Advertisement
Review Article| Volume 36, ISSUE 2, P333-356, April 2020

Typical and Atypical Hemolytic Uremic Syndrome in the Critically Ill

  • Carlos L. Manrique-Caballero
    Affiliations
    Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3347 Forbes Avenue Suite 220, Pittsburgh, PA 15213, USA

    The CRISMA (Clinical Research, Investigation and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Scaife Hall, Suite 600, Pittsburgh, PA 15213, USA
    Search for articles by this author
  • Sadudee Peerapornratana
    Affiliations
    Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3347 Forbes Avenue Suite 220, Pittsburgh, PA 15213, USA

    The CRISMA (Clinical Research, Investigation and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Scaife Hall, Suite 600, Pittsburgh, PA 15213, USA

    Excellence Center for Critical Care Nephrology, Division of Nephrology, Department of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand

    Department of Laboratory Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
    Search for articles by this author
  • Cassandra Formeck
    Affiliations
    Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3347 Forbes Avenue Suite 220, Pittsburgh, PA 15213, USA

    The CRISMA (Clinical Research, Investigation and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Scaife Hall, Suite 600, Pittsburgh, PA 15213, USA

    Department of Nephrology, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Floor 3, Pittsburgh, PA 15224, USA
    Search for articles by this author
  • Gaspar Del Rio-Pertuz
    Affiliations
    Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3347 Forbes Avenue Suite 220, Pittsburgh, PA 15213, USA

    The CRISMA (Clinical Research, Investigation and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Scaife Hall, Suite 600, Pittsburgh, PA 15213, USA
    Search for articles by this author
  • Hernando Gomez Danies
    Affiliations
    Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3347 Forbes Avenue Suite 220, Pittsburgh, PA 15213, USA

    The CRISMA (Clinical Research, Investigation and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Scaife Hall, Suite 600, Pittsburgh, PA 15213, USA
    Search for articles by this author
  • John A. Kellum
    Correspondence
    Corresponding author. Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3347 Forbes Avenue Suite 220, Pittsburgh, PA 15213.
    Affiliations
    Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3347 Forbes Avenue Suite 220, Pittsburgh, PA 15213, USA

    The CRISMA (Clinical Research, Investigation and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Scaife Hall, Suite 600, Pittsburgh, PA 15213, USA
    Search for articles by this author
Published:January 31, 2020DOI:https://doi.org/10.1016/j.ccc.2019.11.004

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.

      Subscribe:

