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Hemolytic Uremic Syndrome

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Abstract

Purpose of review

The emergence of specific treatment of atypical hemolytic uremic syndrome (aHUS) using eculizumab has allowed renal function recovery and safe kidney transplantation (KT). Early and precise recognition of complement-mediated (CM) atypical HUS (aHUS) is challenging and differs between children and adults. Our aim is to facilitate a decision-making process on HUS management.

Recent findings

Hemolytic uremic syndrome (HUS) represents a heterogeneous group of diseases characterized by systemic endothelial cell injury, most often involving kidney, and which leads to thrombotic microangiopathy (TMA). Many inherited factors and environmental triggers cause HUS, but in children and the young, 90% are related to Shiga toxin-producing-Escherichia coli (STEC). Most non-STEC-HUS present primary complement (C) dysregulation and defective protection against C injury at the endothelial surface. Before eculizumab, CM-aHUS mortality was 60%, and progression to end stage kidney disease the rule, with frequent relapses after KT. Worldwide, the most common questions are who could benefit the most from C blockade, the most appropriate monitoring strategy for these individuals, and optimal duration of treatment with eculizumab.

Summary

HUS is a life-threatening disease with poor outcome if untreated. Early and clear distinction between aHUS from other primary TMA (thrombotic thrombocytopenic-purpura, STEC-HUS), rare non-CM-aHUS, and secondary TMA is required as clinical features overlap. The current approach is terminology consensus, classification based on disease pathogenic mechanisms, and patient risk stratification.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Loirat C, Saland J, Bitzan M. Management of hemolytic uremic syndrome. Presse Med. 2012;41(3 Pt 2):e115–35. https://doi.org/10.1016/j.lpm.2011.11.013.

    Article  PubMed  Google Scholar 

  2. •• Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet. 2017;390(10095):681–96. https://doi.org/10.1016/S0140-6736(17)30062-4. Recent and very detailed, high-quality review of HUS focused on differential diagnosis and treatment management in different subgroups of patients.

  3. Gasser C, Gauthier E, Steck A. Hemolytisch uremische syndrome. Med Wochenschr. 1955;85:905–9.

    CAS  Google Scholar 

  4. Gianantonio C, Vitaco M, Mendilaharzu F, Gallo G, Sojo E. Hemolytic uremic syndrome. J Pediatr. 1964;64:478–91.

    Article  CAS  Google Scholar 

  5. Karmali M, Steele B, Petric M, Lim C. Sporadic cases of HUS associated with fecal cytotoxin producing E. Coli in stools. Lancet. 1983;1:619–20.

    Article  CAS  Google Scholar 

  6. Berns JS, Kaplan BS, Mackow RC, Hefter LG. Inherited hemolytic uremic syndrome in adults. Am J Kidney Dis. 1992;19:331–4.

    Article  CAS  Google Scholar 

  7. Warwicker P, Goodship THJ, Goodship JA. 3 Novel polymorphisms in the human complement factor H gene and promoter region. Immunogenetics. 1997;46:437–8.

    Article  CAS  Google Scholar 

  8. Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int. 1998;53(4):836–44.

    Article  CAS  Google Scholar 

  9. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. https://doi.org/10.1186/1750-1172-6-60.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Trachtman H, Austin C, Lewinski M, Stahl RA. Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol. 2012;8(11):658–69. https://doi.org/10.1038/nrneph.2012.196.

    Article  CAS  PubMed  Google Scholar 

  11. Johnson S, Stojanovic J, Ariceta G, Bitzan M, Besbas N, Frieling M, 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(10):1967–78. https://doi.org/10.1007/s00467-014-2817-4.

    Article  PubMed  Google Scholar 

  12. •• 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(1):15–39. https://doi.org/10.1007/s00467-015-3076-8. International expert consensus for diagnosis and management of aHUS in pediatric patients.

  13. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et al. Guideline for the investigation and initial therapy of diarrhea negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24:687–96.

    Article  Google Scholar 

  14. 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. CJASN. 2013;8(4):554–62.

