Overview of hemolytic uremic syndrome in children
- Patrick Niaudet, MD
Patrick Niaudet, MD
- Section Editor — Pediatric Nephrology
- Professor of Pediatrics
- Hôpital Necker-Enfants Malades, Paris, France
The hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury . It is one of the main causes of acute kidney injury in children. Although all pediatric cases exhibit the classic triad of findings that define HUS, there are a number of various etiologies of HUS that result in differences in presentation, management, and outcome.
This topic will provide an overview of the different causes, evaluation, and initial management of HUS in children.
The classification system used to describe the different etiologies of hemolytic uremic syndrome (HUS) has evolved as ongoing research has provided a better understanding of the underlying causes of HUS, especially those due to genetic mutations in the alternative pathway of complement .
Traditionally, HUS had been divided into diarrhea-positive and diarrhea-negative HUS. The former, also referred to as typical HUS, primarily resulted from Shiga toxin-producing Escherichia coli (STEC) infections, and less frequently from Shigella dysenteriae type 1 infection. All other causes of HUS were referred to as atypical HUS or assigned to the diarrhea-negative HUS, even though some patients with non-STEC-associated HUS also presented with diarrhea.
●Primary causes without coexisting disease; such as cases due to complement dysregulation (also referred to as atypical HUS) 
- Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol 2005; 16:1035.
- Goodship TH, Cook HT, Fakhouri F, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2017; 91:539.
- 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; 31:15.
- Ardissino G, Salardi S, Colombo E, et al. Epidemiology of haemolytic uremic syndrome in children. Data from the North Italian HUS network. Eur J Pediatr 2016; 175:465.
- Taylor CM, Machin S, Wigmore SJ, et al. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 2010; 148:37.
- Constantinescu AR, Bitzan M, Weiss LS, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis 2004; 43:976.
- Waters AM, Kerecuk L, Luk D, et al. Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United kingdom experience. J Pediatr 2007; 151:140.
- Noris M, Remuzzi G. Genetic abnormalities of complement regulators in hemolytic uremic syndrome: how do they affect patient management? Nat Clin Pract Nephrol 2005; 1:2.
- Geerdink LM, Westra D, van Wijk JA, et al. Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics. Pediatr Nephrol 2012; 27:1283.
- Veesenmeyer AF, Edmonson MB. Trends in US hospital stays for Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Infect Dis J 2013; 32:731.
- Copelovitch L, Kaplan BS. Streptococcus pneumoniae--associated hemolytic uremic syndrome: classification and the emergence of serotype 19A. Pediatrics 2010; 125:e174.
- Geary DF. Hemolytic uremic syndrome and streptococcus pneumoniae: improving our understanding. J Pediatr 2007; 151:113.
- Szilágyi A, Kiss N, Bereczki C, et al. The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome. Nephrol Dial Transplant 2013; 28:2237.
- Banerjee R, Hersh AL, Newland J, et al. Streptococcus pneumoniae-associated hemolytic uremic syndrome among children in North America. Pediatr Infect Dis J 2011; 30:736.
- Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol 2008; 23:1951.
- Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr 2013; 25:203.
- Turner ME, Kher K, Rakusan T, et al. A typical hemolytic uremic syndrome in human immunodeficiency virus-1-infected children. Pediatr Nephrol 1997; 11:161.
- Caltik A, Akyüz SG, Erdogan O, Demircin G. Hemolytic uremic syndrome triggered with a new pandemic virus: influenza A (H1N1). Pediatr Nephrol 2011; 26:147.
- Golubovic E, Miljkovic P, Zivic S, et al. Hemolytic uremic syndrome associated with novel influenza A H1N1 infection. Pediatr Nephrol 2011; 26:149.
- Rhee H, Song SH, Lee YJ, et al. Pandemic H1N1 influenza A viral infection complicated by atypical hemolytic uremic syndrome and diffuse alveolar hemorrhage. Clin Exp Nephrol 2011; 15:948.
- Trachtman H, Sethna C, Epstein R, et al. Atypical hemolytic uremic syndrome associated with H1N1 influenza A virus infection. Pediatr Nephrol 2011; 26:145.
