Advertisement

The Role of Complement in the Pathogenesis of HUS and the TMA Spectrum Disorders

  • Erin Jacobs
  • Carolina Ortiz
  • Christoph LichtEmail author
Renal (D Noone, Section Editor)
Part of the following topical collections:
  1. Renal

Abstract

Purpose of Review

This review aims to examine the current definitions of primary and secondary hemolytic uremic syndromes. Specifically, it seeks to determine which external conditions can result in secondary Thrombotic microangiopathy (TMA), which can trigger cases of primary atypical uremic syndromes (aHUS), and the role of complement in the pathogenesis of TMA spectrum disorders.

Recent Findings

Building on the growing insight about the pathogenic role of dysregulation of the alternative complement pathway in primary aHUS, the successful use of complement-blocking treatment in cases of thrombotic microangiopathy with coexisting conditions (secondary TMA), along with the identification of complement mutations in some of these cases, indicates a so far possibly under-appreciated pathogenic role for complement in diagnoses within the TMA spectrum.

Summary

Uncontrolled complement activity and pro-thrombotic environments represent a unifying pathogenic mechanism in aHUS and the TMA spectrum disorders and point towards shared diagnostic and therapeutic pathways.

Keywords

Thrombotic microangiopathy Atypical hemolytic uremic syndrome Complement system 

Abbreviations

ADAMTS13

A disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13

AP

Alternative pathway (complement system)

aHUS

Atypical hemolytic uremic syndrome

CMV

Cytomegaloviruses

CP

Classical pathway (complement system)

DEAP-HUS

Deficiency of CFHR plasma proteins and autoantibody-positive form of _______hemolytic uremic syndrome

DGKE

Diacylglycerol kinase epsilon

ESRD

End-stage renal disease

FB

Factor B

FH

Factor H

FHR

Factor H–related protein

FI

Factor I

HELLP

Hemolysis, elevated liver enzymes, and low platelet count

HSCT

Hematopoietic stem cell transplantation

HUS

Hemolytic uremic syndrome

INF2

Inverted formin-2

LP

Lectin pathway (complement system)

MAC

Membrane attack complex

MAHA

Microangiopathic hemolytic anemia

MBL

Mannose-binding lectin

MCP

Membrane cofactor protein (CD46)

SCR

Short consensus repeat

STEC-HUS/eHUS

Shiga toxin–producing E. coli mediated HUS

Stx

Shiga toxin

THBD

Thrombomodulin (CD141)