      Subscribe to Critical Care Clinics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Noris M.
        • Remuzzi G.
        Atypical hemolytic-uremic syndrome.
        N Engl J Med. 2009; 361: 1676-1687
        • George J.N.
        • Nester C.M.
        Syndromes of thrombotic microangiopathy.
        N Engl J Med. 2014; 371: 654-666
        • Gasser C.
        • Gautier E.
        • Steck A.
        • et al.
        Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia.
        Schweiz Med Wochenschr. 1955; 85 ([in German]): 905-909
        • Kavanagh D.
        • Goodship T.H.
        • Richards A.
        Atypical haemolytic uraemic syndrome.
        Br Med Bull. 2006; 77-78: 5-22
        • Goodship T.H.
        • Cook H.T.
        • 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: 539-551
        • Fakhouri F.
        • Zuber J.
        • Fremeaux-Bacchi V.
        • et al.
        Haemolytic uraemic syndrome.
        Lancet. 2017; 390: 681-696
        • 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: 15-39
        • Noris M.
        • Remuzzi G.
        Hemolytic uremic syndrome.
        J Am Soc Nephrol. 2005; 16: 1035-1050
        • Scheiring J.
        • Andreoli S.P.
        • Zimmerhackl L.B.
        Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS).
        Pediatr Nephrol. 2008; 23: 1749-1760
        • Buchholz U.
        • Bernard H.
        • Werber D.
        • et al.
        German outbreak of Escherichia coli O104:H4 associated with sprouts.
        N Engl J Med. 2011; 365: 1763-1770
        • Tarr P.I.
        • Gordon C.A.
        • Chandler W.L.
        Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome.
        Lancet. 2005; 365: 1073-1086
        • Zoufaly A.
        • Cramer J.P.
        • Vettorazzi E.
        • et al.
        Risk factors for development of hemolytic uremic syndrome in a cohort of adult patients with STEC 0104:H4 infection.
        PLoS One. 2013; 8: e59209
        • Ko H.
        • Maymani H.
        • Rojas-Hernandez C.
        Hemolytic uremic syndrome associated with Escherichia coli O157:H7 infection in older adults: a case report and review of the literature.
        J Med Case Rep. 2016; 10: 175
        • Salvadori M.
        • Bertoni E.
        Update on hemolytic uremic syndrome: diagnostic and therapeutic recommendations.
        World J Nephrol. 2013; 2: 56-76
        • Kottke-Marchant K.
        Diagnostic approach to microangiopathic hemolytic disorders.
        Int J Lab Hematol. 2017; 39: 69-75
        • 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: 465-473
        • Gould L.H.
        • Demma L.
        • Jones T.F.
        • et al.
        Hemolytic uremic syndrome and death in persons with Escherichia coli O157:H7 infection, foodborne diseases active surveillance network sites, 2000-2006.
        Clin Infect Dis. 2009; 49: 1480-1485
        • Frank C.
        • Werber D.
        • Cramer J.P.
        • et al.
        Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany.
        N Engl J Med. 2011; 365: 1771-1780
        • Ake J.A.
        • Jelacic S.
        • Ciol M.A.
        • et al.
        Relative nephroprotection during Escherichia coli O157:H7 infections: association with intravenous volume expansion.
        Pediatrics. 2005; 115: e673-e680
        • Garg A.X.
        • Suri R.S.
        • Barrowman N.
        • et al.
        Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression.
        JAMA. 2003; 290: 1360-1370
        • Spinale J.M.
        • Ruebner R.L.
        • Kaplan B.S.
        • et al.
        Update on Streptococcus pneumoniae associated hemolytic uremic syndrome.
        Curr Opin Pediatr. 2013; 25: 203-208
        • Waters A.M.
        • Kerecuk L.
        • Luk D.
        • et al.
        Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United Kingdom experience.
        J Pediatr. 2007; 151: 140-144
        • Constantinescu A.R.
        • Bitzan M.
        • Weiss L.S.
        • et al.
        Non-enteropathic hemolytic uremic syndrome: causes and short-term course.
        Am J Kidney Dis. 2004; 43: 976-982
        • Shimizu M.
        • Yokoyama T.
        • Sakashita N.
        • et al.
        Thomsen-Friedenreich antigen exposure as a cause of Streptococcus pyogenes-associated hemolytic-uremic syndrome.
        Clin Nephrol. 2012; 78: 328-331
        • Zimmerhackl L.B.
        • Besbas N.
        • Jungraithmayr T.
        • et al.
        Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome.
        Semin Thromb Hemost. 2006; 32: 113-120