- Allen U, Licht C. Pandemic H1N1 influenza A infection and (atypical) HUS--more than just another trigger? Pediatr Nephrol 2011; 26:3.
- Bento D, Mapril J, Rocha C, et al. Triggering of atypical hemolytic uremic syndrome by influenza A (H1N1). Ren Fail 2010; 32:753.
- Watanabe T. Renal complications of seasonal and pandemic influenza A virus infections. Eur J Pediatr 2013; 172:15.
- Printza N, Roilides E, Kotsiou M, et al. Pandemic influenza A (H1N1) 2009-associated hemolytic uremic syndrome. Pediatr Nephrol 2011; 26:143.
- Lei TH, Hsia SH, Wu CT, Lin JJ. Streptococcus pneumoniae-associated haemolytic uremic syndrome following influenza A virus infection. Eur J Pediatr 2010; 169:237.
- Al-Akash SI, Almond PS, Savell VH Jr, et al. Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation. Pediatr Nephrol 2011; 26:613.
- Cavagnaro F, Guzmán C, Harris P. Hemolytic uremic syndrome associated with Entamoeba histolytica intestinal infection. Pediatr Nephrol 2006; 21:126.
- Godron A, Pereyre S, Monet C, et al. Hemolytic uremic syndrome complicating Mycoplasma pneumoniae infection. Pediatr Nephrol 2013; 28:2057.
- Noris M, Bresin E, Mele C et al. Atypical Hemoltyic-Uremic Syndrome. GeneReviews. http://www.ncbi.nlm.nih.gov/books/NBK1367/ (Accessed on April 15, 2013).
- Ogier de Baulny H, Gérard M, Saudubray JM, Zittoun J. Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 1998; 157 Suppl 2:S77.
- Beck BB, van Spronsen F, Diepstra A, et al. Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity. Pediatr Nephrol 2017; 32:733.
- Kind T, Levy J, Lee M, et al. Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period. J Pediatr Hematol Oncol 2002; 24:327.
- Sharma AP, Greenberg CR, Prasad AN, Prasad C. Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatr Nephrol 2007; 22:2097.
- Guigonis V, Frémeaux-Bacchi V, Giraudier S, et al. Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. Am J Kidney Dis 2005; 45:588.
- Van Hove JL, Van Damme-Lombaerts R, Grünewald S, et al. Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy. Am J Med Genet 2002; 111:195.
- Fischer S, Huemer M, Baumgartner M, et al. Clinical presentation and outcome in a series of 88 patients with the cblC defect. J Inherit Metab Dis 2014; 37:831.
- Menni F, Testa S, Guez S, et al. Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria. Pediatr Nephrol 2012; 27:1401.
- Carrillo-Carrasco N, Chandler RJ, Venditti CP. Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. J Inherit Metab Dis 2012; 35:91.
- Jodele S, Davies SM, Lane A, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood 2014; 124:645.
- Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008; 358:1129.
- Bruel A, Kavanagh D, Noris M, et al. Hemolytic Uremic Syndrome in Pregnancy and Postpartum. Clin J Am Soc Nephrol 2017.
- Fakhouri F. Pregnancy-related thrombotic microangiopathies: Clues from complement biology. Transfus Apher Sci 2016; 54:199.
- Habib R. Pathology of the hemolytic uremic syndrome. In: Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura, Kaplan B, Trompeter R, Moake J (Eds), Marcel Dekker, New York 1992. p.315.
- PRIMARY HUS: COMPLEMENT-MEDIATED HUS
- INFECTION-INDUCED SECONDARY HUS
- Shiga toxin-producing E. coli (STEC)
- Streptococcus pneumoniae
- - Epidemiology
- - Pathogenesis
- - Clinical manifestations
- - Management
- - Outcome
- HIV infection
- H1N1 influenza A
- NON-INFECTIOUS SECONDARY CAUSES
- DIFFERENTIAL DIAGNOSIS
- SUMMARY AND RECOMMENDATIONS