    Article  CAS  Google Scholar 

  15. •• Schaefer F, Ardissino G, Ariceta G, et al. Global aHUS Registry. Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome. Kidney Int. 2018;94(2):408–18 Real-world data regarding diagnosis and treatment of aHUS patients with eculizumab collected at the largest disease global disease registry.

    Article  Google Scholar 

  16. Striker G, Striker LJ, D’Agati V. Hemolytic uremic syndrome and thrombotic thrombocytic purpura. In: Striker G, Striker LJ, D’Agati V, editors. The renal biopsy. Major problems in pathology. 3rd ed. Philadelphia: WB Saunders Company; 1997.

    Google Scholar 

  17. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365:1073–86. https://doi.org/10.1016/S0140-6736(05)71144-2.

    Article  CAS  PubMed  Google Scholar 

  18. Noris M, Remuzzi G. Atypical hemolytic uremic syndrome. N Engl J Med. 2009;361:1676–87. https://doi.org/10.1056/NEJMra0902814.

    Article  CAS  PubMed  Google Scholar 

  19. •• Scully M, Cataland S, Coppo P, de la Rubia J, Friedman KD, Kremer Hovinga J, et al. International Working Group for Thrombotic Thrombocytopenic Purpura. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost. 2017;15(2):312–22. https://doi.org/10.1111/jth.13571. Nice review of current terminology and need for standardization of TMA subgroups.

    Article  CAS  PubMed  Google Scholar 

  20. 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. CJASN. 2010;5(10):1844–59.

    Article  CAS  Google Scholar 

  21. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey, Macher MA, Niaudet P, Guest G, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392–00.

    Article  CAS  Google Scholar 

  22. •• Campistol JM, Arias M, Ariceta G, Blasco M, Espinosa L, Espinosa M, et al. An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia. 2015;35(5):421–47. https://doi.org/10.1016/j.nefro.2015.07.005. Expert consensus for diagnosis and management of aHUS in adult patients.

    Article  PubMed  Google Scholar 

  23. • 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;368:2169–81 Main publication with the pivotal clinical trial leading to eculizumab approval as specific treatment for aHUS in adult patients.

    Article  CAS  Google Scholar 

  24. Fakhouri F, Hourmant M, Campistol JM, 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;2016:84–93.

    Article  Google Scholar 

  25. •• Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89:701–11 Main publication with the pivotal clinical trial leading to eculizumab approval as specific treatment for aHUS in pediatric patients.

    Article  CAS  Google Scholar 

  26. • Licht C, Greenbaum LA, 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;87:1061–73 Main publication with the results of studies extension of pivotal clinical trial leading to eculizumab approval as specific treatment for aHUS in adult and pediatric patients.

    Article  CAS  Google Scholar 

  27. Fakhouri F, Loirat C. Anticomplement treatment in atypical and typical hemolytic uremic syndrome. Semin Hematol. 2018;55(3):150–8. https://doi.org/10.1053/j.seminhematol.2018.04.009.

    Article  PubMed  Google Scholar 

  28. Zuber J, Le Quintrec M, Krid S, et al. French study group for atypical HUS. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012;12(12):3337–54.

    Article  CAS  Google Scholar 

  29. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1585–94. https://doi.org/10.1056/NEJM199811263392203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33:508–30.

    Article  CAS  Google Scholar 

  31. Nester CM, Barbour T, de Cordoba SR, et al. Atypical aHUS: state of the art. Mol Immunol. 2015;67(1):31–42.

    Article  CAS  Google Scholar 

  32. •• Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Frémeaux-Bacchi V, Kavanagh D, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539–51. https://doi.org/10.1016/j.kint.2016.10.005. Recent International expert consensus document for diagnosis and management of aHUS and other renal diseases driven by complement abnormalities.

    Article  CAS  PubMed  Google Scholar 

  33. Ariceta G. Optimal duration of treatment with eculizumab in atypical hemolytic uremic syndrome (aHUS)-a question to be addressed in a scientific way. Pediatr Nephrol. 2019;34(5):943–9. https://doi.org/10.1007/s00467-019-4192-7.

