225PubMedCrossRefGoogle Scholar
  24. 24.
    Wong CS, Mooney JC, Brandt JR, Staples AO, Jelacic S, Boster DR, Watkins SL, Tarr PI (2012) Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: A multivariable analysis. Clin Infect Dis 55:33–41PubMedCrossRefGoogle Scholar
  25. 25.
    Gianviti A, Tozzi AE, De Petris L, Caprioli A, Rava L, Edefonti A, Ardissino G, Montini G, Zacchello G, Ferretti A, Pecoraro C, De Palo T, Caringella A, Gaido M, Coppo R, Perfumo F, Miglietti N, Ratsche I, Penza R, Capasso G, Maringhini S, Li Volti S, Setzu C, Pennesi M, Bettinelli A, Peratoner L, Pela I, Salvaggio E, Lama G, Maffei S, Rizzoni G (2003) Risk factors for poor renal prognosis in children with hemolytic uremic syndrome. Pediatr Nephrol 18:1229–1235PubMedCrossRefGoogle Scholar
  26. 26.
    Coad NA, Marshall T, Rowe B, Taylor CM (1991) Changes in the postenteropathic form of the hemolytic uremic syndrome in children. Clin Nephrol 35:10–16PubMedGoogle Scholar
  27. 27.
    Balestracci A, Martin SM, Toledo I, Alvarado C, Wainsztein RE (2012) Dehydration at admission increased the need for dialysis in hemolytic uremic syndrome children. Pediatr Nephrol 27:1407–1410PubMedCrossRefGoogle Scholar
  28. 28.
    Siegler RL (1994) Spectrum of extrarenal involvement in postdiarrheal hemolytic-uremic syndrome. J Pediatr 125:511–518PubMedCrossRefGoogle Scholar
  29. 29.
    Siegler RL, Pavia AT, Christofferson RD, Milligan MK (1994) A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in Utah. Pediatrics 94:35–40PubMedGoogle Scholar
  30. 30.
    Spizzirri FD, Rahman RC, Bibiloni N, Ruscasso JD, Amoreo OR (1997) Childhood hemolytic uremic syndrome in Argentina: Long-term follow-up and prognostic features. Pediatr Nephrol 11:156–160PubMedCrossRefGoogle Scholar
  31. 31.
    Milford DV, White RH, Taylor CM (1991) Prognostic significance of proteinuria one year after onset of diarrhea-associated hemolytic-uremic syndrome. J Pediatr 118:191–194PubMedCrossRefGoogle Scholar
  32. 32.
    Tufro A, Arrizurieta EE, Repetto H (1991) Renal functional reserve in children with a previous episode of haemolytic-uraemic syndrome. Pediatr Nephrol 5:184–188PubMedCrossRefGoogle Scholar
  33. 33.
    Small G, Watson AR, Evans JH, Gallagher J (1999) Hemolytic uremic syndrome: Defining the need for long-term follow-up. Clin Nephrol 52:352–356PubMedGoogle Scholar
  34. 34.
    Repetto HA (2005) Long-term course and mechanisms of progression of renal disease in hemolytic uremic syndrome. Kidney Int Suppl (97):S102–S106Google Scholar
  35. 35.
    Suri RS, Mahon JL, Clark WF, Moist LM, Salvadori M, Garg AX (2009) Relationship between Escherichia coli O157:H7 and diabetes mellitus. Kidney Int Suppl (112):S44–S46Google Scholar
  36. 36.
    Schlieper A, Rowe PC, Orrbine E, Zoubek M, Clark W, Wolfish N, McLaine PN (1992) Sequelae of haemolytic uraemic syndrome. Arch Dis Child 67:930–934PubMedCrossRefGoogle Scholar
  37. 37.
    Nathanson S, Kwon T, Elmaleh M, Charbit M, Launay EA, Harambat J, Brun M, Ranchin B, Bandin F, Cloarec S, Bourdat-Michel G, Pietrement C, Champion G, Ulinski T, Deschenes G (2010) Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 5:1218–1228PubMedCrossRefGoogle Scholar
  38. 38.
    Bennett B, Booth T, Quan A (2003) Late onset seizures, hemiparesis and blindness in hemolytic uremic syndrome. Clin Nephrol 59:196–200PubMedCrossRefGoogle Scholar
  39. 39.
    Theobald I, Kuwertz-Broking E, Schiborr M, Heindel W (2001) Central nervous system involvement in hemolytic uremic syndrome (HUS)–a retrospective analysis of cerebral CT and MRI studies. Clin Nephrol 56:S3–S8PubMedGoogle Scholar
  40. 40.
    Fitzpatrick MM, Shah V, Trompeter RS, Dillon MJ, Barratt TM (1991) Long term renal outcome of childhood haemolytic uraemic syndrome. BMJ 303:489–492PubMedCrossRefGoogle Scholar
  41. 41.