        • Fremeaux-Bacchi V.
        • Fakhouri F.
        • Garnier A.
        • et al.
        Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.
        Clin J Am Soc Nephrol. 2013; 8: 554-562
        • Sheerin N.S.
        • Kavanagh D.
        • Goodship T.H.
        • et al.
        A national specialized service in England for atypical haemolytic uraemic syndrome-the first year's experience.
        QJM. 2016; 109: 27-33
        • Johnson S.
        • Stojanovic J.
        • Ariceta G.
        • et al.
        An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome.
        Pediatr Nephrol. 2014; 29: 1967-1978
        • Loirat C.
        • Fremeaux-Bacchi V.
        Atypical hemolytic uremic syndrome.
        Orphanet J Rare Dis. 2011; 6: 60
        • Taylor C.M.
        • Machin S.
        • Wigmore S.J.
        • et al.
        Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom.
        Br J Haematol. 2010; 148: 37-47
        • Veesenmeyer A.F.
        • Edmonson M.B.
        Trends in US hospital stays for Streptococcus pneumoniae-associated hemolytic uremic syndrome.
        Pediatr Infect Dis J. 2013; 32: 731-735
        • Scallan E.
        • Crim S.M.
        • Runkle A.
        • et al.
        Bacterial enteric infections among older adults in the United States: foodborne diseases active surveillance network, 1996-2012.
        Foodborne Pathog Dis. 2015; 12: 492-499
        • Safdar N.
        • Said A.
        • Gangnon R.E.
        • et al.
        Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis.
        JAMA. 2002; 288: 996-1001
        • Ardissino G.
        • Dacco V.
        • Testa S.
        • et al.
        Hemoconcentration: a major risk factor for neurological involvement in hemolytic uremic syndrome.
        Pediatr Nephrol. 2015; 30: 345-352
        • Campistol J.M.
        • Arias M.
        • Ariceta G.
        • et al.
        An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.
        Nefrologia. 2015; 35: 421-447
        • Franchini M.
        Atypical hemolytic uremic syndrome: from diagnosis to treatment.
        Clin Chem Lab Med. 2015; 53: 1679-1688
        • Thurman J.M.
        • Marians R.
        • Emlen W.
        • et al.
        Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome.
        Clin J Am Soc Nephrol. 2009; 4: 1920-1924
        • Masias C.
        • Vasu S.
        • Cataland S.R.
        None of the above: thrombotic microangiopathy beyond TTP and HUS.
        Blood. 2017; 129: 2857-2863
        • Thachil J.
        • Warkentin T.E.
        How do we approach thrombocytopenia in critically ill patients?.
        Br J Haematol. 2017; 177: 27-38
        • Boral B.M.
        • Williams D.J.
        • Boral L.I.
        Disseminated intravascular coagulation.
        Am J Clin Pathol. 2016; 146: 670-680
        • Joly B.S.
        • Coppo P.
        • Veyradier A.
        Thrombotic thrombocytopenic purpura.
        Blood. 2017; 129: 2836-2846
        • Trachtman H.
        HUS and TTP in children.
        Pediatr Clin North Am. 2013; 60: 1513-1526
        • Legendre C.M.
        • Licht C.
        • Muus P.
        • et al.
        Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.
        N Engl J Med. 2013; 368: 2169-2181
        • Coppo P.
        • Schwarzinger M.
        • Buffet M.
        • et al.
        Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience.
        PLoS One. 2010; 5: e10208
        • Bentley M.J.
        • Lehman C.M.
        • Blaylock R.C.
        • et al.
        The utility of patient characteristics in predicting severe ADAMTS13 deficiency and response to plasma exchange.
        Transfusion. 2010; 50: 1654-1664
        • Bendapudi P.K.
        • Hurwitz S.
        • Fry A.
        • et al.
        Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study.
        Lancet Haematol. 2017; 4: e157-e164
        • Bentley M.J.
        • Wilson A.R.
        • Rodgers G.M.
        Performance of a clinical prediction score for thrombotic thrombocytopenic purpura in an independent cohort.
        Vox Sang. 2013; 105: 313-318
        • Li A.
        • Khalighi P.R.
        • Wu Q.
        • et al.
        External validation of the PLASMIC score: a clinical prediction tool for thrombotic thrombocytopenic purpura diagnosis and treatment.
        J Thromb Haemost. 2018; 16: 164-169
        • Laurence J.
        • Haller H.
        • Mannucci P.M.
        • et al.
        Atypical hemolytic uremic syndrome (aHUS): essential aspects of an accurate diagnosis.
        Clin Adv Hematol Oncol. 2016; 14 Suppl 11: 2-15