TMA

Thrombotic microangiopathy

TTP

Thrombotic thrombocytopenic purpura

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

  1. 1.
    George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654–66.CrossRefPubMedGoogle Scholar
  2. 2.
    Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16(4):1035–50.CrossRefPubMedGoogle Scholar
  3. 3.
    Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33(6):508–30.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mayer CL, Leibowitz CS, Kurosawa S, Stearns-Kurosawa DJ. Shiga toxins and the pathophysiology of hemolytic uremic syndrome in humans and animals. Toxins. 2012;4(11):1261–87.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344(14):1058–66.CrossRefGoogle Scholar
  6. 6.
    Keating GM. Eculizumab: a review of its use in atypical haemolytic uraemic syndrome. Drugs. 2013;73(18):2053–66.CrossRefPubMedGoogle Scholar
  7. 7.
    Schaefer F, Ardissino G, Ariceta G, Fakhouri F, Scully M, Isbel N, et al. Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome. Kidney Int. 2018;94(2):408–18.CrossRefPubMedGoogle Scholar
  8. 8.
    Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clinical journal of the American Society of Nephrology : CJASN. 2010;5(10):1844–59.CrossRefPubMedGoogle Scholar
  9. 9.
    Brocklebank V, Wood KM, Kavanagh D. Thrombotic microangiopathy and the kidney. Clin J Am Soc Nephrol. 2018;13(2):300–17.CrossRefPubMedGoogle Scholar
  10. 10.
    Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368(23):2169–81.CrossRefPubMedGoogle Scholar
  11. 11.
    Riedl M, Fakhouri F, Le Quintrec M, Noone DG, Jungraithmayr TC, Fremeaux-Bacchi V, et al. Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches. Semin Thromb Hemost. 2014;40(4):444–64.CrossRefPubMedGoogle Scholar
  12. 12.
    Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343(1):227–35.CrossRefPubMedGoogle Scholar
  13. 13.
    Kavanagh D, Goodship T. Genetics and complement in atypical HUS. Pediatr Nephrol. 2010;25(12):2431–42.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ferreira VP, Pangburn MK, Cortes C. Complement control protein factor H: the good, the bad, and the inadequate. Mol Immunol. 2010;47(13):2187–97.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Stahl AL, Vaziri-Sani F, Heinen S, Kristoffersson AC, Gydell KH, Raafat R, et al. Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation. Blood. 2008;111(11):5307–15.CrossRefPubMedGoogle Scholar
  16. 16.
    Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(17):1676–87.CrossRefPubMedGoogle Scholar
  17. 17.
    Atkinson JP, Goodship THJ. Complement factor H and the hemolytic uremic syndrome. J Exp Med. 2007;204:1245–8.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010;31(6):E1445–60.CrossRefPubMedGoogle Scholar
  19. 19.
    Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, et al. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol. 2007;44(1–3):111–22.CrossRefPubMedGoogle Scholar
  20. 20.
    Schramm EC, Roumenina LT, Rybkine T, Chauvet S, Vieira-Martins P, Hue C, et al. Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome. Blood. 2015;125(15):2359–69.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kavanagh D, Pappworth IY, Anderson H, Hayes CM, Moore I, Hunze EM, et al. Factor I autoantibodies in patients with atypical hemolytic uremic syndrome: disease-associated or an epiphenomenon? Clin J Am Soc Nephrol. 2012;7(3):417–26.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Noone D, Waters A, Pluthero FG, Geary DF, Kirschfink M, Zipfel PF, et al. Successful treatment of DEAP-HUS with eculizumab. Pediatr Nephrol. 2014;29(5):841–51.CrossRefPubMedGoogle Scholar
  23. 23.
    Weiler H, Isermann BH. Thrombomodulin. J Thromb Haemost. 2003;1(7):1515–24.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Delvaeye M, DeVriese A, Moons M, Esmon N, Esmon C, Conway EM. Regulation of complement activation by thrombomodulin. Blood: American Society of Hematology; 2009. p. 5127.Google Scholar
  25. 25.
    Bu F, Maga T, Meyer NC, Wang K, Thomas CP, Nester CM, et al. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2014;25(1):55–64.CrossRefPubMedGoogle Scholar
  26. 26.
    Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45(5):531–6.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hofer J, Janecke AR, Zimmerhackl LB, Riedl M, Rosales A, Giner T, et al. Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2013;8(3):407–15.CrossRefPubMedGoogle Scholar
  28. 28.
    Hofer J, Giner T, Jozsi M. Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment. Semin Thromb Hemost. 2014;40(4):431–43.CrossRefPubMedGoogle Scholar
  29. 29.
    Zipfel PF, Mache C, Muller D, Licht C, Wigger M, Skerka C. DEAP-HUS: deficiency of CFHR plasma proteins and autoantibody-positive form of hemolytic uremic syndrome. Pediatr Nephrol. 2010;25(10):2009–19.CrossRefPubMedGoogle Scholar
  30. 30.
    Marinozzi MC, Vergoz L, Rybkine T, Ngo S, Bettoni S, Pashov A, et al. Complement factor B mutations in atypical hemolytic uremic syndrome—disease-relevant or benign? J Am Soc Nephrol. 2014;25(9):2053–65.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, et al. Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int. 2014;85(5):1151–60.CrossRefPubMedGoogle Scholar
  32. 32.
    Azukaitis K, Simkova E, Majid MA, Galiano M, Benz K, Amann K, et al. The phenotypic spectrum of nephropathies associated with mutations in diacylglycerol kinase epsilon. J Am Soc Nephrol. 2017;28(10):3066–75.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Challis RC, Ring T, Xu Y, Wong EKS, Flossmann O, Roberts ISD, et al. Thrombotic microangiopathy in inverted formin 2–mediated renal disease. J Am Soc Nephrol. 2017;28:1084–91.CrossRefPubMedGoogle Scholar
  34. 34.
    Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016;31(1):15–39.CrossRefPubMedGoogle Scholar
  35. 35.
    Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr. 2013;25(2):203–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Watanabe T. Renal complications of seasonal and pandemic influenza A virus infections. Eur J Pediatr. 2013;172(1):15–22.CrossRefPubMedGoogle Scholar
  37. 37.
    Freist M, Garrouste C, Szlavik N, Coppo P, Lautrette A, Heng AE. Efficacy of eculizumab in an adult patient with HIV-associated hemolytic uremic syndrome: a case report. Medicine. 2017;96(51):e9358.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Saab KR, Elhadad S, Copertino D, Laurence J. Thrombotic microangiopathy in the setting of HIV infection: a case report and review of the differential diagnosis and therapy. AIDS Patient Care STDs. 2016;30(8):359–64.CrossRefPubMedGoogle Scholar
  39. 39.
    Jin A, Boroujerdi-Rad L, Shah G, Chen JL. Thrombotic microangiopathy and human immunodeficiency virus in the era of eculizumab. Clin Kidney J. 2016;9(4):576–9.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    van Hoeve K, Vandermeulen C, Van Ranst M, Levtchenko E, van den Heuvel L, Mekahli D. Occurrence of atypical HUS associated with influenza B. Eur J Pediatr. 2017;176(4):449–54.CrossRefPubMedGoogle Scholar
  41. 41.
    Mittal N, Hartemayer R, Jandeska S, Giordano L. Steroid responsive atypical hemolytic uremic syndrome triggered by influenza B infection. J Pediatr Hematol Oncol. 2018.Google Scholar
  42. 42.
    Kobbe R, Schild R, Christner M, Oh J, Loos S, Kemper MJ. Case report - atypical hemolytic uremic syndrome triggered by influenza B. BMC Nephrol. 2017;18(1):96.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Brocklebank V, Wong EKS, Fielding R, Goodship THJ, Kavanagh D. Atypical haemolytic uraemic syndrome associated with a CD46 mutation triggered by Shigella flexneri. Clin Kidney J. 2014;7(3):286–8.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Miklaszewska M, Zachwieja K, Drozdz D, Pallinger E, Takacs B, Szilagyi A, et al. Hemolytic uremic syndrome with mycoplasma pneumoniae infection and membrane cofactor protein mutation - case report. Przegl Lek. 2016;73(11):862–4.PubMedGoogle Scholar
  45. 45.
    Omura T, Watanabe E, Otsuka Y, Yoshida Y, Kato H, Nangaku M, et al. Complete remission of thrombotic microangiopathy after treatment with eculizumab in a patient with non-Shiga toxin-associated bacterial enteritis: a case report. Medicine. 2016;95(27):e4104.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Lee MD, Tzen CY, Lin CC, Huang FY, Liu HC, Tsai JD. Hemolytic uremic syndrome caused by enteroviral infection. Pediatr Neonatol. 2013;54(3):207–10.CrossRefPubMedGoogle Scholar
  47. 47.
    Java A, Edwards A, Rossi A, Pandey R, Gaut J, Delos Santos R, et al. Cytomegalovirus-induced thrombotic microangiopathy after renal transplant successfully treated with eculizumab: case report and review of the literature. Transpl Int. 2015;28(9):1121–5.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Fraga-Rodriguez GM, Brio-Sanagustin S, Turon-Vinas E, Dixon BP, Carreras-Gonzalez E. Eculizumab in a child with atypical haemolytic uraemic syndrome and haemophagocytic lymphohistiocytosis triggered by cytomegalovirus infection. BMJ Case Rep. 2017.Google Scholar
  49. 49.
    Mathur P, Hollowoa B, Lala N, Thanendrarajan S, Matin A, Kothari A, et al. Enterococcus raffinosus infection with atypical hemolytic uremic syndrome in a multiple myeloma patient after autologous stem cell transplant. Hematol Rep. 2017;9(3):7094.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Inglis JM, Barbara JA, Juneja R, Milton C, Passaris G, Li JYZ. Atypical haemolytic uraemic syndrome associated with Clostridium difficile infection successfully treated with eculizumab. Case Rep Nephrol. 2018;2018:1759138.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Condom P, Mansuy JM, Decramer S, Izopet J, Mengelle C. Atypical hemolytic uremic syndrome triggered by varicella infection. IDCases. 2017;9:89–90.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Buyon JP. Systemic lupus erythematosus. In: Klipper J, Stone J, Crofford L, White P, editors. Primer on the rheumatic diseases. Springer: Springer; 2008. p. 303–38.Google Scholar
  53. 53.
    de Holanda MI, Porto LC, Wagner T, Christiani LF, Palma LMP. Use of eculizumab in a systemic lupus erythemathosus patient presenting thrombotic microangiopathy and heterozygous deletion in CFHR1-CFHR3. A case report and systematic review. Clin Rheumatol. 2017;36(12):2859–67.CrossRefPubMedGoogle Scholar
  54. 54.
    Bermea RS, Sharma N, Cohen K, Liarski VM. Use of eculizumab in atypical hemolytic uremic syndrome, complicating systemic lupus erythematosus. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2016;22(6):320–3.CrossRefGoogle Scholar
  55. 55.
    El-Husseini A, Hannan S, Awad A, Jennings S, Cornea V, Sawaya BP. Thrombotic microangiopathy in systemic lupus erythematosus: efficacy of eculizumab. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2015;65(1):127–30.CrossRefGoogle Scholar
  56. 56.
    Raufi AG, Scott S, Darwish O, Harley K, Kahlon K, Desai S, et al. Atypical hemolytic uremic syndrome secondary to lupus nephritis. Responsive to Eculizumab Hematology reports. 2016;8(3):6625.PubMedGoogle Scholar
  57. 57.
    Attar RZ, Ramel EI, Safdar OY, Desoky S. A case of patient with renal lupus with an initial presentation of hemolytic uremic syndrome triggered by streptococcal infection. Clinical case reports. 2018;6(4):712–8.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Ono M, Ohashi N, Namikawa A, Katahashi N, Ishigaki S, Tsuji N, et al. A rare case of lupus nephritis presenting as thrombotic microangiopathy with diffuse pseudotubulization possibly caused by atypical hemolytic uremic syndrome. Intern Med. 2018;57(11):1617–23.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Coppo R, Peruzzi L, Amore A, Martino S, Vergano L, Lastauka I, et al. Dramatic effects of eculizumab in a child with diffuse proliferative lupus nephritis resistant to conventional therapy. Pediatr Nephrol. 2015;30(1):167–72.CrossRefPubMedGoogle Scholar
  60. 60.
    Weitz IC. Thrombotic microangiopathy in cancer. Thromb Res. 2018;164(Suppl 1):S103–s5.CrossRefPubMedGoogle Scholar
  61. 61.
    Sussman TA, Abazeed M, McCrae K, Khorana AA. RNA sequencing approached to identify novel biomarkers for venous thromboembolism (VTE) in lung cancer. Blood: Am Soc Hematol; 2017. p. 554.Google Scholar
  62. 62.
    Krisinger MJ, Goebeler V, Lu Z, Meixner SC, Myles T, Pryzdial EL, et al. Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Blood. 2012;120(8):1717–25.CrossRefPubMedGoogle Scholar
  63. 63.
    Krishnappa V, Gupta M, Shah H, Das A, Tanphaichitr N, Novak R, et al. The use of eculizumab in gemcitabine induced thrombotic microangiopathy. BMC Nephrol. 2018;19(1):9.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129–36.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Blake-Haskins JA, Lechleider RJ, Kreitman RJ. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res. 2011;17(18):5858–66.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Allison SJ. VEGF–complement interactions.Google Scholar
  67. 67.
    Quinn CT. Minireview: clinical severity in sickle cell disease: the challenges of definition and prognostication. Exp Biol Med (Maywood). 2016;241(7):679–88.CrossRefPubMedCentralGoogle Scholar
  68. 68.
    Chudwin DS, Korenblit AD, Kingzette M, Artrip S, Rao S. Increased activation of the alternative complement pathway in sickle cell disease. Clin Immunol Immunopathol. 1985;37(1):93–7.CrossRefPubMedGoogle Scholar
  69. 69.
    Gavriilaki E, Mainou M, Christodoulou I, Koravou EE, Paleta A, Touloumenidou T, et al. In vitro evidence of complement activation in patients with sickle cell disease. Haematologica. 2017;102:e481–e2.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Johnston RB Jr. Increased susceptibility to infection in sickle cell disease: review of its occurrence and possible causes. South Med J. 1974;67(11):1342–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Mold C, Tamerius JD, Phillips G Jr. Complement activation during painful crisis in sickle cell anemia. Clin Immunol Immunopathol. 1995;76(3 Pt 1):314–20.CrossRefPubMedGoogle Scholar
  72. 72.
    Barrett-Connor E. Bacterial infection and sickle cell anemia. An analysis of 250 infections in 166 patients and a review of the literature. Medicine. 1971;50(2):97–112.CrossRefPubMedGoogle Scholar
  73. 73.
    Frimat M, Tabarin F, Dimitrov JD, Poitou C, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood. 2013;122(2):282–92.CrossRefPubMedGoogle Scholar
  74. 74.
    Chonat S, Chandrakasan S, Kalinyak KA, Ingala D, Gruppo R, Kalfa TA. Atypical haemolytic uraemic syndrome in a patient with sickle cell disease, successfully treated with eculizumab. Br J Haematol. 2016;175(4):744–7.CrossRefPubMedGoogle Scholar
  75. 75.
    Chen M, Zhuang J, Yang J, Wang D, Yang Q. Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia: a case report and literature review. Medicine. 2017;96(43):e8284.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Adrovic A, Canpolat N, Caliskan S, Sever L, Kiykim E, Agbas A, et al. Cobalamin C defect-hemolytic uremic syndrome caused by new mutation in MMACHC. Pediatr Int. 2016;58(8):763–5.CrossRefPubMedGoogle Scholar
  77. 77.
    Barlas UK, Kihtir HS, Goknar N, Ersoy M, Akcay N, Sevketoglu E. Hemolytic uremic syndrome with dual caution in an infant: cobalamin C defect and complement dysregulation successfully treated with eculizumab. Pediatr Nephrol. 2018;33(6):1093–6.CrossRefPubMedGoogle Scholar
  78. 78.
    Ardissino G, Perrone M, Tel F, Testa S, Morrone A, Possenti I, et al. Late onset cobalamin disorder and hemolytic uremic syndrome: a rare cause of nephrotic syndrome. Case Rep Pediatr. 2017;2017:2794060.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Navarro D, Azevedo A, Sequeira S, Ferreira AC, Carvalho F, Fidalgo T, et al. Atypical adult-onset methylmalonic acidemia and homocystinuria presenting as hemolytic uremic syndrome. CEN Case Rep. 2018;7(1):73–6.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Zhu Z, Chen H, Gill R, Wang J, Spitalewitz S, Gotlieb V. Diabetic ketoacidosis presenting with atypical hemolytic uremic syndrome associated with a variant of complement factor B in an adult: a case report. J Med Case Rep. 2016;10:38.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Williams CR, Gooch JL. Calcineurin inhibitors and immunosuppression - a tale of two isoforms. Expert Rev Mol Med. 2012;14:e14.CrossRefPubMedGoogle Scholar
  82. 82.
    Trimarchi HM, Truong LD, Brennan S, Gonzalez JM, Suki WN. FK506-associated thrombotic microangiopathy: report of two cases and review of the literature. Transplantation. 1999;67(4):539–44.CrossRefPubMedGoogle Scholar
  83. 83.
    Merola J, Yoo PS, Schaub J, Smith JD, Rodriguez-Davalos MI, Tichy E, et al. Belatacept and eculizumab for treatment of calcineurin inhibitor-induced thrombotic microangiopathy after kidney transplantation: case report. Transplant Proc. 2016;48(9):3106–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Renner B, Klawitter J, Goldberg R, McCullough JW, Ferreira VP, Cooper JE, et al. Cyclosporine induces endothelial cell release of complement-activating microparticles. J Am Soc Nephrol. 2013;24(11):1849–62.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Ikeda T, Okumi M, Unagami K, Kanzawa T, Sawada A, Kawanishi K, et al. Two cases of kidney transplantation-associated thrombotic microangiopathy successfully treated with eculizumab. Nephrology (Carlton). 2016;21(Suppl 1):35–40.CrossRefPubMedGoogle Scholar
  86. 86.
    Shochet L, Kanellis J, Simpson I, Ta J, Mulley W. De novo thrombotic microangiopathy following simultaneous pancreas and kidney transplantation managed with eculizumab. Nephrology (Carlton). 2017;22(Suppl 1):23–7.CrossRefPubMedGoogle Scholar
  87. 87.
    Gray JM, Ameduri RK. Tacrolimus-associated hemolytic uremic syndrome in a pediatric heart transplant recipient. Pediatr Transplant. 2016;20(6):866–7.CrossRefPubMedGoogle Scholar
  88. 88.
    Vardas PN, Hashmi ZA, Hadi MA. Identification and management of atypical hemolytic uremic syndrome immediately post-heart transplantation. J Card Surg. 2015;30(4):373–5.CrossRefPubMedGoogle Scholar
  89. 89.
    Le Quintrec M, Lionet A, Kamar N, Karras A, Barbier S, Buchler M, et al. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant. 2008;8(8):1694–701.CrossRefPubMedGoogle Scholar
  90. 90.
    Garg N, Rennke HG, Pavlakis M, Zandi-Nejad K. De novo thrombotic microangiopathy after kidney transplantation. Transplant Rev (Orlando). 2018;32(1):58–68.CrossRefGoogle Scholar
  91. 91.
    Jodele S, Licht C, Goebel J, Dixon BP, Zhang K, Sivakumaran TA, et al. Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood. 2013;122(12):2003–7.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Jodele S, Fukuda T, Vinks A, Mizuno K, Laskin BL, Goebel J, et al. Eculizumab therapy in children with severe hematopoietic stem cell transplantation–associated thrombotic microangiopathy. Biol Blood Marrow Transplant. 2014;20(4):518–25.CrossRefPubMedGoogle Scholar
  93. 93.
    Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, et al. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016;127(8):989–96.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Hasegawa D, Saito A, Nino N, Uemura S, Takafuji S, Yokoi T, et al. Successful treatment of transplantation-associated atypical hemolytic uremic syndrome with eculizumab. J Pediatr Hematol Oncol. 2018;40(1):e41–e4.PubMedGoogle Scholar
  95. 95.
    Dashe JS, Ramin SM, Cunningham FG. The long-term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy. Obstet Gynecol. 1998;91(5 Pt 1):662–8.PubMedGoogle Scholar
  96. 96.
    Bruel A, Kavanagh D, Noris M, Delmas Y, Wong EKS, Bresin E, et al. Hemolytic uremic syndrome in pregnancy and postpartum. Clin J Am Soc Nephrol. 2017;12(8):1237–47.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Saad AF, Roman J, Wyble A, Pacheco LD. Pregnancy-associated atypical hemolytic-uremic syndrome. AJP Rep. 2016;6(1):e125–8.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S, Couzi L, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21(5):859–67.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Huerta A, Arjona E, Portoles J, Lopez-Sanchez P, Rabasco C, Espinosa M, et al. A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome. Kidney Int. 2018;93(2):450–9.CrossRefPubMedGoogle Scholar
  100. 100.
    Chua J, Paizis K, He SZ, Mount P. Suspected atypical haemolytic uraemic syndrome in two post-partum patients with foetal-death in utero responding to eculizumab. Nephrology (Carlton). 2017;22(Suppl 1):18–22.CrossRefGoogle Scholar
  101. 101.
    Gately R, San A, Kurtkoti J, Parnham A. Life-threatening pregnancy-associated atypical haemolytic uraemic syndrome and its response to eculizumab. Nephrology (Carlton). 2017;22(Suppl 1):32–5.CrossRefGoogle Scholar
  102. 102.
    Baghli S, Abendroth C, Farooq U, Schaub JA. Atypical presentation of pregnancy-related hemolytic uremic syndrome. Am J Kidney Dis. 2018;72:451–6.CrossRefPubMedGoogle Scholar
  103. 103.
    Saad AF, Roman J, Wyble A, Pacheco LD.Google Scholar
  104. 104.
    Andries G, Karass M, Yandrapalli S, Linder K, Liu D, Nelson J, et al. Atypical hemolytic uremic syndrome in first trimester pregnancy successfully treated with eculizumab. Exp Hematol Oncol. 2017;6:4.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Timmermans S, Abdul-Hamid MA, Vanderlocht J, Damoiseaux J, Reutelingsperger CP, van Paassen P. Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities. Kidney Int. 2017;91(6):1420–5.CrossRefPubMedGoogle Scholar
  106. 106.
    Nzerue C, Oluwole K, Adejorin D, Paueksakon P, Fremont R, Akatue R, et al. Malignant hypertension with thrombotic microangiopathy and persistent acute kidney injury (AKI). Clin Kidney J. 2014;7(6):586–9.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Zhang B, Xing C, Yu X, Sun B, Zhao X, Qian J. Renal thrombotic microangiopathies induced by severe hypertension. Hypertens Res. 2008;31(3):479–83.CrossRefPubMedGoogle Scholar
  108. 108.
    Thind G, Kailasam K. Malignant hypertension as a rare cause of thrombotic microangiopathy. BMJ Case Rep. 2017.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Erin Jacobs
    • 1
  • Carolina Ortiz
    • 1
  • Christoph Licht
    • 1
    • 2
    • 3
    Email author
  1. 1.Cell Biology Program, Research InstituteThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Department of PediatricsUniversity of TorontoTorontoCanada
  3. 3.Division of NephrologyThe Hospital for Sick ChildrenTorontoCanada

Personalised recommendations