    Caletti MG, Gallo G, Gianantonio CA (1996) Development of focal segmental sclerosis and hyalinosis in hemolytic uremic syndrome. Pediatr Nephrol 10:687–692PubMedCrossRefGoogle Scholar
  42. 42.
    Sharma AP, Filler G, Dwight P, Clark WF (2010) Chronic renal disease is more prevalent in patients with hemolytic uremic syndrome who had a positive history of diarrhea. Kidney Int 78:598–604PubMedCrossRefGoogle Scholar
  43. 43.
    Garg AX, Salvadori M, Okell JM, Thiessen-Philbrook HR, Suri RS, Filler G, Moist L, Matsell D, Clark WF (2008) Albuminuria and estimated GFR 5 years after Escherichia coli O157 hemolytic uremic syndrome: An update. Am J Kidney Dis 51:435–444PubMedCrossRefGoogle Scholar
  44. 44.
    Dobiliene D, Pundziene B, Mitkiene R (2007) The clinical course and long-term outcome of hemolytic-uremic syndrome in children. Medicina (Kaunas) 43(1):23–27Google Scholar
  45. 45.
    Cobenas CJ, Alconcher LF, Spizzirri AP, Rahman RC (2007) Long-term follow-up of Argentinean patients with hemolytic uremic syndrome who had not undergone dialysis. Pediatr Nephrol 22:1343–1347PubMedCrossRefGoogle Scholar
  46. 46.
    Caletti MG, Missoni M, Vezzani C, Grignoli M, Piantanida JJ, Repetto HA, Exeni R, Rasse SM (2011) Effect of diet, enalapril, or losartan in post-diarrheal hemolytic uremic syndrome nephropathy. Pediatr Nephrol 26:1247–1254PubMedCrossRefGoogle Scholar
  47. 47.
    National Kidney Foundation (2002) K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 39:S1–S266Google Scholar
  48. 48.
    O’Regan S, Blais N, Russo P, Pison CF, Rousseau E (1989) Hemolytic uremic syndrome: Glomerular filtration rate, 6 to 11 years later measured by 99mTc DTPA plasma slope clearance. Clin Nephrol 32:217–220PubMedGoogle Scholar
  49. 49.
    NAPRTCS: 2010 Annual Report, Rockville, MD, EMMES, 2010. Available at Accessed on 14 September 2012
  50. 50.
    Krmar RT, Ferraris JR, Ramirez JA, Ruiz S, Salomon A, Galvez HM, Janson JJ, Galarza CR, Waisman G (2001) Ambulatory blood pressure monitoring after recovery from hemolytic uremic syndrome. Pediatr Nephrol 16:812–816PubMedCrossRefGoogle Scholar
  51. 51.
    De Petris L, Gianviti A, Giordano U, Calzolari A, Tozzi AE, Rizzoni G (2004) Blood pressure in the long-term follow-up of children with hemolytic uremic syndrome. Pediatr Nephrol 19:1241–1244PubMedCrossRefGoogle Scholar
  52. 52.
    Rahman RC, Cobenas CJ, Drut R, Amoreo OR, Ruscasso JD, Spizzirri AP, Suarez Adel C, Zalba JH, Ferrari C, Gatti MC (2012) Hemorrhagic colitis in postdiarrheal hemolytic uremic syndrome: Retrospective analysis of 54 children. Pediatr Nephrol 27:229–233PubMedCrossRefGoogle Scholar
  53. 53.
    Suri RS, Clark WF, Barrowman N, Mahon JL, Thiessen-Philbrook HR, Rosas-Arellano MP, Zarnke K, Garland JS, Garg AX (2005) Diabetes during diarrhea-associated hemolytic uremic syndrome: a systematic review and meta-analysis. Diabetes Care 28:2556–2562PubMedCrossRefGoogle Scholar
  54. 54.
    Loos S, Ahlenstiel T, Kranz B, Staude H, Pape L, Hartel C, Vester U, Buchtala L, Benz K, Hoppe B, Beringer O, Krause M, Muller D, Pohl M, Lemke J, Hillebrand G, Kreuzer M, Konig J, Wigger M, Konrad M, Haffner D, Oh J, Kemper MJ (2012) 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 55:753–759PubMedCrossRefGoogle Scholar
  55. 55.
    Siegler R (1992) Cardiovascular involvement in the hemolytic uremic syndrome. In: Kaplan BS, Trompeter RS, Moake JL (eds) Hemolytic uremic syndrome and thrombotic thrombocytopenia purpura. Dekker, New York, pp 143–149Google Scholar
  56. 56.
    Poulton J, Taylor CM, De Giovanni JV (1987) Dilated cardiomyopathy associated with haemolytic uraemic syndrome. Br Heart J 57:181–183PubMedCrossRefGoogle Scholar
  57. 57.