    Article  PubMed  Google Scholar 

  34. Volokhina E, Wijnsma K, van der Molen R, et al. Eculizumab dosing regimen in atypical HUS: possibilities for individualized treatment. Clin Pharmacol Ther. 2017;102:671–8.

    Article  CAS  Google Scholar 

  35. Ardissino G, Testa S, Possenti I, et al. Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 case.s. Am J Kidney Dis. 2014;64(4):633–7.

    Article  CAS  Google Scholar 

  36. Ardissino G, Tel F, Sgarbanti M, et al. Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome: an update. Pediatr Nephrol. 2018;33(3):457–61.

    Article  Google Scholar 

  37. Mele C, Remuzzi G, Noris M. Hemolytic uremic syndrome. Semin Immunopathol. 2014;36(4):399–420.

    Article  CAS  Google Scholar 

  38. Macia M, de Alvaro Moreno F, Dutt T, et al. Current evidence on the discontinuation of eculizumab in patients with atypical haemolytic uraemic syndrome. Clin Kidney J. 2017;10(3):310–9. https://doi.org/10.1093/ckj/sfw115.

    Article  CAS  PubMed  Google Scholar 

  39. Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360:544–6.

    Article  CAS  Google Scholar 

  40. Cavero T, Rabasco C, López A, et al. Eculizumab in secondary atypical haemolytic uraemic syndrome. Nephrol Dial Transplant. 2017;32(3):466–74. https://doi.org/10.1093/ndt/gfw453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Roumenina LT, Jablonski M, Hue C, et al. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood. 2009;114(13):2837–45.

    Article  CAS  Google Scholar 

  42. • Noris M, Galbusera M, Gastoldi S, et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood. 2014;124(11):1715–26 This article explains the current challenges in aHUS disease activity and patient monitoring.

    Article  CAS  Google Scholar 

  43. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339:1578–84.

    Article  CAS  Google Scholar 

  44. Loirat C, Garnier A, Sellier-Leclerc AL, Kwon T. Plasmatherapy in atypical hemolytic uremic syndrome. Semin Thromb Hemost. 2010;36:673–81.

    Article  Google Scholar 

  45. • Olson LE, Sulpizio E, Shatzel JJ, Rueda JF, De Loughery TG. When to stop eculizumab in complement-mediated thrombotic microangiopathies. Am J Nephrol. 2018;48(2):96–107. https://doi.org/10.1159/000492033. Recent review of current status of eculizumab treatment duration and monitoring.

  46. Food US, Administration D. Soliris (eculizumab) [prescribing information]. Cheshire: Alexion Pharmaceuticals, Inc.; 2015.

    Google Scholar 

  47. Rondeau E, Scully M, Ariceta G, et al. The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naive to complement inhibitor treatment. Kidney Int. 2020;97(6):1287–96. https://doi.org/10.1016/j.kint.2020.01.035.

  48. European Medicines Agency. Soliris (eculizumab): EU summary of product characteristics http://www.emea.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000791/WC500054208.pdf. Accessed 31 Oct 2020.

  49. Menne J, Delmas Y, Fakhouri F, et al. Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study. Clin Kidney J. 2018:1–10.

  50. Fakhouri F, Fila M, Provôt F, et al. Pathogenic variants in complement genes and risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Clin J Am Soc Nephrol. 2017;12(1):50–9. https://doi.org/10.2215/CJN.06440616.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Pediatric Nephrology, Hospital Universitari Vall d’Hebron, Universitat Autonoma Barcelona, Hospital Infantil 2ª planta, 119-129, 08035, Barcelona, Spain

    Gema Ariceta MD, PhD

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Dr. Ariceta reports lecture and travelling support from Alexion, Chiesi, Recordati Rare Diseases, and Kyowa Kirim. She also reports advisory activity for Alexion, Chiesi, Recordati Rare Diseases, Kyowa Kirim, Advicenne, Dicerna and Alnylam. She is also a Scientific Advisory Board member of the global Registry of HUS (supported by Alexion).

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Ariceta, G. Hemolytic Uremic Syndrome. Curr Treat Options Peds 6, 252–262 (2020). https://doi.org/10.1007/s40746-020-00216-1

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