        • Grys T.E.
        • Sloan L.M.
        • Rosenblatt J.E.
        • et al.
        Rapid and sensitive detection of Shiga toxin-producing Escherichia coli from nonenriched stool specimens by real-time PCR in comparison to enzyme immunoassay and culture.
        J Clin Microbiol. 2009; 47: 2008-2012
        • Copelovitch L.
        • Kaplan B.S.
        Streptococcus pneumoniae--associated hemolytic uremic syndrome: classification and the emergence of serotype 19A.
        Pediatrics. 2010; 125: e174-e182
        • Azoulay E.
        • Knoebl P.
        • Garnacho-Montero J.
        • et al.
        Expert statements on the standard of care in critically ill adult patients with atypical hemolytic uremic syndrome.
        Chest. 2017; 152: 424-434
        • Ohanian M.
        • Cable C.
        • Halka K.
        Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndrome.
        Clin Pharmacol. 2011; 3: 5-12
        • Castro V.S.
        • Figueiredo E.E.S.
        • Stanford K.
        • et al.
        Shiga-toxin producing Escherichia coli in Brazil: a systematic review.
        Microorganisms. 2019; 7 ([pii:E137])
        • Council of State and Territorial Epidemiologists
        Public Health reporting and National Notification for Shiga toxin-producing Escherichia coli (STEC).
        Council of State and Territorial Epidemiologists, Atlanta (Georgia)2017
        • Cody E.M.
        • Dixon B.P.
        Hemolytic uremic syndrome.
        Pediatr Clin North Am. 2019; 66: 235-246
        • Orth D.
        • Khan A.B.
        • Naim A.
        • et al.
        Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome.
        J Immunol. 2009; 182: 6394-6400
        • Liu F.
        • Huang J.
        • Sadler J.E.
        Shiga toxin (Stx)1B and Stx2B induce von Willebrand factor secretion from human umbilical vein endothelial cells through different signaling pathways.
        Blood. 2011; 118: 3392-3398
        • Petruzziello-Pellegrini T.N.
        • Marsden P.A.
        Shiga toxin-associated hemolytic uremic syndrome: advances in pathogenesis and therapeutics.
        Curr Opin Nephrol Hypertens. 2012; 21: 433-440
        • Morigi M.
        • Galbusera M.
        • Gastoldi S.
        • et al.
        Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis.
        J Immunol. 2011; 187: 172-180
        • Monnens L.
        • Molenaar J.
        • Lambert P.H.
        • et al.
        The complement system in hemolytic-uremic syndrome in childhood.
        Clin Nephrol. 1980; 13: 168-171
        • Nathanson S.
        • Kwon T.
        • Elmaleh M.
        • et al.
        Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome.
        Clin J Am Soc Nephrol. 2010; 5: 1218-1228
        • Talarico V.
        • Aloe M.
        • Monzani A.
        • et al.
        Hemolytic uremic syndrome in children.
        Minerva Pediatr. 2016; 68: 441-455
        • Borowitz M.J.
        • Craig F.E.
        • Digiuseppe J.A.
        • et al.
        Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry.
        Cytometry B Clin Cytom. 2010; 78: 211-230
        • Shibagaki Y.
        • Fujita T.
        Thrombotic microangiopathy in malignant hypertension and hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP): can we differentiate one from the other?.
        Hypertens Res. 2005; 28: 89-95
        • Hickey C.A.
        • Beattie T.J.
        • Cowieson J.
        • et al.
        Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.
        Arch Pediatr Adolesc Med. 2011; 165: 884-889
        • Smith K.E.
        • Wilker P.R.
        • Reiter P.L.
        • et al.
        Antibiotic treatment of Escherichia coli O157 infection and the risk of hemolytic uremic syndrome, Minnesota.
        Pediatr Infect Dis J. 2012; 31: 37-41
        • Wong C.S.
        • Jelacic S.
        • Habeeb R.L.
        • et al.
        The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections.
        N Engl J Med. 2000; 342: 1930-1936
        • Beneke J.
        • Sartison A.
        • Kielstein J.T.
        • et al.
        Clinical and laboratory consequences of platelet transfusion in shiga toxin-mediated hemolytic uremic syndrome.
        Transfus Med Rev. 2017; 31: 51-55
        • Balestracci A.
        • Martin S.M.
        • Toledo I.
        • et al.
        Impact of platelet transfusions in children with post-diarrheal hemolytic uremic syndrome.
        Pediatr Nephrol. 2013; 28: 919-925
        • Balestracci A.
        • Martin S.M.
        • Toledo I.
        Hemoconcentration in hemolytic uremic syndrome: time to review the standard case definition?.
        Pediatr Nephrol. 2015; 30: 361
        • Weil B.R.
        • Andreoli S.P.
        • Billmire D.F.
        Bleeding risk for surgical dialysis procedures in children with hemolytic uremic syndrome.
        Pediatr Nephrol. 2010; 25: 1693-1698
        • Keenswijk W.
        • Raes A.
        • De Clerck M.
        • et al.
        Is plasma exchange efficacious in shiga toxin-associated hemolytic uremic syndrome? A narrative review of current evidence.
        Ther Apher Dial. 2019; 23: 118-125
        • Menne J.
        • Nitschke M.
        • Stingele R.
        • et al.
        Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study.
        BMJ. 2012; 345: e4565
        • Spinale J.M.
        • Ruebner R.L.
        • Copelovitch L.
        • et al.
        Long-term outcomes of Shiga toxin hemolytic uremic syndrome.
        Pediatr Nephrol. 2013; 28: 2097-2105
        • Spizzirri F.D.
        • Rahman R.C.
        • Bibiloni N.
        • et al.
        Childhood hemolytic uremic syndrome in Argentina: long-term follow-up and prognostic features.
        Pediatr Nephrol. 1997; 11: 156-160
        • Small G.
        • Watson A.R.
        • Evans J.H.
        • et al.
        Hemolytic uremic syndrome: defining the need for long-term follow-up.
        Clin Nephrol. 1999; 52: 352-356
        • Siegler R.
        • Oakes R.
        Hemolytic uremic syndrome; pathogenesis, treatment, and outcome.
        Curr Opin Pediatr. 2005; 17: 200-204
        • Rahman R.C.
        • Cobenas C.J.
        • Drut R.
        • et al.
        Hemorrhagic colitis in postdiarrheal hemolytic uremic syndrome: retrospective analysis of 54 children.
        Pediatr Nephrol. 2012; 27: 229-233
        • Suri R.S.
        • Mahon J.L.
        • Clark W.F.
        • et al.
        Relationship between Escherichia coli O157:H7 and diabetes mellitus.
        Kidney Int Suppl. 2009; : S44-S46
        • Theobald I.
        • Kuwertz-Broking E.
        • Schiborr M.
        • et al.
        Central nervous system involvement in hemolytic uremic syndrome (HUS)--a retrospective analysis of cerebral CT and MRI studies.
        Clin Nephrol. 2001; 56: S3-S8
        • Bennett B.
        • Booth T.
        • Quan A.
        Late onset seizures, hemiparesis and blindness in hemolytic uremic syndrome.
        Clin Nephrol. 2003; 59: 196-200
        • Noris M.
        • Caprioli J.
        • Bresin E.
        • et al.
        Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.
        Clin J Am Soc Nephrol. 2010; 5: 1844-1859
        • Mannucci P.M.
        Understanding organ dysfunction in thrombotic thrombocytopenic purpura.
        Intensive Care Med. 2015; 41: 715-718
        • Caprioli J.
        • Noris M.
        • Brioschi S.
        • et al.
        Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.
        Blood. 2006; 108: 1267-1279
        • Buddles M.R.
        • Donne R.L.
        • Richards A.
        • et al.
        Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.
        Am J Hum Genet. 2000; 66: 1721-1722
        • Fremeaux-Bacchi V.
        • Miller E.C.
        • Liszewski M.K.
        • et al.
        Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome.
        Blood. 2008; 112: 4948-4952
        • Sansbury F.H.
        • Cordell H.J.
        • Bingham C.
        • et al.
        Factors determining penetrance in familial atypical haemolytic uraemic syndrome.
        J Med Genet. 2014; 51: 756-764
        • 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: 2-3
        • Geerdink L.M.
        • Westra D.
        • van Wijk J.A.
        • et al.
        Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics.
        Pediatr Nephrol. 2012; 27: 1283-1291
        • Dragon-Durey M.A.
        • Loirat C.
        • Cloarec S.
        • et al.
        Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome.
        J Am Soc Nephrol. 2005; 16: 555-563
        • Kernan K.F.
        • Ghaloul-Gonzalez L.
        • Shakoory B.
        • et al.
        Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation.
        Genes Immun. 2019; 20: 520-526
        • Lemaire M.
        • Fremeaux-Bacchi V.
        • Schaefer F.
        • et al.
        Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.
        Nat Genet. 2013; 45: 531-536
        • Scully M.
        • Hunt B.J.
        • Benjamin S.
        • et al.
        Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies.
        Br J Haematol. 2012; 158: 323-335
        • Cataland S.R.
        • Holers V.M.
        • Geyer S.
        • et al.
        Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP.
        Blood. 2014; 123: 3733-3738
        • Gerber A.
        • Karch H.
        • Allerberger F.
        • et al.
        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. 2002; 186: 493-500
        • Licht C.
        • Greenbaum L.A.
        • Muus P.
        • et al.
        Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies.
        Kidney Int. 2015; 87: 1061-1073
        • Greenbaum L.A.
        • Fila M.
        • Ardissino G.
        • et al.
        Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.
        Kidney Int. 2016; 89: 701-711
        • Fakhouri F.
        • Hourmant M.
        • Campistol J.M.
        • et al.
        Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial.
        Am J Kidney Dis. 2016; 68: 84-93
        • Goodship T.H.J.
        • Cook H.T.
        • 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: 539-551
        • Cataland S.R.
        • Wu H.M.
        How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome.
        Blood. 2014; 123: 2478-2484
        • Povey H.
        • Vundru R.
        • Junglee N.
        • et al.
        Renal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysis.
        Clin Nephrol. 2014; 82: 326-331
        • Cavero T.
        • Rabasco C.
        • Lopez A.
        • et al.
        Eculizumab in secondary atypical haemolytic uraemic syndrome.
        Nephrol Dial Transpl. 2017; 32: 466-474
        • Cochran J.B.
        • Panzarino V.M.
        • Maes L.Y.
        • et al.
        Pneumococcus-induced T-antigen activation in hemolytic uremic syndrome and anemia.
        Pediatr Nephrol. 2004; 19: 317-321
        • Huang D.T.
        • Chi H.
        • Lee H.C.
        • et al.
        T-antigen activation for prediction of pneumococcus-induced hemolytic uremic syndrome and hemolytic anemia.
        Pediatr Infect Dis J. 2006; 25: 608-610
        • Szilagyi A.
        • Gyorke Z.
        • Bereczki C.
        • et al.
        The use of a rapid fluorogenic neuraminidase assay to differentiate acute Streptococcus pneumoniae-associated hemolytic uremic syndrome (HUS) from other forms of HUS.
        Clin Chem Lab Med. 2015; 53: e117-e119
        • Geary D.F.
        Hemolytic uremic syndrome and streptococcus pneumoniae: improving our understanding.
        J Pediatr. 2007; 151: 113-114
        • Smith A.
        • Johnston C.
        • Inverarity D.
        • et al.
        Investigating the role of pneumococcal neuraminidase A activity in isolates from pneumococcal haemolytic uraemic syndrome.
        J Med Microbiol. 2013; 62: 1735-1742
        • Meinel C.
        • Sparta G.
        • Dahse H.M.
        • et al.
        Streptococcus pneumoniae from patients with hemolytic uremic syndrome binds human plasminogen via the surface protein PspC and uses plasmin to damage human endothelial cells.
        J Infect Dis. 2018; 217: 358-370
        • Bitzan M.
        • AlKandari O.
        • Whittemore B.
        • et al.
        Complement depletion and Coombs positivity in pneumococcal hemolytic uremic syndrome (pnHUS). Case series and plea to revisit an old pathogenetic concept.
        Int J Med Microbiol. 2018; 308: 1096-1104
        • Szilagyi A.
        • Kiss N.
        • Bereczki C.
        • et al.
        The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome.
        Nephrol Dial Transpl. 2013; 28: 2237-2245
        • Banerjee R.
        • Hersh A.L.
        • Newland J.
        • et al.
        Streptococcus pneumoniae-associated hemolytic uremic syndrome among children in North America.
        Pediatr Infect Dis J. 2011; 30: 736-739
        • Cabrera G.R.
        • Fortenberry J.D.
        • Warshaw B.L.
        • et al.
        Hemolytic uremic syndrome associated with invasive Streptococcus pneumoniae infection.
        Pediatrics. 1998; 101: 699-703
        • Kaplan S.L.
        • Mason Jr., E.O.
        • Barson W.J.
        • et al.
        Three-year multicenter surveillance of systemic pneumococcal infections in children.
        Pediatrics. 1998; 102: 538-545
        • Krysan D.J.
        • Flynn J.T.
        Renal transplantation after Streptococcus pneumoniae-associated hemolytic uremic syndrome.
        Am J Kidney Dis. 2001; 37: E15
        • Copelovitch L.
        • Kaplan B.S.
        Streptococcus pneumoniae-associated hemolytic uremic syndrome.
        Pediatr Nephrol. 2008; 23: 1951-1956
        • Huang Y.H.
        • Lin T.Y.
        • Wong K.S.
        • et al.
        Hemolytic uremic syndrome associated with pneumococcal pneumonia in Taiwan.
        Eur J Pediatr. 2006; 165: 332-335
        • Brandt J.
        • Wong C.
        • Mihm S.
        • et al.
        Invasive pneumococcal disease and hemolytic uremic syndrome.
        Pediatrics. 2002; 110: 371-376
        • Angurana S.K.
        • Mehta A.
        • Agrawal T.
        • et al.
        Streptococcus pneumoniae-associated hemolytic uremic syndrome.
        Indian J Pediatr. 2018; 85: 797-799
        • Kumar N.D.
        • Sethi S.
        T-transformed red cells--role of minor cross-match in patients with T antigen activation.
        Vox Sang. 1993; 64: 129
        • Lee C.S.
        • Chen M.J.
        • Chiou Y.H.
        • et al.
        Invasive pneumococcal pneumonia is the major cause of paediatric haemolytic-uraemic syndrome in Taiwan.
        Nephrology (Carlton). 2012; 17: 48-52
        • von Vigier R.O.
        • Seibel K.
        • Bianchetti M.G.
        Positive Coombs test in pneumococcus-associated hemolytic uremic syndrome. A review of the literature.
        Nephron. 1999; 82: 183-184
        • Osborn D.A.
        • Lui K.
        • Pussell P.
        • et al.
        T and Tk antigen activation in necrotising enterocolitis: manifestations, severity of illness, and effectiveness of testing.
        Arch Dis Child Fetal Neonatal Ed. 1999; 80: F192-F197
        • Petras M.L.
        • Dunbar N.M.
        • Filiano J.J.
        • et al.
        Therapeutic plasma exchange in Streptococcus pneumoniae-associated hemolytic uremic syndrome: a case report.
        J Clin Apher. 2012; 27: 212-214
        • Anastaze Stelle K.
        • Cachat F.
        • Perez M.H.
        • et al.
        Streptococcus pneumoniae-associated hemolytic and uremic syndrome with cholestasis: a case report and brief literature review.
        Clin Pediatr (Phila). 2016; 55: 189-191
        • Fakhouri F.
        • Roumenina L.
        • Provot F.
        • et al.
        Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.
        J Am Soc Nephrol. 2010; 21: 859-867
        • Jim B.
        • Garovic V.D.
        Acute kidney injury in pregnancy.
        Semin Nephrol. 2017; 37: 378-385
        • De Sousa Amorim E.
        • Blasco M.
        • Quintana L.
        • et al.
        Eculizumab in pregnancy-associated atypical hemolytic uremic syndrome: insights for optimizing management.
        J Nephrol. 2015; 28: 641-645
        • Zschiedrich S.
        • Prager E.P.
        • Kuehn E.W.
        Successful treatment of the postpartum atypical hemolytic uremic syndrome with eculizumab.
        Ann Intern Med. 2013; 159: 76
        • Ardissino G.
        • Wally Ossola M.
        • Baffero G.M.
        • et al.
        Eculizumab for atypical hemolytic uremic syndrome in pregnancy.
        Obstet Gynecol. 2013; 122: 487-489
        • Bonser R.S.
        • Adu D.
        • Franklin I.
        • et al.
        Cyclosporin-induced haemolytic uraemic syndrome in liver allograft recipient.
        Lancet. 1984; 2: 1337
        • Young B.A.
        • Marsh C.L.
        • Alpers C.E.
        • et al.
        Cyclosporine-associated thrombotic microangiopathy/hemolytic uremic syndrome following kidney and kidney-pancreas transplantation.
        Am J Kidney Dis. 1996; 28: 561-571
        • Besbas N.
        • Karpman D.
        • Landau D.
        • et al.
        A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders.
        Kidney Int. 2006; 70: 423-431
        • Noris M.
        • Remuzzi G.
        Thrombotic microangiopathy after kidney transplantation.
        Am J Transplant. 2010; 10: 1517-1523
        • Al-Nouri Z.L.
        • Reese J.A.
        • Terrell D.R.
        • et al.
        Drug-induced thrombotic microangiopathy: a systematic review of published reports.
        Blood. 2015; 125: 616-618
        • Reese J.A.
        • Bougie D.W.
        • Curtis B.R.
        • et al.
        Drug-induced thrombotic microangiopathy: experience of the Oklahoma Registry and the BloodCenter of Wisconsin.
        Am J Hematol. 2015; 90: 406-410
        • Medina P.J.
        • Sipols J.M.
        • George J.N.
        Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
        Curr Opin Hematol. 2001; 8: 286-293
        • Page E.E.
        • Little D.J.
        • Vesely S.K.
        • et al.
        Quinine-induced thrombotic microangiopathy: a report of 19 patients.
        Am J Kidney Dis. 2017; 70: 686-695
        • Walport M.J.
        Complement. First of two parts.
        N Engl J Med. 2001; 344: 1058-1066