    Mohammed J, Filler G, Price A, Sharma AP (2009) Cardiac tamponade in diarrhoea-positive haemolytic uraemic syndrome. Nephrol Dial Transplant 24:679–681PubMedCrossRefGoogle Scholar
  58. 58.
    Askiti V, Hendrickson K, Fish AJ, Braunlin E, Sinaiko AR (2004) Troponin I levels in a hemolytic uremic syndrome patient with severe cardiac failure. Pediatr Nephrol 19:345–348PubMedCrossRefGoogle Scholar
  59. 59.
    Nitschke M, Sayk F, Hartel C, Roseland RT, Hauswaldt S, Steinhoff J, Fellermann K, Derad I, Wellhoner P, Buning J, Tiemer B, Katalinic A, Rupp J, Lehnert H, Solbach W, Knobloch JK (2012) Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA 307:1046–1052PubMedCrossRefGoogle Scholar
  60. 60.
    Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, Bremer JP, Brunkhorst R, Busch V, Dengler R, Deuschl G, Fellermann K, Fickenscher H, Gerigk C, Goettsche A, Greeve J, Hafer C, Hagenmuller F, Haller H, Herget-Rosenthal S, Hertenstein B, Hofmann C, Lang M, Kielstein JT, Klostermeier UC, Knobloch J, Kuehbacher M, Kunzendorf U, Lehnert H, Manns MP, Menne TF, Meyer TN, Michael C, Munte T, Neumann-Grutzeck C, Nuernberger J, Pavenstaedt H, Ramazan L, Renders L, Repenthin J, Ries W, Rohr A, Rump LC, Samuelsson O, Sayk F, Schmidt BM, Schnatter S, Schocklmann H, Schreiber S, von Seydewitz CU, Steinhoff J, Stracke S, Suerbaum S, van de Loo A, Vischedyk M, Weissenborn K, Wellhoner P, Wiesner M, Zeissig S, Büning J, Schiffer M, Kuehbacher T, EHEC-HUS consortium (2012) Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: Case–control study. BMJ 345:e4565PubMedCrossRefGoogle Scholar
  61. 61.
    Hickey CA, Beattie TJ, Cowieson J, Miyashita Y, Strife CF, Frem JC, Peterson JM, Butani L, Jones DP, Havens PL, Patel HP, Wong CS, Andreoli SP, Rothbaum RJ, Beck AM, Tarr PI (2011) Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome. Arch Pediatr Adolesc Med 165:884–889PubMedCrossRefGoogle Scholar
  62. 62.
    Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, Proulx F, Clermont MJ, Le Deist F, Niaudet P, Schaefer F (2011) Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med 364:2561–2563PubMedCrossRefGoogle Scholar
  63. 63.
    Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C, Kuhlmann U, Bramstedt J, Panzer U, Vischedyk M, Busch V, Ries W, Mitzner S, Mees S, Stracke S, Nurnberger J, Gerke P, Wiesner M, Sucke B, Abu-Tair M, Kribben A, Klause N, Schindler R, Merkel F, Schnatter S, Dorresteijn EM, Samuelsson O, Brunkhorst R, on behalf of the collaborators of the DS-HUSr (2012) 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 27:3807–3815PubMedCrossRefGoogle Scholar
  64. 64.
    Loirat C, Sonsino E, Varga Moreno A, Pillion G, Mercier JC, Beaufils F, Mathieu H (1984) Hemolytic-uremic syndrome: an analysis of the natural history and prognostic features. Acta Paediatr Scand 73:505–514PubMedCrossRefGoogle Scholar
  65. 65.
    Walters MD, Matthei IU, Kay R, Dillon MJ, Barratt TM (1989) The polymorphonuclear leucocyte count in childhood haemolytic uraemic syndrome. Pediatr Nephrol 3:130–134PubMedCrossRefGoogle Scholar
  66. 66.
    Siegler RL, Pavia AT, Hansen FL, Christofferson RD, Cook JB (1996) Atypical hemolytic-uremic syndrome: a comparison with postdiarrheal disease. J Pediatr 128:505–511PubMedCrossRefGoogle Scholar
  67. 67.
    Lopez EL, Devoto S, Fayad A, Canepa C, Morrow AL, Cleary TG (1992) Association between severity of gastrointestinal prodrome and long-term prognosis in classic hemolytic-uremic syndrome. J Pediatr 120:210–215PubMedCrossRefGoogle Scholar
  68. 68.
    Renaud C, Niaudet P, Gagnadoux MF, Broyer M, Habib R (1995) Haemolytic uraemic syndrome: prognostic factors in children over 3 years of age. Pediatr Nephrol 9:24–29PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2012

Authors and Affiliations

  • Joann M. Spinale
    • 1
  • Rebecca L. Ruebner
    • 1
  • Lawrence Copelovitch
    • 1
  • Bernard S. Kaplan
    • 1
    • 2
  1. 1.Division of Pediatric Nephrology, Department of PediatricsThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Division of NephrologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations